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Zhang F, Du H, Liu K, Guo Q, Liang M, Shi J, Feng S, He T, Lu XA, Tang Y, Wang L, Li Q, Meng X, Liu SH, Ding Y, Kong Y. MUC18-Directed chimeric antigen receptor T cells for the treatment of mucosal melanoma. J Transl Med 2025; 23:473. [PMID: 40275251 PMCID: PMC12020318 DOI: 10.1186/s12967-025-06365-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Accepted: 03/08/2025] [Indexed: 04/26/2025] Open
Abstract
PURPOSE Mucosal melanoma, a highly aggressive form of skin cancer, remains challenging to manage due to the lack of effective therapies. Mucin 18 (MUC18) is overexpressed in both primary and metastatic lesions of melanoma but rarely in normal tissues. The expression profile makes MUC18 a potential target for development of therapeutic antibodies or chimeric antigen receptor-T (CAR-T) cell therapy. This study aims to generate an effective CAR-T targeting MUC18-positive melanoma and evaluate its preclinical antitumor activity. EXPERIMENTAL DESIGN A humanized anti-MUC18 single chain antibody fragment (scFv) was used to construct CAR-T with various designs of the hinge, transmembrane, co-stimulatory, and CD3ζ domains. The antitumor efficacy of MUC18 CAR-T cells was assessed in vitro, in MUC18-positive primary and rechallenged xenograft models, as well as in patient-derived xenograft (PDX) models of human mucosal melanoma. RESULTS The humanized scFv selectively bound to MUC18 with high affinity. Various MUC18 CAR-T cells specifically killed MUC18-positive melanoma cells and could proliferate as a result of exposure to antigen. Among them, CAR-T cells containing an IgG4-derived hinge domain and a CD28 co-stimulatory domain demonstrated superior antitumor efficiency. Robust tumor regression and CAR-T cell expansion were observed in multiple MUC18-positive xenograft models after treatment with the IgG4 hinge and CD28 empowered CAR-T cells. CONCLUSIONS This study demonstrated the development of a novel CAR-T therapy for mucosal melanoma, MUC18 CAR-T, that showed strong potency in tumor eradication and inhibition of tumor relapse. This candidate CAR-T therapy could provide a promising strategy for the treatment of the refractory melanoma.
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Affiliation(s)
- Fenghao Zhang
- Department of Renal Cancer and Melanoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Haizhen Du
- Department of Renal Cancer and Melanoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Kaiping Liu
- Department of Renal Cancer and Melanoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Qian Guo
- Department of Renal Cancer and Melanoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | | | - Jing Shi
- Multitude Therapeutics, Shanghai, China
| | - Shi Feng
- Beijing Imunopharm Technology Co., Ltd, Beijing, China
| | - Ting He
- Beijing Imunopharm Technology Co., Ltd, Beijing, China
| | - Xin-An Lu
- Beijing Imunopharm Technology Co., Ltd, Beijing, China
| | | | - Lihua Wang
- Beijing Imunopharm Technology Co., Ltd, Beijing, China
| | - Qiaozhen Li
- Beijing Imunopharm Technology Co., Ltd, Beijing, China
| | - Xun Meng
- Multitude Therapeutics, Shanghai, China
| | | | - Yanping Ding
- Beijing Imunopharm Technology Co., Ltd, Beijing, China.
| | - Yan Kong
- Department of Renal Cancer and Melanoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
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Xue C, Chu Q, Shi Q, Zeng Y, Lu J, Li L. Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances. Signal Transduct Target Ther 2025; 10:106. [PMID: 40180907 PMCID: PMC11968978 DOI: 10.1038/s41392-025-02142-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 11/13/2024] [Accepted: 12/29/2024] [Indexed: 04/05/2025] Open
Abstract
The Wnt signaling pathway is critically involved in orchestrating cellular functions such as proliferation, migration, survival, and cell fate determination during development. Given its pivotal role in cellular communication, aberrant Wnt signaling has been extensively linked to the pathogenesis of various diseases. This review offers an in-depth analysis of the Wnt pathway, detailing its signal transduction mechanisms and principal components. Furthermore, the complex network of interactions between Wnt cascades and other key signaling pathways, such as Notch, Hedgehog, TGF-β, FGF, and NF-κB, is explored. Genetic mutations affecting the Wnt pathway play a pivotal role in disease progression, with particular emphasis on Wnt signaling's involvement in cancer stem cell biology and the tumor microenvironment. Additionally, this review underscores the diverse mechanisms through which Wnt signaling contributes to diseases such as cardiovascular conditions, neurodegenerative disorders, metabolic syndromes, autoimmune diseases, and cancer. Finally, a comprehensive overview of the therapeutic progress targeting Wnt signaling was given, and the latest progress in disease treatment targeting key components of the Wnt signaling pathway was summarized in detail, including Wnt ligands/receptors, β-catenin destruction complexes, and β-catenin/TCF transcription complexes. The development of small molecule inhibitors, monoclonal antibodies, and combination therapy strategies was emphasized, while the current potential therapeutic challenges were summarized. This aims to enhance the current understanding of this key pathway.
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Affiliation(s)
- Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yifan Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Braun AD, Mengoni M, Tüting T, Gaffal E. MCAM Expression Facilitates Melanoma-Endothelial Interactions and Promotes Metastatic Disease Progression. Exp Dermatol 2025; 34:e70059. [PMID: 39945026 PMCID: PMC11822558 DOI: 10.1111/exd.70059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 01/16/2025] [Accepted: 01/26/2025] [Indexed: 02/16/2025]
Abstract
Invasive growth and metastatic dissemination represent the primary cause of death in cancer patients. In order to successfully detach from the primary tumour and establish metastases in distant tissues, cancer cells need to dynamically rewire their cell adhesion machinery. Here we revisit the potential association of MCAM, a member of the immunoglobulin superfamily that was initially identified as a melanoma antigen, with disease progression. Using immunohistochemical stainings and bioinformatic analyses of published datasets, we find abundant MCAM expression both in primary and metastatic human melanomas. In additional bioinformatic analyses, we show that MCAM is highly expressed in foetal melanocytes and subsequently downregulated during melanocyte maturation. Bioinformatic inference of cellular communication networks reveals that melanoma cells with high MCAM expression more actively engage in signalling crosstalk with endothelial cells. Experimental investigations demonstrate that disruption of MCAM in melanoma cells inhibits their migration on endothelial cell surfaces in vitro and decreases their ability to develop spontaneous lung metastases in vivo. Taken together, our results could not confirm the notion that MCAM expression represents a useful biomarker for disease progression but provide evidence that MCAM expression might represent part of a reactivated embryonal transcriptional program that facilitates melanoma-endothelial cell interactions during metastatic progression.
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Affiliation(s)
- Andreas Dominik Braun
- Laboratory for Experimental Dermatology, Department of DermatologyUniversity Hospital MagdeburgMagdeburgGermany
| | - Miriam Mengoni
- Laboratory for Experimental Dermatology, Department of DermatologyUniversity Hospital MagdeburgMagdeburgGermany
| | - Thomas Tüting
- Laboratory for Experimental Dermatology, Department of DermatologyUniversity Hospital MagdeburgMagdeburgGermany
| | - Evelyn Gaffal
- Laboratory for Experimental Dermatology, Department of DermatologyUniversity Hospital MagdeburgMagdeburgGermany
- Department of Dermatology, Allergy, and VenereologyUniversity of LübeckLübeckGermany
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Hilage P, Damle MN, Sharma RK, Joshi MG. Melanoma Cell Adhesion Molecule (CD 146) in Endometrial Physiology and Disorder. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1474:131-148. [PMID: 39400880 DOI: 10.1007/5584_2024_826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
The human endometrium, the innermost lining of the uterus, is the anatomic prerequisite for pregnancy. It is the only dynamic tissue that undergoes more than 400 cycles of regeneration throughout the reproductive life of women. Key to this function are endometrial stem cells as well as cell adhesion molecules. Melanoma cell adhesion molecule (MCAM/CD146/MUC18) is a membrane glycoprotein of the mucin family and a key cell adhesion protein, highly expressed by endometrial cells. CD146 is a significant molecule pivotal in endometrial physiology, assisting tissue regeneration and angiogenesis. Endometrium also acts as a culprit in causing several endometrial dysfunctions, such as endometriosis, endometrial hyperplasia, and endometrial carcinoma, due to interrupted molecular and functional mechanisms. Though most of the endometrial dysfunctions arise as a result of endocrine disturbance, it has a major pathological role associated with angiogenesis. It has already been proven that CD146 is a potential marker for the diagnosis of angiogenic dysfunctions and malignancy, including endometrial cancer. However, its mechanistic role in causing the pathology is a mystery. This chapter explores the role of CD146 in normal and pathological endometrial conditions and the therapeutic implications of CD146.
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Affiliation(s)
- Priyanka Hilage
- Department of Stem Cells & Regenerative Medicine, D.Y. Patil Education Society (Deemed to be University), Kolhapur, Maharashtra, India
| | - Mrunal N Damle
- Department of Stem Cells & Regenerative Medicine, D.Y. Patil Education Society (Deemed to be University), Kolhapur, Maharashtra, India
| | - Rakesh Kumar Sharma
- Department of Obstetrics and Gynecology, D.Y. Patil Medical College, Kolhapur, Maharashtra, India.
| | - Meghnad G Joshi
- Department of Stem Cells & Regenerative Medicine, D.Y. Patil Education Society (Deemed to be University), Kolhapur, Maharashtra, India
- Stem Plus Biotech Pvt. Ltd, Sangli, Maharashtra, India
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Chen JM, He J, Qiu JM, Yang GG, Wang D, Shen Z. Netrin-1-CD146 and netrin-1-S100A9 are associated with early stage of lymph node metastasis in colorectal cancer. BMC Gastroenterol 2024; 24:308. [PMID: 39261771 PMCID: PMC11389491 DOI: 10.1186/s12876-024-03401-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 09/03/2024] [Indexed: 09/13/2024] Open
Abstract
BACKGROUND The netrin-1/CD146 pathway regulates colorectal cancer (CRC) liver metastasis, angiogenesis, and vascular development. However, few investigations have yet examined the biological function of netrin-1/CD146 complex in CRC. In this work, we investigated the relationship between the netrin-1/CD146 axis and S100 proteins in sentinel lymph node, and revealed a possible new clue for vascular metastasis of CRC. METHODS The expression levels of netrin-1 and CD146 proteins in CRC, as well as S100A8 and S100A9 proteins in the sentinel lymph nodes were determined by immunohistochemistry. Using GEPIA and UALCAN, we analyzed netrin-1 and CD146 gene expression in CRC, their association with CRC stage, and their expression levels and prognosis in CRC patients. RESULTS The expression level of netrin-1 in N1a+1b (CRC lymphatic metastasis groups, exculded N1c) was positively increased with N0 (p = 0.012). The level of netrin-1 protein was positively correlated with CD146 protein (p < 0.05). The level of S100A9 protein was positively correlated with CD146 protein (r = 0.492, p = 0.007). Moreover, netrin-1 expression was obviously correlated with S100A9 expression in the N1 stage (r = 0.867, p = 0.000). CD146 level was correlated with S100A9 level in the N2 stage (r = 0.731, p = 0.039). CD146 mRNA expression was higher in normal colorectal tissues than in CRC (p < 0.05). Netrin-1 and CD146 expression were not significantly associated with the tumor stages and prognosis of patients with CRC (p > 0.05). CONCLUSIONS The netrin-1/CD146 and netrin-1/S100A9 axis in CRC tissues might related with early stage of lymph node metastasis, thus providing potential novel channels for blocking lymphatic metastasis and guiding biomarker discovery in CRC patients.
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Affiliation(s)
- Jin-Ming Chen
- Department of Anorectal Surgery, the Third People's Hospital of Hangzhou, 38 West Lake Avenue, 310009, Hangzhou, People's Republic of China.
| | - Jun He
- Department of Anorectal Surgery, the Third People's Hospital of Hangzhou, 38 West Lake Avenue, 310009, Hangzhou, People's Republic of China
| | - Jian-Ming Qiu
- Department of Anorectal Surgery, the Third People's Hospital of Hangzhou, 38 West Lake Avenue, 310009, Hangzhou, People's Republic of China
| | - Guan-Gen Yang
- Department of Anorectal Surgery, the Third People's Hospital of Hangzhou, 38 West Lake Avenue, 310009, Hangzhou, People's Republic of China
| | - Dong Wang
- Department of Anorectal Surgery, the Third People's Hospital of Hangzhou, 38 West Lake Avenue, 310009, Hangzhou, People's Republic of China
| | - Zhong Shen
- Department of Anorectal Surgery, the Third People's Hospital of Hangzhou, 38 West Lake Avenue, 310009, Hangzhou, People's Republic of China.
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Laganà A, Totaro M, Bisegna ML, Elia L, Intoppa S, Beldinanzi M, Matarazzo M, di Trani M, Costa A, Maglione R, Mandelli B, Chiaretti S, Martelli M, De Propris MS. CD146 Molecule Expression in B Cells Acute Lymphoblastic Leukemia (B-ALLs): A Flow-Cytometric Marker for an Accurate Diagnostic Workup. Mediterr J Hematol Infect Dis 2024; 16:e2024064. [PMID: 39258185 PMCID: PMC11385270 DOI: 10.4084/mjhid.2024.064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 08/02/2024] [Indexed: 09/12/2024] Open
Abstract
Background B-lineage acute lymphoblastic leukemias (B-ALL) harboring the t(9;22)(q34;q11)/BCR::ABL1 rearrangement represent a category with previously dismal prognosis whose management and outcome dramatically changed thanks to the use of tyrosine kinase inhibitors (TKIs) usage and more recently full chemo-free approaches. The prompt identification of these cases represents an important clinical need. Objectives We sought to identify an optimized cytofluorimetric diagnostic panel to predict the presence of Philadelphia chromosome (Ph) in B-ALL cases by the introduction of CD146 in our multiparametric flow cytometry (MFC) panels. Methods We prospectively evaluated a total of 245 cases of newly diagnosed B-ALLs with a CD146 positivity threshold >10% referred to the Division of Hematology of 'Sapienza' University of Rome. We compared the results of CD146 expression percentage and its mean fluorescence intensity (MFI) between Ph+ ALLs, Ph-like ALLs, and molecularly negative ALLs. Results Seventy-nine of the 245 B-ALL cases (32%) did not present mutations at molecular testing, with 144/245 (59%) resulting in Ph+ ALL and 19/245 (8%) Ph-like ALLs. Comparing the 3 groups, we found that Ph+ B-ALLs were characterized by higher expression percentage of myeloid markers such as CD13, CD33, and CD66c and low expression of CD38; Ph+ B-ALL showed a higher CD146 expression percentage and MFI when compared with both molecular negative B-ALL and Ph-like ALLs; neither the mean percentage of CD146 expression neither CD146 MFI were statically different between molecular negative B-ALL and Ph-like ALLs. Conclusions Our data demonstrate the association between CD146 expression and Ph+ ALLs. CD146, along with myeloid markers, may help to identify a distinctive immunophenotypic pattern, useful for rapid identification in the diagnostic routine of this subtype of B-ALLs that benefits from a specific therapeutic approach.
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Affiliation(s)
- Alessandro Laganà
- Hematology, Department of Translational and Precision Medicine, Sapienza University, 00161 Rome, Italy
| | - Matteo Totaro
- Hematology, Department of Translational and Precision Medicine, Sapienza University, 00161 Rome, Italy
| | - Maria Laura Bisegna
- Hematology, Department of Translational and Precision Medicine, Sapienza University, 00161 Rome, Italy
| | - Loredana Elia
- Hematology, Department of Translational and Precision Medicine, Sapienza University, 00161 Rome, Italy
| | - Stefania Intoppa
- Hematology, Department of Translational and Precision Medicine, Sapienza University, 00161 Rome, Italy
| | - Marco Beldinanzi
- Hematology, Department of Translational and Precision Medicine, Sapienza University, 00161 Rome, Italy
| | - Mabel Matarazzo
- Hematology, Department of Translational and Precision Medicine, Sapienza University, 00161 Rome, Italy
| | - Mariangela di Trani
- Hematology, Department of Translational and Precision Medicine, Sapienza University, 00161 Rome, Italy
| | - Alessandro Costa
- Hematology Unit, Businco Hospital, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Raffaele Maglione
- Hematology, Department of Translational and Precision Medicine, Sapienza University, 00161 Rome, Italy
| | - Biancamaria Mandelli
- Hematology, Department of Translational and Precision Medicine, Sapienza University, 00161 Rome, Italy
| | - Sabina Chiaretti
- Hematology, Department of Translational and Precision Medicine, Sapienza University, 00161 Rome, Italy
| | - Maurizio Martelli
- Hematology, Department of Translational and Precision Medicine, Sapienza University, 00161 Rome, Italy
| | - Maria Stefania De Propris
- Hematology, Department of Translational and Precision Medicine, Sapienza University, 00161 Rome, Italy
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Wu Z, Zang Y, Li C, He Z, Liu J, Du Z, Ma X, Jing L, Duan H, Feng J, Yan X. CD146, a therapeutic target involved in cell plasticity. SCIENCE CHINA. LIFE SCIENCES 2024; 67:1563-1578. [PMID: 38613742 DOI: 10.1007/s11427-023-2521-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 12/28/2023] [Indexed: 04/15/2024]
Abstract
Since its identification as a marker for advanced melanoma in the 1980s, CD146 has been found to have multiple functions in both physiological and pathological processes, including embryonic development, tissue repair and regeneration, tumor progression, fibrosis disease, and inflammations. Subsequent research has revealed that CD146 is involved in various signaling pathways as a receptor or co-receptor in these processes. This correlation between CD146 and multiple diseases has sparked interest in its potential applications in diagnosis, prognosis, and targeted therapy. To better comprehend the versatile roles of CD146, we have summarized its research history and synthesized findings from numerous reports, proposing that cell plasticity serves as the underlying mechanism through which CD146 contributes to development, regeneration, and various diseases. Targeting CD146 would consequently halt cell state shifting during the onset and progression of these related diseases. Therefore, the development of therapy targeting CD146 holds significant practical value.
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Affiliation(s)
- Zhenzhen Wu
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Yuzhe Zang
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chuyi Li
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhiheng He
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jingyu Liu
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhaoqi Du
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xinran Ma
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Lin Jing
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Hongxia Duan
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- Nanozyme Laboratory in Zhongyuan, Henan Academy of Innovations in Medical Science, Zhengzhou, 451163, China.
| | - Jing Feng
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Xiyun Yan
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
- Nanozyme Laboratory in Zhongyuan, Henan Academy of Innovations in Medical Science, Zhengzhou, 451163, China.
- Joint Laboratory of Nanozymes in Zhengzhou University, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
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Wang M, Schedel M, Gelfand EW. Gene editing in allergic diseases: Identification of novel pathways and impact of deleting allergen genes. J Allergy Clin Immunol 2024; 154:51-58. [PMID: 38555980 PMCID: PMC11227406 DOI: 10.1016/j.jaci.2024.03.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 02/14/2024] [Accepted: 03/04/2024] [Indexed: 04/02/2024]
Abstract
Gene editing technology has emerged as a powerful tool in all aspects of health research and continues to advance our understanding of critical and essential elements in disease pathophysiology. The clustered regularly interspaced short palindromic repeats (CRISPR) gene editing technology has been used with precision to generate gene knockouts, alter genes, and identify genes that cause disease. The full spectrum of allergic/atopic diseases, in part because of shared pathophysiology, is ripe for studies with this technology. In this way, novel culprit genes are being identified and allow for manipulation of triggering allergens to reduce allergenicity and disease. Notwithstanding current limitations on precision and potential off-target effects, newer approaches are rapidly being introduced to more fully understand specific gene functions as well as the consequences of genetic manipulation. In this review, we examine the impact of editing technologies of novel genes relevant to peanut allergy and asthma as well as how gene modification of common allergens may lead to the deletion of allergenic proteins.
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Affiliation(s)
- Meiqin Wang
- Department of Pediatrics, Division of Cell Biology, National Jewish Health, Denver, Colo
| | - Michaela Schedel
- Department of Pediatrics, Division of Cell Biology, National Jewish Health, Denver, Colo; Department of Pulmonary Medicine, University Hospital Essen-Ruhrlandklinik, Essen, Germany; Department of Pulmonary Medicine, University Hospital, Essen, Germany
| | - Erwin W Gelfand
- Department of Pediatrics, Division of Cell Biology, National Jewish Health, Denver, Colo.
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Riera-Ferrer E, Del Pozo R, Muñoz-Berruezo U, Palenzuela O, Sitjà-Bobadilla A, Estensoro I, Piazzon MC. Mucosal affairs: glycosylation and expression changes of gill goblet cells and mucins in a fish-polyopisthocotylidan interaction. Front Vet Sci 2024; 11:1347707. [PMID: 38655531 PMCID: PMC11035888 DOI: 10.3389/fvets.2024.1347707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 03/22/2024] [Indexed: 04/26/2024] Open
Abstract
Introduction Secreted mucins are highly O-glycosylated glycoproteins produced by goblet cells in mucosal epithelia. They constitute the protective viscous gel layer overlying the epithelia and are involved in pathogen recognition, adhesion and expulsion. The gill polyopisthocotylidan ectoparasite Sparicotyle chrysophrii, feeds on gilthead seabream (Sparus aurata) blood eliciting severe anemia. Methods Control unexposed and recipient (R) gill samples of gilthead seabream experimentally infected with S. chrysophrii were obtained at six consecutive times (0, 11, 20, 32, 41, and 61 days post-exposure (dpe)). In histological samples, goblet cell numbers and their intensity of lectin labelling was registered. Expression of nine mucin genes (muc2, muc2a, muc2b, muc5a/c, muc4, muc13, muc18, muc19, imuc) and three regulatory factors involved in goblet cell differentiation (hes1, elf3, agr2) was studied by qPCR. In addition, differential expression of glycosyltransferases and glycosidases was analyzed in silico from previously obtained RNAseq datasets of S. chrysophrii-infected gilthead seabream gills with two different infection intensities. Results and Discussion Increased goblet cell differentiation (up-regulated elf3 and agr2) leading to neutral goblet cell hyperplasia on gill lamellae of R fish gills was found from 32 dpe on, when adult parasite stages were first detected. At this time point, acute increased expression of both secreted (muc2a, muc2b, muc5a/c) and membrane-bound mucins (imuc, muc4, muc18) occurred in R gills. Mucins did not acidify during the course of infection, but their glycosylation pattern varied towards more complex glycoconjugates with sialylated, fucosylated and branched structures, according to lectin labelling and the shift of glycosyltransferase expression patterns. Gilthead seabream gill mucosal response against S. chrysophrii involved neutral mucus hypersecretion, which could contribute to worm expulsion and facilitate gas exchange to counterbalance parasite-induced hypoxia. Stress induced by the sparicotylosis condition seems to lead to changes in glycosylation characteristic of more structurally complex mucins.
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Affiliation(s)
| | | | | | | | | | - Itziar Estensoro
- Fish Pathology Group, Instituto de Acuicultura Torre de la Sal, Consejo Superior de Investigaciones Científicas (IATS, CSIC), Castellón, Spain
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Mohamad SF, El Koussa R, Ghosh J, Blosser R, Gunawan A, Layer J, Zhang C, Karnik S, Davé U, Kacena MA, Srour EF. Osteomacs promote maintenance of murine hematopoiesis through megakaryocyte-induced upregulation of Embigin and CD166. Stem Cell Reports 2024; 19:486-500. [PMID: 38458190 PMCID: PMC11096441 DOI: 10.1016/j.stemcr.2024.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 02/06/2024] [Accepted: 02/07/2024] [Indexed: 03/10/2024] Open
Abstract
Maintenance of hematopoietic stem cell (HSC) function in the niche is an orchestrated event. Osteomacs (OM) are key cellular components of the niche. Previously, we documented that osteoblasts, OM, and megakaryocytes interact to promote hematopoiesis. Here, we further characterize OM and identify megakaryocyte-induced mediators that augment the role of OM in the niche. Single-cell mRNA-seq, mass spectrometry, and CyTOF examination of megakaryocyte-stimulated OM suggested that upregulation of CD166 and Embigin on OM augment their hematopoiesis maintenance function. CD166 knockout OM or shRNA-Embigin knockdown OM confirmed that the loss of these molecules significantly reduced the ability of OM to augment the osteoblast-mediated hematopoietic-enhancing activity. Recombinant CD166 and Embigin partially substituted for OM function, characterizing both proteins as critical mediators of OM hematopoietic function. Our data identify Embigin and CD166 as OM-regulated critical components of HSC function in the niche and potential participants in various in vitro manipulations of stem cells.
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Affiliation(s)
- Safa F Mohamad
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Roy El Koussa
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Joydeep Ghosh
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Rachel Blosser
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Andrea Gunawan
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Justin Layer
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chi Zhang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Sonali Karnik
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Utpal Davé
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Melissa A Kacena
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Edward F Srour
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
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11
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Miller SG, Hoh M, Ebmeier CC, Tay JW, Ahn NG. Cooperative polarization of MCAM/CD146 and ERM family proteins in melanoma. Mol Biol Cell 2024; 35:ar31. [PMID: 38117590 PMCID: PMC10916866 DOI: 10.1091/mbc.e23-06-0255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 11/22/2023] [Accepted: 12/15/2023] [Indexed: 12/22/2023] Open
Abstract
The WRAMP structure is a protein network associated with tail-end actomyosin contractility, membrane retraction, and directional persistence during cell migration. A marker of WRAMP structures is melanoma cell adhesion molecule (MCAM) which dynamically polarizes to the cell rear. However, factors that mediate MCAM polarization are still unknown. In this study, BioID using MCAM as bait identifies the ERM family proteins, moesin, ezrin, and radixin, as WRAMP structure components. We also present a novel image analysis pipeline, Protein Polarity by Percentile ("3P"), which classifies protein polarization using machine learning and facilitates quantitative analysis. Using 3P, we find that depletion of moesin, and to a lesser extent ezrin, decreases the proportion of cells with polarized MCAM. Furthermore, although copolarized MCAM and ERM proteins show high spatial overlap, 3P identifies subpopulations with ERM proteins closer to the cell periphery. Live-cell imaging confirms that MCAM and ERM protein polarization is tightly coordinated, but ERM proteins enrich at the cell edge first. Finally, deletion of a juxtamembrane segment in MCAM previously shown to promote ERM protein interactions impedes MCAM polarization. Our findings highlight the requirement for ERM proteins in recruitment of MCAM to WRAMP structures and an advanced computational tool to characterize protein polarization.
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Affiliation(s)
- Suzannah G. Miller
- Department of Biochemistry, University of Colorado Boulder, Boulder CO 80303
| | - Maria Hoh
- Department of Biochemistry, University of Colorado Boulder, Boulder CO 80303
| | | | - Jian Wei Tay
- BioFrontiers Institute, University of Colorado Boulder, Boulder CO 80303
| | - Natalie G. Ahn
- Department of Biochemistry, University of Colorado Boulder, Boulder CO 80303
- BioFrontiers Institute, University of Colorado Boulder, Boulder CO 80303
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12
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Jia X, Jiang J, Yang C, Zhang S, Wu J, Ma Q, Wang Z, Chen Z, Zhang M, Huang M, Ji N. Plasma sCD146 is a potential biomarker for acute exacerbation of chronic obstructive pulmonary disease. Clin Transl Sci 2024; 17:e13754. [PMID: 38476031 PMCID: PMC10933638 DOI: 10.1111/cts.13754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 01/15/2024] [Accepted: 02/13/2024] [Indexed: 03/14/2024] Open
Abstract
This study examined the levels of soluble CD146 (sCD146) in plasma samples from patients with chronic obstructive pulmonary disease (COPD) and assessed the relationship between sCD146 and the severity of COPD. A total of 97 COPD patients were recruited from 20 medical centers in Jiangsu, China, including 13 stable subjects and 84 exacerbated subjects. The plasma sCD146 level in exacerbated subjects (28.77 ± 10.80 ng/mL) was significantly lower than that in stable subjects (38.84 ± 15.00 ng/mL). In the high sCD146 group, the proportion of subjects with modified Medical Research Council (mMRC) scores of 0-1 was higher, the proportion of subjects with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 4 was lower, and the proportion of subjects with ≥1 hospitalizations in the past year was lower. The plasma sCD146 level was negatively correlated with the COPD Assessment Test (CAT) score (r = -0.2664, p = 0.0087). Logistic regression analysis showed that sCD146 was an independent risk factor for acute exacerbation of COPD (AECOPD). Receiver operating characteristic (ROC) analysis suggested that sCD146 combined with sex, age, pulmonary function, and acute exacerbations in the past year had clinical value for the accurate identification of AECOPD, with an area under the ROC curve (AUC) of 0.908 (95% CI: 0.810-1.000, p < 0.001). In addition, there was a significant negative correlation between plasma sCD146 and S100A9 (r = -0.3939, p < 0.001).
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Affiliation(s)
- Xinyu Jia
- Department of Respiratory and Critical Care MedicineThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Jingxian Jiang
- Department of Respiratory and Critical Care MedicineThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Chen Yang
- Department of Immunology, Jiangsu Province Engineering Research Center of Antibody Drug, NHC Key Laboratory of Antibody TechniqueNanjing Medical UniversityNanjingChina
| | - Sujuan Zhang
- Department of Respiratory and Critical Care MedicineThe First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow UniversityChangzhouChina
| | - Jingjing Wu
- Department of Respiratory and Critical Care MedicineThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Qiyun Ma
- Department of Respiratory and Critical Care MedicineThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
- Department of Respiratory and Critical Care MedicineThe Affiliated Huaian No. 1 People's Hospital of Nanjing Medical UniversityHuaianChina
| | - Zhengxia Wang
- Department of Respiratory and Critical Care MedicineThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Zhongqi Chen
- Department of Respiratory and Critical Care MedicineThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Mingshun Zhang
- Department of Immunology, Jiangsu Province Engineering Research Center of Antibody Drug, NHC Key Laboratory of Antibody TechniqueNanjing Medical UniversityNanjingChina
| | - Mao Huang
- Department of Respiratory and Critical Care MedicineThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Ningfei Ji
- Department of Respiratory and Critical Care MedicineThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
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13
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Jiang J, Wang M, Shen W, Wu J, Ma Q, Wang Z, Chen Z, Bian T, Ji N, Huang M, Zhang M. CD146 deficiency aggravates chronic obstructive pulmonary disease via the increased production of S100A9 and MMP-9 in macrophages. Int Immunopharmacol 2024; 127:111410. [PMID: 38109838 DOI: 10.1016/j.intimp.2023.111410] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 12/05/2023] [Accepted: 12/15/2023] [Indexed: 12/20/2023]
Abstract
Chronic obstructive pulmonary disease (COPD) is a leading cause of global death. As a molecule beyond adhesion, CD146 is involved in COPD pathogenesis. However, the mechanisms of CD146 in COPD remain largely elusive. We hypothesized that CD146 regulates the production of matrix metalloproteinase-9 (MMP-9) in macrophages and thereby contributes to COPD. Here, we constructed a murine model of COPD using lipopolysaccharide (LPS) and porcine pancreatic elastase (PPE). In COPD-like mice, LPS and PPE decreased the pulmonary expression of CD146. MMP-9 expression and bioactivity were increased in CD146 knockout COPD-like mice. In vitro, LPS decreased CD146 expression in macrophages. With or without LPS challenge, CD146-defective macrophages produced more MMP-9. Transcriptome analysis based on next-generation sequencing (NGS) revealed that S100A9 regulated MMP-9 production in CD146-defective macrophages. Targeting S100A9 with paquinimod decreased lung inflammation and alleviated alveolar destruction in COPD-like mice. Collectively, our study suggests that CD146 negatively regulates MMP-9 production in macrophages via the S100A9 pathway in COPD.
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Affiliation(s)
- Jingxian Jiang
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Min Wang
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Weiyu Shen
- Departments of Respiratory and Critical Care Medicine, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Jingjing Wu
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qiyun Ma
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Department of Respiratory and Critical Care Medicine, the Affiliated Huaian NO.1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Zhengxia Wang
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhongqi Chen
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tao Bian
- Departments of Respiratory and Critical Care Medicine, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Ningfei Ji
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Mao Huang
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Mingshun Zhang
- Jiangsu Province Engineering Research Center of Antibody Drug, NHC Key Laboratory of Antibody Technique, Department of Immunology, Nanjing Medical University, Nanjing, China.
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14
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Sautreuil C, Lecointre M, Dalmasso J, Lebon A, Leuillier M, Janin F, Lecuyer M, Bekri S, Marret S, Laquerrière A, Brasse-Lagnel C, Gil S, Gonzalez BJ. Expression of placental CD146 is dysregulated by prenatal alcohol exposure and contributes in cortical vasculature development and positioning of vessel-associated oligodendrocytes. Front Cell Neurosci 2024; 17:1294746. [PMID: 38269113 PMCID: PMC10806802 DOI: 10.3389/fncel.2023.1294746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 12/11/2023] [Indexed: 01/26/2024] Open
Abstract
Recent data showed that prenatal alcohol exposure (PAE) impairs the "placenta-brain" axis controlling fetal brain angiogenesis in human and preclinical models. Placental growth factor (PlGF) has been identified as a proangiogenic messenger between these two organs. CD146, a partner of the VEGFR-1/2 signalosome, is involved in placental angiogenesis and exists as a soluble circulating form. The aim of the present study was to investigate whether placental CD146 may contribute to brain vascular defects described in fetal alcohol spectrum disorder. At a physiological level, quantitative reverse transcription polymerase chain reaction experiments performed in human placenta showed that CD146 is expressed in developing villi and that membrane and soluble forms of CD146 are differentially expressed from the first trimester to term. In the mouse placenta, a similar expression pattern of CD146 was found. CD146 immunoreactivity was detected in the labyrinth zone and colocalized with CD31-positive endothelial cells. Significant amounts of soluble CD146 were quantified by ELISA in fetal blood, and the levels decreased after birth. In the fetal brain, the membrane form of CD146 was the majority and colocalized with microvessels. At a pathophysiological level, PAE induced marked dysregulation of CD146 expression. The soluble form of CD146 decreased in both placenta and fetal blood, whereas it increased in the fetal brain. Similarly, the expression of several members of the CD146 signalosome, such as VEGFR2 and PSEN, was differentially impaired between the two organs by PAE. At a functional level, targeted repression of placental CD146 by in utero electroporation (IUE) of CRISPR/Cas9 lentiviral plasmids resulted in (i) a decrease in cortical vessel density, (ii) a loss of radial vascular organization, and (iii) a reduced density of oligodendrocytes. Statistical analysis showed that the more the vasculature was impaired, the more the cortical oligodendrocyte density was reduced. Altogether, these data support that placental CD146 contributes to the proangiogenic "placenta-brain" axis and that placental CD146 dysfunction contributes to the cortical oligo-vascular development. Soluble CD146 would represent a promising placental biomarker candidate representative of alcohol-induced neurovascular defects in neonates, as recently suggested by PlGF (patents WO2016207253 and WO2018100143).
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Affiliation(s)
- Camille Sautreuil
- Rouen Université, Inserm U1245 – Team “Epigenetics and Pathophysiology of Neurodevelopmental Disorders”, Normandie Université, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
| | - Maryline Lecointre
- Rouen Université, Inserm U1245 – Team “Epigenetics and Pathophysiology of Neurodevelopmental Disorders”, Normandie Université, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
| | | | - Alexis Lebon
- Rouen Université, US51 HeRacLeS, PRIMACEN Platform, Faculty of Biological Sciences, Normandie Université, Mont-Saint-Aignan, France
| | | | - François Janin
- Rouen Université, Inserm U1245 – Team “Epigenetics and Pathophysiology of Neurodevelopmental Disorders”, Normandie Université, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
| | - Matthieu Lecuyer
- Rouen Université, Inserm U1245 – Team “Epigenetics and Pathophysiology of Neurodevelopmental Disorders”, Normandie Université, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
| | - Soumeya Bekri
- Rouen Université, Inserm U1245 – Team “Epigenetics and Pathophysiology of Neurodevelopmental Disorders”, Normandie Université, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
- Rouen Université, CHU Rouen, Department of Metabolic Biochemistry, Normandie University, Rouen, France
| | - Stéphane Marret
- Rouen Université, Inserm U1245 – Team “Epigenetics and Pathophysiology of Neurodevelopmental Disorders”, Normandie Université, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
- Rouen Université, CHU Rouen, Department of Neonatal Pediatrics and Intensive Care, Rouen, France
| | - Annie Laquerrière
- Rouen Université, Inserm U1245 – Team “Epigenetics and Pathophysiology of Neurodevelopmental Disorders”, Normandie Université, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
- Rouen Université, CHU Rouen, Department of Pathology, Rouen Normandy Hospital, Rouen, France
| | - Carole Brasse-Lagnel
- Rouen Université, Inserm U1245 – Team “Epigenetics and Pathophysiology of Neurodevelopmental Disorders”, Normandie Université, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
| | - Sophie Gil
- Université de Paris, INSERM, UMR-S 1139, 3PHM, Paris, France
| | - Bruno J. Gonzalez
- Rouen Université, Inserm U1245 – Team “Epigenetics and Pathophysiology of Neurodevelopmental Disorders”, Normandie Université, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
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15
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Sharma A, Somasundaram I, Chabaud MB. CD146 as a prognostic marker in breast cancer: A meta-analysis. J Cancer Res Ther 2024; 20:193-198. [PMID: 38554320 DOI: 10.4103/jcrt.jcrt_738_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 09/15/2022] [Indexed: 04/01/2024]
Abstract
BACKGROUND CD146, a cell adhesion molecule, was first discovered in melanoma. Since then, it has been established as a promoter of tumor progression and metastasis. Many recent clinical studies have associated CD146 overexpression with poor prognosis in various cancers. However, clinical relevance of CD146 in prognosis of breast cancer has been poorly studied. METHODS We performed meta-analysis of data of all clinical studies associated with the prognostic value of CD146 expression in breast cancer. Relevant studies were retrieved from PubMed database as per the inclusion and exclusion criteria, data were extracted independently and carefully by two reviewers with the help of standardized form, and meta-analysis was performed to correlate CD146 expression with molecular subtypes, lymph node metastasis, and overall survival in breast cancer. RESULTS Our findings suggest that CD146 expression is predominantly found in triple-negative breast cancer subtype (pooled odds ratio = 2.98, 95% confidence interval [CI] =2.19-4.05, P < .00001) and breast tumors overexpressing CD146 have a higher risk of lymph node metastasis (pooled relative risk = 1.64, 95% CI = 1.44-1.87, P < .00001). Furthermore, high expression of CD146 was associated with poor prognosis in breast cancer (pooled hazard ratio = 1.51, 95% CI = 1.21-1.87, P = .0002). CONCLUSION Overall results suggested that CD146 may be a potential prognostic marker to predict metastatic potential and disease outcomes in breast cancer and can be used as a therapeutic target.
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Affiliation(s)
- Akshita Sharma
- Department of Stem Cell and Regenerative Medicine, Centre for Inter Disciplinary Research, D. Y. Patil Education Society (Deemed to be University), Kolhapur, Maharashtra, India
| | - Indumathi Somasundaram
- Department of Stem Cell and Regenerative Medicine, Centre for Inter Disciplinary Research, D. Y. Patil Education Society (Deemed to be University), Kolhapur, Maharashtra, India
| | - Marcel Blot Chabaud
- INSERM U1263, Centre for Cardiovascular and Nutrition Research (C2VN), Aix-Marseille University Marseille, France
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16
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Li Q, Wang Y, Gao W, Qian G, Chen X, Liu Y, Yu S. A microfluidic device for enhanced capture and high activity release of heterogeneous CTCs from whole blood. Talanta 2024; 266:125007. [PMID: 37556952 DOI: 10.1016/j.talanta.2023.125007] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/24/2023] [Accepted: 07/28/2023] [Indexed: 08/11/2023]
Abstract
Circulating tumor cells (CTCs) are tumor cells that spontaneously detach from the primary focus, and early detection and characterization of CTCs is vital for cancer diagnosis and appropriate treatment. Current methods commonly use EpCAM to capture CTCs, but this results in a loss of information on other CTC subsets (EpCAM-negative cells) due to the heterogeneity of CTCs. Here, we report a novel microfluidic device that integrates the capture and release of heterogeneous CTCs directly from whole blood. A spiral chip was designed for the separation of differently sized cells, and larger CTCs were effectively separated from smaller blood cells with a 98% recovery rate. CD146-containing magnetic beads were used to complement the EpCAM-based CTC capture methods, and the capture efficiency of Fe3O4@Gelatin@CD146/EpCAM increased by 20% over Fe3O4@Gelatin@EpCAM. Finally, MMP-9 was employed to release CTCs with high efficiency and less damage by degrading gelatins on the surface of Fe3O4. The established method was successfully applied to CTC capture and release in a simulated patient's whole blood. The developed method achieved enhanced capture and high activity release of heterogeneous CTCs with less interference by blood cells, which contributes to the early detection and clinical downstream analysis of CTCs.
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Affiliation(s)
- Qiaoyu Li
- Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China; Institute of Mass Spectrometry, School of Material Science and Chemical Engineering; Ningbo University, Ningbo, Zhejiang, 315211, China; Department of Chemistry, Fudan University, Shanghai 200438, China
| | - Yanlin Wang
- Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China; Institute of Mass Spectrometry, School of Material Science and Chemical Engineering; Ningbo University, Ningbo, Zhejiang, 315211, China; Department of Chemistry, Fudan University, Shanghai 200438, China
| | - Wenjing Gao
- Institute of Mass Spectrometry, School of Material Science and Chemical Engineering; Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Guoqing Qian
- Department of Infectious Diseases, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Xueqin Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, 315211, China.
| | - Yushan Liu
- Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China.
| | - Shaoning Yu
- Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China; Institute of Mass Spectrometry, School of Material Science and Chemical Engineering; Ningbo University, Ningbo, Zhejiang, 315211, China; Department of Chemistry, Fudan University, Shanghai 200438, China.
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17
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Sun Y, Chu JZ, Geng JR, Guan FL, Zhang SC, Ma YC, Zuo QQ, Jing XZ, Du HL. Label-free based quantitative proteomics analysis to explore the molecular mechanism of gynecological cold coagulation and blood stasis syndrome. Anat Rec (Hoboken) 2023; 306:3033-3049. [PMID: 36136292 DOI: 10.1002/ar.25035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 04/26/2022] [Accepted: 04/29/2022] [Indexed: 11/08/2022]
Abstract
Cold coagulation and blood stasis (CCBS) syndrome is one of the common traditional Chinese medicine (TCM) syndromes of gynecological diseases. However, the molecular mechanism of CCBS syndrome is still unclear. Thus, there is a need to reveal the occurrence and regulation mechanism of CCBS syndrome, in order to provide a theoretical basis for the treatment of CCBS syndrome in gynecological diseases. The plasma proteins in primary dysmenorrhea (PD) patients with CCBS syndrome, endometriosis (EMS) patients with CCBS syndrome, and healthy women were screened using Label-free quantitative proteomics. Based on the TCM theory of "same TCM syndrome in different diseases," the differentially expressed proteins (DEPs) identified in each group were subjected to intersection mapping to obtain common DEPs in CCBS syndrome. The DEPs of gynecological CCBS syndrome in the intersection part were again cross-mapped with the DEPs of gynecological CCBS syndrome obtained by the research group according to the TCM theory of "different TCM syndromes in same disease" theory in the early stage, so as to obtain the DEPs of gynecological CCBS syndrome that were shared by the two parts. The common DEPs were subjected to bioinformatics analysis, and were verified by enzyme-linked immunosorbent assay (ELISA). A total of 67 common DEPs were identified in CCBS syndrome, of which 33 DEPs were upregulated and 34 DEPs were downregulated. The functional classification of DEPs involved in metabolic process, energy production and conversion, immune system process, antioxidant activity, response to stimulus, and biological adhesion. The subcellular location mainly located in the cytoplasm, nucleus, and extracellular. Gene ontology (GO) enrichment analysis showed that the upregulated DEPs mainly concentrated in lipid transport, cell migration, and inflammatory reaction, and the downregulated DEPs mostly related to cell junction, metabolism, and energy response. Protein domain enrichment analysis and clustering analysis revealed that the DEPs mainly related to cell proliferation and differentiation, cell morphology, metabolism, and immunity. The Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis clustering analysis showed that the upregulated DEPs were involved in inflammation and oxidative damage, while the downregulated DEPs were involved in inflammation, cell adhesion, cell apoptosis, and metabolism. The results of ELISA showed significantly increased levels of Cell surface glycoprotein MUC18 (MCAM) and Apolipoprotein C1 (APOC1), and significantly decreased levels of Vasodilator-stimulated phosphoprotein (VASP), Fatty acid-binding protein 5 (FABP5), and Vinculin (VCL) in patients with CCBS syndrome compared with healthy women. We speculated that cold evil may affect the immune process, inflammatory response, metabolic process, energy production and conversion, oxidative damage, endothelial cell dysfunction, and other differential proteins expression to cause CCBS syndrome in gynecological diseases.
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Affiliation(s)
- Ying Sun
- College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
- Institute of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Shijiazhuang, China
| | - Jian-Zi Chu
- First Affiliated Hospital of Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Jing-Ran Geng
- College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Feng-Li Guan
- College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Shuan-Cheng Zhang
- College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Yu-Cong Ma
- College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
- Institute of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Shijiazhuang, China
| | - Qian-Qian Zuo
- College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Xiao-Zhao Jing
- College of Acupuncture-Moxibustion and Tuina, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Hui-Lan Du
- College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
- Institute of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Shijiazhuang, China
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18
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Kumar Murmu A, Pal A, Debnath M, Chakraborty A, Pal S, Banerjee S, Pal A, Ghosh N, Karmakar U, Samanta R. Role of mucin 2 gene for growth in Anas platyrhynchos: a novel report. Front Vet Sci 2023; 10:1089451. [PMID: 38026626 PMCID: PMC10666069 DOI: 10.3389/fvets.2023.1089451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 07/17/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction The mucin gene is expressed in the mucous membrane of the inner layer of the internal organs. Intestinalmucin 2 (MUC2), amajor gel-formingmucin, represents a primary barrier component of mucus layers. Materials and methods This is the first report on the role of mucin genes in growth traits in animals. In this study, we randomly studied Bengal ducks (Anas platyrhynchos) reared from day old to 10 weeks of age under an organized farm and studied the growth parameters as well as body weight and average daily body weight gain. Result and discussion We characterized the mucin gene for Bengal ducks and observed glycosylation and EGF1 (EGF-like domain signature) as important domains for growth traits in ducks. We observed a better expression profile for the mucin gene in high-growing ducks in comparison to that of low-growing ducks with real-time PCR. Hence, the mucin gene may be employed as a marker for growth traits.
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Affiliation(s)
- Anuj Kumar Murmu
- Department of Livestock Production and Management, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal, India
| | - Aruna Pal
- Department of Livestock Farm Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal, India
| | - Manti Debnath
- Department of Livestock Farm Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal, India
| | - Argha Chakraborty
- Department of Livestock Farm Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal, India
| | - Subhamoy Pal
- Department of Animal Science, Visva-Bharati University, Santiniketan, West Bengal, India
| | - Samiddha Banerjee
- Department of Livestock Farm Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal, India
| | - Abantika Pal
- Department of Computer Science, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India
- University of California, San Francisco, San Francisco, CA, United States
| | - Nilotpal Ghosh
- Department of Livestock Production and Management, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal, India
| | - Utpal Karmakar
- Department of Animal Resource Development, Government of West Bengal, Kolkata, India
| | - Rajarshi Samanta
- Department of Livestock Production and Management, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal, India
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Haferkamp U, Hartmann C, Abid CL, Brachner A, Höchner A, Gerhartl A, Harwardt B, Leckzik S, Leu J, Metzger M, Nastainczyk-Wulf M, Neuhaus W, Oerter S, Pless O, Rujescu D, Jung M, Appelt-Menzel A. Human isogenic cells of the neurovascular unit exert transcriptomic cell type-specific effects on a blood-brain barrier in vitro model of late-onset Alzheimer disease. Fluids Barriers CNS 2023; 20:78. [PMID: 37907966 PMCID: PMC10617216 DOI: 10.1186/s12987-023-00471-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 10/01/2023] [Indexed: 11/02/2023] Open
Abstract
BACKGROUND The function of the blood-brain barrier (BBB) is impaired in late-onset Alzheimer disease (LOAD), but the associated molecular mechanisms, particularly with respect to the high-risk APOE4/4 genotype, are not well understood. For this purpose, we developed a multicellular isogenic model of the neurovascular unit (NVU) based on human induced pluripotent stem cells. METHODS The human NVU was modeled in vitro using isogenic co-cultures of astrocytes, brain capillary endothelial-like cells (BCECs), microglia-like cells, neural stem cells (NSCs), and pericytes. Physiological and pathophysiological properties were investigated as well as the influence of each single cell type on the characteristics and function of BCECs. The barriers established by BCECs were analyzed for specific gene transcription using high-throughput quantitative PCR. RESULTS Co-cultures were found to tighten the barrier of BCECs and alter its transcriptomic profile under both healthy and disease conditions. In vitro differentiation of brain cell types that constitute the NVU was not affected by the LOAD background. The supportive effect of NSCs on the barrier established by BCECs was diminished under LOAD conditions. Transcriptomes of LOAD BCECs were modulated by different brain cell types. NSCs were found to have the strongest effect on BCEC gene regulation and maintenance of the BBB. Co-cultures showed cell type-specific functional contributions to BBB integrity under healthy and LOAD conditions. CONCLUSIONS Cell type-dependent transcriptional effects on LOAD BCECs were identified. Our study suggests that different brain cell types of the NVU have unique roles in maintaining barrier integrity that vary under healthy and LOAD conditions. .
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Affiliation(s)
- Undine Haferkamp
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525, Hamburg, Germany
| | - Carla Hartmann
- Institute for Physiological Chemistry, Medical Faculty of the Martin, Luther University Halle-Wittenberg, Hollystrasse 1, 06114, Halle (Saale), Germany
| | - Chaudhry Luqman Abid
- Institute for Physiological Chemistry, Medical Faculty of the Martin, Luther University Halle-Wittenberg, Hollystrasse 1, 06114, Halle (Saale), Germany
| | - Andreas Brachner
- Center Health and Bioresources, Competence Unit Molecular Diagnostics, AIT Austrian Institute of Technology GmbH, Vienna, 1210, Austria
| | - Alevtina Höchner
- Fraunhofer Institute for Silicate Research ISC, Translational Center Regenerative Therapies (TLC-RT), 97070, Würzburg, Germany
| | - Anna Gerhartl
- Center Health and Bioresources, Competence Unit Molecular Diagnostics, AIT Austrian Institute of Technology GmbH, Vienna, 1210, Austria
| | - Bernadette Harwardt
- Institute for Physiological Chemistry, Medical Faculty of the Martin, Luther University Halle-Wittenberg, Hollystrasse 1, 06114, Halle (Saale), Germany
| | - Selin Leckzik
- Institute for Physiological Chemistry, Medical Faculty of the Martin, Luther University Halle-Wittenberg, Hollystrasse 1, 06114, Halle (Saale), Germany
| | - Jennifer Leu
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525, Hamburg, Germany
| | - Marco Metzger
- Fraunhofer Institute for Silicate Research ISC, Translational Center Regenerative Therapies (TLC-RT), 97070, Würzburg, Germany
- Chair Tissue Engineering and Regenerative Medicine (TERM), University Hospital Würzburg, 97070, Würzburg, Germany
| | | | - Winfried Neuhaus
- Center Health and Bioresources, Competence Unit Molecular Diagnostics, AIT Austrian Institute of Technology GmbH, Vienna, 1210, Austria
- Department of Medicine, Faculty of Medicine and Dentistry, Danube Private University, Krems, 3500, Austria
| | - Sabrina Oerter
- Fraunhofer Institute for Silicate Research ISC, Translational Center Regenerative Therapies (TLC-RT), 97070, Würzburg, Germany
- Chair Tissue Engineering and Regenerative Medicine (TERM), University Hospital Würzburg, 97070, Würzburg, Germany
| | - Ole Pless
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525, Hamburg, Germany
| | - Dan Rujescu
- Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Vienna, 1090, Austria
| | - Matthias Jung
- Institute for Physiological Chemistry, Medical Faculty of the Martin, Luther University Halle-Wittenberg, Hollystrasse 1, 06114, Halle (Saale), Germany.
| | - Antje Appelt-Menzel
- Fraunhofer Institute for Silicate Research ISC, Translational Center Regenerative Therapies (TLC-RT), 97070, Würzburg, Germany.
- Chair Tissue Engineering and Regenerative Medicine (TERM), University Hospital Würzburg, 97070, Würzburg, Germany.
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20
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Nguyen JN, Mohan EC, Pandya G, Ali U, Tan C, Kofler JK, Shapiro L, Marrelli SP, Chauhan A. CD13 facilitates immune cell migration and aggravates acute injury but promotes chronic post-stroke recovery. J Neuroinflammation 2023; 20:232. [PMID: 37817190 PMCID: PMC10566099 DOI: 10.1186/s12974-023-02918-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 10/01/2023] [Indexed: 10/12/2023] Open
Abstract
INTRODUCTION Acute stroke leads to the activation of myeloid cells. These cells express adhesion molecules and transmigrate to the brain, thereby aggravating injury. Chronically after stroke, repair processes, including angiogenesis, are activated and enhance post-stroke recovery. Activated myeloid cells express CD13, which facilitates their migration into the site of injury. However, angiogenic blood vessels which play a role in recovery also express CD13. Overall, the specific contribution of CD13 to acute and chronic stroke outcomes is unknown. METHODS CD13 expression was estimated in both mice and humans after the ischemic stroke. Young (8-12 weeks) male wild-type and global CD13 knockout (KO) mice were used for this study. Mice underwent 60 min of middle cerebral artery occlusion (MCAO) followed by reperfusion. For acute studies, the mice were euthanized at either 24- or 72 h post-stroke. For chronic studies, the Y-maze, Barnes maze, and the open field were performed on day 7 and day 28 post-stroke. Mice were euthanized at day 30 post-stroke and the brains were collected for assessment of inflammation, white matter injury, tissue loss, and angiogenesis. Flow cytometry was performed on days 3 and 7 post-stroke to quantify infiltrated monocytes and neutrophils and CXCL12/CXCR4 signaling. RESULTS Brain CD13 expression and infiltrated CD13+ monocytes and neutrophils increased acutely after the stroke. The brain CD13+lectin+ blood vessels increased on day 15 after the stroke. Similarly, an increase in the percentage area CD13 was observed in human stroke patients at the subacute time after stroke. Deletion of CD13 resulted in reduced infarct volume and improved neurological recovery after acute stroke. However, CD13KO mice had significantly worse memory deficits, amplified gliosis, and white matter damage compared to wild-type animals at chronic time points. CD13-deficient mice had an increased percentage of CXCL12+cells but a reduced percentage of CXCR4+cells and decreased angiogenesis at day 30 post-stroke. CONCLUSIONS CD13 is involved in the trans-migration of monocytes and neutrophils after stroke, and acutely, led to decreased infarct size and improved behavioral outcomes. However, loss of CD13 led to reductions in post-stroke angiogenesis by reducing CXCL12/CXCR4 signaling.
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Affiliation(s)
- Justin N Nguyen
- University of Texas McGovern Medical School at Houston, Houston, TX, USA
| | - Eric C Mohan
- University of Texas McGovern Medical School at Houston, Houston, TX, USA
| | - Gargee Pandya
- Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX, USA
| | - Uzma Ali
- Baylor University, Waco, TX, USA
| | - Chunfeng Tan
- Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX, USA
| | - Julia K Kofler
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Linda Shapiro
- Center for Vascular Biology, The University of Connecticut Health Center, Farmington, CT, USA
| | - Sean P Marrelli
- Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX, USA
| | - Anjali Chauhan
- Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX, USA.
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21
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Zhao Z, Li T, Yuan Y, Zhu Y. What is new in cancer-associated fibroblast biomarkers? Cell Commun Signal 2023; 21:96. [PMID: 37143134 PMCID: PMC10158035 DOI: 10.1186/s12964-023-01125-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 04/05/2023] [Indexed: 05/06/2023] Open
Abstract
The tumor microenvironment is one of the important drivers of tumor development. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma and actively participate in tumor development, invasion, metastasis, drug resistance, and other biological behaviors. CAFs are a highly heterogeneous group of cells, a reflection of the diversity of their origin, biomarkers, and functions. The diversity of CAF origin determines the complexity of CAF biomarkers, and CAF subpopulations expressing different biomarkers may play contrasting roles in tumor progression. In this review, we provide an overview of these emerging CAF biomarkers and the biological functions that they suggest, which may give a better understanding of the relationship between CAFs and tumor cells and be of great significance for breakthroughs in precision targeted therapy for tumors. Video Abstract.
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Affiliation(s)
- Zehua Zhao
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), No. 44 of Xiaoheyan Road, Dadong District, Shenyang, 110042, China
| | - Tianming Li
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), No. 44 of Xiaoheyan Road, Dadong District, Shenyang, 110042, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, No. 155 of Nanjing Road, Heping District, Shenyang, 110001, China.
| | - Yanmei Zhu
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), No. 44 of Xiaoheyan Road, Dadong District, Shenyang, 110042, China.
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22
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Wu JC, Wu GJ. METCAM Is a Potential Biomarker for Predicting the Malignant Propensity of and as a Therapeutic Target for Prostate Cancer. Biomedicines 2023; 11:biomedicines11010205. [PMID: 36672713 PMCID: PMC9855335 DOI: 10.3390/biomedicines11010205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/30/2022] [Accepted: 01/07/2023] [Indexed: 01/15/2023] Open
Abstract
Prostate cancer is the second leading cause of cancer-related death worldwide. This is because it is still unknown why indolent prostate cancer becomes an aggressive one, though many risk factors for this type of cancer have been suggested. Currently, many diagnostic markers have been suggested for predicting malignant prostatic carcinoma cancer; however, only a few, such as PSA (prostate-specific antigen), Prostate Health Index (PHI), and PCA3, have been approved by the FDA. However, each biomarker has its merits as well as shortcomings. The serum PSA test is incapable of differentiating prostate cancer from BPH and also has an about 25% false-positive prediction rate for the malignant status of cancer. The PHI test has the potential to replace the PSA test for the discrimination of BPH from prostate cancer and for the prediction of high-grade cancer avoiding unnecessary biopsies; however, the free form of PSA is unstable and expensive. PCA3 is not associated with locally advanced disease and is limited in terms of its prediction of aggressive cancer. Currently, several urine biomarkers have shown high potential in terms of being used to replace circulating biomarkers, which require a more invasive method of sample collection, such as via serum. Currently, the combined multiple tumor biomarkers may turn out to be a major trend in the diagnosis and assessment of the treatment effectiveness of prostate cancer. Thus, there is still a need to search for more novel biomarkers to develop a perfect cocktail, which consists of multiple biomarkers, in order to predict malignant prostate cancer and follow the efficacy of the treatment. We have discovered that METCAM, a cell adhesion molecule in the Ig-like superfamily, has great potential regarding its use as a biomarker for differentiating prostate cancer from BPH, predicting the malignant propensity of prostate cancer at the early premalignant stage, and differentiating indolent prostate cancers from aggressive cancers. Since METCAM has also been shown to be able to initiate the spread of prostate cancer cell lines to multiple organs, we suggest that it may be used as a therapeutic target for the clinical treatment of patients with malignant prostate cancer.
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Affiliation(s)
- Jui-Chuang Wu
- Department of Chemical Engineering, Chung Yuan Christian University, Taoyuan City 32023, Taiwan
- Research Center for Circular Economy, Chung Yuan Christian University, Taoyuan City 32023, Taiwan
| | - Guang-Jer Wu
- Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan City 32023, Taiwan
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Correspondence:
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Feng J, Wang Y, Li B, Yu X, Lei L, Wu J, Zhang X, Chen Q, Zhou Y, Gou J, Li H, Tan Z, Dai Z, Li X, Guan F. Loss of bisecting GlcNAcylation on MCAM of bone marrow stoma determined pro-tumoral niche in MDS/AML. Leukemia 2023; 37:113-121. [PMID: 36335262 DOI: 10.1038/s41375-022-01748-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 10/21/2022] [Accepted: 10/26/2022] [Indexed: 11/06/2022]
Abstract
Bone marrow (BM) stroma plays key roles in supporting hematopoietic stem cell (HSC) growth. Glycosylation contributes to the interactions between HSC and surrounding microenvironment. We observed that bisecting N-acetylglucosamine (GlcNAc) structures, in BM stromal cells were significantly lower for MDS/AML patients than for healthy subjects. Malignant clonal cells delivered exosomal miR-188-5p to recipient stromal cells, where it suppressed bisecting GlcNAc by targeting MGAT3 gene. Proteomic analysis revealed reduced GlcNAc structures and enhanced expression of MCAM, a marker of BM niche. We characterized MCAM as a bisecting GlcNAc-bearing target protein, and identified Asn 56 as bisecting GlcNAc modification site on MCAM. MCAM on stromal cell surface with reduced bisecting GlcNAc bound strongly to CD13 on myeloid cells, activated responding ERK signaling, and thereby promoted myeloid cell growth. Our findings, taken together, suggest a novel mechanism whereby MDS/AML clonal cells generate a self-permissive niche by modifying glycosylation level of stromal cells.
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Affiliation(s)
- Jingjing Feng
- Institute of Hematology, Provincial Key Laboratory of Biotechnology, School of Medicine, Northwest University, Xi'an, China
| | - Yi Wang
- Department of Hematology, Provincial People's Hospital, Xi'an, China
| | - Bingxin Li
- Institute of Hematology, Provincial Key Laboratory of Biotechnology, School of Medicine, Northwest University, Xi'an, China
| | - Xinwen Yu
- Institute of Hematology, Provincial Key Laboratory of Biotechnology, School of Medicine, Northwest University, Xi'an, China
| | - Lei Lei
- Institute of Hematology, Provincial Key Laboratory of Biotechnology, School of Medicine, Northwest University, Xi'an, China
| | - Jinpeng Wu
- Institute of Hematology, Provincial Key Laboratory of Biotechnology, School of Medicine, Northwest University, Xi'an, China
| | - Xin Zhang
- Institute of Hematology, Provincial Key Laboratory of Biotechnology, School of Medicine, Northwest University, Xi'an, China
| | | | - Yue Zhou
- Institute of Hematology, Provincial Key Laboratory of Biotechnology, School of Medicine, Northwest University, Xi'an, China
| | - Junjie Gou
- Institute of Hematology, Provincial Key Laboratory of Biotechnology, School of Medicine, Northwest University, Xi'an, China
| | - Hongjiao Li
- Institute of Hematology, Provincial Key Laboratory of Biotechnology, School of Medicine, Northwest University, Xi'an, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, China
| | - Zengqi Tan
- Institute of Hematology, Provincial Key Laboratory of Biotechnology, School of Medicine, Northwest University, Xi'an, China
| | - Zhijun Dai
- Department of Breast Surgery, the First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Xiang Li
- Institute of Hematology, Provincial Key Laboratory of Biotechnology, School of Medicine, Northwest University, Xi'an, China.
| | - Feng Guan
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, China.
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METCAM/MUC18 Plays a Tumor Suppressor Role in the Development of Nasopharyngeal Carcinoma Type I. Int J Mol Sci 2022; 23:ijms232113389. [PMID: 36362174 PMCID: PMC9655335 DOI: 10.3390/ijms232113389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/26/2022] [Accepted: 10/30/2022] [Indexed: 11/06/2022] Open
Abstract
From previous studies of negatively correlating the expression of human METCAM/MUC18 with the pathology of nasopharyngeal carcinoma (NPC), we have suggested that human METCAM/MUC18 (huMETCAM/MUC18) might play a tumor suppressor role in the development of nasopharyngeal carcinoma. To scrutinize this hypothesis, we investigated the effects of huMETCAM/MUC18′s over-expression on in vitro cellular behavior and on the in vivo tumorigenesis of one NPC cell line (NPC-TW01). HuMETCAM/MUC18 cDNA was first transfected into the NPC-TW01 cell line, which was established from NPC type I, and many G418-resistant clones were obtained. Then, two NPC-TW01 clones, which expressed high and medium levels of huMETCAM/MUC18, respectively, and one empty vector (control) clone were used to test the effects of huMETCAM/MUC18′s over-expression on in vitro behaviors and on in vivo tumorigenesis (via subcutaneous injection) in athymic nude mice (Balb/cAnN.Cg-Foxnlnu/Cr1Nar1). The time course of tumor proliferation and the final tumor weights were determined. Tumor sections were used for the histology and immunohistochemistry (IHC) studies. Tumor lysates were used for determining the expression levels of huMETCAM/MUC18 and various downstream key effectors. HuMETCAM/MUC18′s over-expression reduced in vitro motility and invasiveness and altered growth behaviors in 3D basement membrane culture assays, and it decreased the in vivo tumorigenicity of the NPC-TW01 cells. The tumor cells from a high-expressing clone were clustered and confined in small areas, whereas those from a vector control clone were more spread out, suggesting that the tumor cells from the high-expressing clone appeared to stay dormant in micro-clusters. Expression levels of the proliferation index, an index of the metabolic switch to aerobic glycolysis, angiogenesis indexes, and survival pathway indexes were reduced, whereas the pro-apoptosis index increased in the corresponding tumors. The over-expression of huMETCAM/MUC18 in the NPC-TW01 cells decreased the epithelial-to-mesenchymal transition and the in vitro and in vitro tumorigenesis, suggesting that it plays a tumor suppressor role in the development of type I NPC, perhaps by increasing apoptosis and decreasing angiogenesis, proliferation, and the metabolic switch to aerobic glycolysis.
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Rasile M, Lauranzano E, Faggiani E, Ravanelli MM, Colombo FS, Mirabella F, Corradini I, Malosio ML, Borreca A, Focchi E, Pozzi D, Giorgino T, Barajon I, Matteoli M. Maternal immune activation leads to defective brain-blood vessels and intracerebral hemorrhages in male offspring. EMBO J 2022; 41:e111192. [PMID: 36314682 PMCID: PMC9713716 DOI: 10.15252/embj.2022111192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 09/21/2022] [Accepted: 09/27/2022] [Indexed: 12/04/2022] Open
Abstract
Intracerebral hemorrhages are recognized risk factors for neurodevelopmental disorders and represent early biomarkers for cognitive dysfunction and mental disability, but the pathways leading to their occurrence are not well defined. We report that a single intrauterine exposure of the immunostimulant Poly I:C to pregnant mice at gestational day 9, which models a prenatal viral infection and the consequent maternal immune activation, induces the defective formation of brain vessels and causes intracerebral hemorrhagic events, specifically in male offspring. We demonstrate that maternal immune activation promotes the production of the TGF-β1 active form and the consequent enhancement of pSMAD1-5 in males' brain endothelial cells. TGF-β1, in combination with IL-1β, reduces the endothelial expression of CD146 and claudin-5, alters the endothelium-pericyte interplay resulting in low pericyte coverage, and increases hemorrhagic events in the adult offspring. By showing that exposure to Poly I:C at the beginning of fetal cerebral angiogenesis results in sex-specific alterations of brain vessels, we provide a mechanistic framework for the association between intragravidic infections and anomalies of the neural vasculature, which may contribute to neuropsychiatric disorders.
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Affiliation(s)
- Marco Rasile
- Department of Biomedical SciencesHumanitas UniversityPieve EmanueleItaly,IRCCS Humanitas Clinical and Research CenterRozzanoItaly
| | | | - Elisa Faggiani
- IRCCS Humanitas Clinical and Research CenterRozzanoItaly
| | - Margherita M Ravanelli
- Department of Biomedical SciencesHumanitas UniversityPieve EmanueleItaly,IRCCS Humanitas Clinical and Research CenterRozzanoItaly
| | | | - Filippo Mirabella
- Department of Biomedical SciencesHumanitas UniversityPieve EmanueleItaly,IRCCS Humanitas Clinical and Research CenterRozzanoItaly
| | - Irene Corradini
- IRCCS Humanitas Clinical and Research CenterRozzanoItaly,Institute of Neuroscience (IN‐CNR)National Research Council of ItalyMilanItaly
| | - Maria L Malosio
- IRCCS Humanitas Clinical and Research CenterRozzanoItaly,Institute of Neuroscience (IN‐CNR)National Research Council of ItalyMilanItaly
| | - Antonella Borreca
- IRCCS Humanitas Clinical and Research CenterRozzanoItaly,Institute of Neuroscience (IN‐CNR)National Research Council of ItalyMilanItaly
| | - Elisa Focchi
- Institute of Neuroscience (IN‐CNR)National Research Council of ItalyMilanItaly
| | - Davide Pozzi
- Department of Biomedical SciencesHumanitas UniversityPieve EmanueleItaly,IRCCS Humanitas Clinical and Research CenterRozzanoItaly
| | - Toni Giorgino
- Institute of Biophysics (IBF‐CNR)National Research Council of ItalyMilanItaly
| | - Isabella Barajon
- Department of Biomedical SciencesHumanitas UniversityPieve EmanueleItaly,IRCCS Humanitas Clinical and Research CenterRozzanoItaly
| | - Michela Matteoli
- Department of Biomedical SciencesHumanitas UniversityPieve EmanueleItaly,Institute of Neuroscience (IN‐CNR)National Research Council of ItalyMilanItaly
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Wang J, Wu Z, Zheng M, Yu S, Zhang X, Xu X. CD146 is closely associated with the prognosis and molecular features of osteosarcoma: Guidance for personalized clinical treatment. Front Genet 2022; 13:1025306. [PMID: 36338992 PMCID: PMC9635853 DOI: 10.3389/fgene.2022.1025306] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 09/29/2022] [Indexed: 11/29/2022] Open
Abstract
Background: Osteosarcoma (OSA), a focus for orthopedic surgeons, always results in severe death due to metastasis. CD146 is severely expressed in several tumors, indicating its potential as a biomarker for OSA. Method: Two OSA cohorts were enrolled in this study. A Therapeutically Applicable Research to Generate Effective Treatments-Osteosarcoma (TARGET-OS) cohort was used as a training cohort, and GSE21257 was used as the external validation cohort. The R package “limma” was used to discriminate the differentially expressed genes among CD146-high and CD146-low patients and was further annotated by the enriched signaling pathways. The R package MOVICS was used to evaluate immune infiltration and the response to chemotherapy and immunotherapy. All statistical analyses were performed by R version 4.0.2, and p < 0.05 was considered statistically significant. Result: CD146 plays an important role in promoting the progression, invasion, and metastasis of several tumors. In the current study, we first revealed an integrative unfavorable prognosis in patients with tumors (p < 0.01, HR: 1.10, 95% CI: 1.07-1.14). CD146 is tightly correlated with m5C RNA methylation modification genes in OSA. Furthermore, we revealed that CD146 acts as an oncogene in OSA patients and is linked to poor prognosis in both the TARGET-OS cohort (p = 0.019, HR: 2.61, 95% CI: 1.171-5.834) and the GSE21257 cohort (p = 0.005, HR: 3.61, 95% CI: 1.474-8.855), with a total of 137 patients, regardless of whether they were adjusted for clinical pathological features. Highly-expressed CD146 impacts the signaling pathways of cytokine‒cytokine receptor interactions and is associated with the high infiltration of immunocytes. Moreover, patients with high CD146 expression were more likely to be sensitive to anti-PD-1 immunotherapy, while patients with low expression of CD146 were more likely to be sensitive to cisplatin and doxorubicin chemotherapy. Conclusion: Overall, CD146 is an independent prognostic factor for OSA patients and can help doctors select clinical treatment strategies.
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Mukherjee A, Ha P, Wai KC, Naara S. The Role of ECM Remodeling, EMT, and Adhesion Molecules in Cancerous Neural Invasion: Changing Perspectives. Adv Biol (Weinh) 2022; 6:e2200039. [PMID: 35798312 DOI: 10.1002/adbi.202200039] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 05/05/2022] [Indexed: 01/28/2023]
Abstract
Perineural invasion (PNI) refers to the cancerous invasion of nerves. It provides an alternative route for metastatic invasion and can exist independently in the absence of lymphatic or vascular invasion. It is a prominent characteristic of specific aggressive malignancies where it correlates with poor prognosis. The clinical significance of PNI is widely recognized despite a lack of understanding of the molecular mechanisms underlying its pathogenesis. The interaction between the nerve and the cancer cells is the most pivotal PNI step which is mediated by the activation or inhibition of multiple signaling pathways that include chemokines, interleukins, nerve growth factors, and matrix metalloproteinases, to name a few. The nerve-cancer cell interaction brings about specific changes in the perineural niche, which not only affects the regular nerve functions, but also enhances the migratory, invasive, and adherent properties of the tumor cells. This review aims to elucidate the vital role of adhesion molecules, extracellular matrix, and epithelial-mesenchymal proteins that promote PNI, which may serve as therapeutic targets in the future.
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Affiliation(s)
- Abhishek Mukherjee
- Department of Genetics and Developmental BiologyRappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 3525422, Israel
| | - Patrick Ha
- Department of Otolaryngology-Head and Neck Surgery, University of California-San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94158, USA
| | - Katherine C Wai
- Department of Otolaryngology-Head and Neck Surgery, University of California-San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94158, USA
| | - Shorook Naara
- Department of Genetics and Developmental BiologyRappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 3525422, Israel.,Department of Otolaryngology-Head and Neck Surgery, University of California-San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94158, USA
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Zhang ZY, Zhai C, Yang XY, Li HB, Wu LL, Li L. Knockdown of CD146 promotes endothelial-to-mesenchymal transition via Wnt/β-catenin pathway. PLoS One 2022; 17:e0273542. [PMID: 36001597 PMCID: PMC9401105 DOI: 10.1371/journal.pone.0273542] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 08/10/2022] [Indexed: 11/27/2022] Open
Abstract
Purpose Cardiac fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) proteins and leads to the maladaptive changes in myocardium. Endothelial cells (ECs) undergoing mesenchymal transition contributes to the occurrence and development of cardiac fibrosis. CD146 is an adhesion molecule highly expressed in ECs. The present study was performed to explore the role of CD146 in modulating endothelial to mesenchymal transition (EndMT). Methods C57BL/6 mice were subjected to subcutaneous implantation of osmotic minipump infused with angiotensin II (Ang Ⅱ). Adenovirus carrying CD146 short hairpin RNA (shRNA) or CD146 encoding sequence were infected into cultured human umbilical vein endothelial cells (HUVECs) followed by stimulation with Ang II or transforming growth factor-β1 (TGF-β1). Differentially expressed genes were revealed by RNA-sequencing (RNA-Seq) analysis. Gene expression was measured by quantitative real-time PCR, and protein expression and distribution were determined by Western blot and immunofluorescence staining, respectively. Results CD146 was predominantly expressed by ECs in normal mouse hearts. CD146 was upregulated in ECs but not fibroblasts and myocytes in hearts of Ang II-infused mice and in HUVECs stimulated with Ang Ⅱ. RNA-Seq analysis revealed the differentially expressed genes related to EndMT and Wnt/β-catenin signaling pathway. CD146 knockdown and overexpression facilitated and attenuated, respectively, EndMT induced by Ang II or TGF-β1. CD146 knockdown upregulated Wnt pathway-related genes including Wnt4, LEF1, HNF4A, FOXA1, SOX6, and CCND3, and increased the protein level and nuclear translocation of β-catenin. Conclusions Knockdown of CD146 exerts promotional effects on EndMT via activating Wnt/β-catenin pathway and the upregulation of CD146 might play a protective role against EndMT and cardiac fibrosis.
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Affiliation(s)
- Zhao-Yu Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Chao Zhai
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Xue-Yuan Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Hai-Bing Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Li-Ling Wu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Li Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
- * E-mail:
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Mohammed NBB, Antonopoulos A, Dell A, Haslam SM, Dimitroff CJ. The pleiotropic role of galectin-3 in melanoma progression: Unraveling the enigma. Adv Cancer Res 2022; 157:157-193. [PMID: 36725108 PMCID: PMC9895887 DOI: 10.1016/bs.acr.2022.06.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Melanoma is a highly aggressive skin cancer with poor outcomes associated with distant metastasis. Intrinsic properties of melanoma cells alongside the crosstalk between melanoma cells and surrounding microenvironment determine the tumor behavior. Galectin-3 (Gal-3), a ß-galactoside-binding lectin, has emerged as a major effector in cancer progression, including melanoma behavior. Data from melanoma models and patient studies reveal that Gal-3 expression is dysregulated, both intracellularly and extracellularly, throughout the stages of melanoma progression. This review summarizes the most recent data and hypotheses on Gal-3 and its tumor-modulating functions, highlighting its role in driving melanoma growth, invasion, and metastatic colonization. It also provides insight into potential Gal-3-targeted strategies for melanoma diagnosis and treatment.
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Affiliation(s)
- Norhan B B Mohammed
- Department of Translational Medicine, Translational Glycobiology Institute at FIU (TGIF), Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States; Department of Medical Biochemistry, Faculty of Medicine, South Valley University, Qena, Egypt
| | | | - Anne Dell
- Department of Life Sciences, Imperial College London, London, United Kingdom
| | - Stuart M Haslam
- Department of Life Sciences, Imperial College London, London, United Kingdom
| | - Charles J Dimitroff
- Department of Translational Medicine, Translational Glycobiology Institute at FIU (TGIF), Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States.
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Zhang L, Sun Y, Zhang XX, Liu YB, Sun HY, Wu CT, Xiao FJ, Wang LS. Comparison of CD146 +/- mesenchymal stem cells in improving premature ovarian failure. Stem Cell Res Ther 2022; 13:267. [PMID: 35729643 PMCID: PMC9209844 DOI: 10.1186/s13287-022-02916-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 04/04/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are a heterogeneous group of subpopulations with differentially expressed surface markers. CD146 + MSCs correlate with high therapeutic and secretory potency. However, their therapeutic efficacy and mechanisms in premature ovarian failure (POF) have not been explored. METHODS The umbilical cord (UC)-derived CD146 +/- MSCs were sorted using magnetic beads. The proliferation of MSCs was assayed by dye670 staining and flow cytometry. A mouse POF model was established by injection of cyclophosphamide and busulfan, followed by treatment with CD146 +/- MSCs. The therapeutic effect of CD146 +/- MSCs was evaluated based on body weight, hormone levels, follicle count and reproductive ability. Differential gene expression was identified by mRNA sequencing and validated by RT-PCR. The lymphocyte percentage was detected by flow cytometry. RESULTS CD146 +/- MSCs had similar morphology and surface marker expression. However, CD146 + MSCs exhibited a significantly stronger proliferation ability. Gene profiles revealed that CD146 + MSCs had a lower levels of immunoregulatory factor expression. CD146 + MSCs exhibited a stronger ability to inhibit T cell proliferation. CD146 +/- MSCs treatment markedly restored FSH and E2 hormone secretion level, reduced follicular atresia, and increased sinus follicle numbers in a mouse POF model. The recovery function of CD146 + MSCs in a reproductive assay was slightly improved than that of CD146 - MSCs. Ovary mRNA sequencing data indicated that UC-MSCs therapy improved ovarian endocrine locally, which was through PPAR and cholesterol metabolism pathways. The percentages of CD3, CD4, and CD8 lymphocytes were significantly reduced in the POF group compared to the control group. CD146 + MSCs treatment significantly reversed the changes in lymphocyte percentages. Meanwhile, CD146 - MSCs could not improve the decrease in CD4/8 ratio induced by chemotherapy. CONCLUSION UC-MSCs therapy improved premature ovarian failure significantly. CD146 +/- MSCs both had similar therapeutic effects in repairing reproductive ability. CD146 + MSCs had advantages in modulating immunology and cell proliferation characteristics.
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Affiliation(s)
- Lin Zhang
- Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.,Laboratory of Molecular Diagnosis and Regenerative Medicine, Medical Research Center, The Affiliate Hospital of Qingdao University, Qingdao, 266000, People's Republic of China
| | - Yang Sun
- Laboratory of Molecular Diagnosis and Regenerative Medicine, Medical Research Center, The Affiliate Hospital of Qingdao University, Qingdao, 266000, People's Republic of China
| | - Xiao-Xu Zhang
- Laboratory of Molecular Diagnosis and Regenerative Medicine, Medical Research Center, The Affiliate Hospital of Qingdao University, Qingdao, 266000, People's Republic of China
| | - Yu-Bin Liu
- Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
| | - Hui-Yan Sun
- Yanda Medical Research Institute, Hebei Yanda Hospital, Sanhe, 065201, Hebei Province, People's Republic of China
| | - Chu-Tse Wu
- Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.
| | - Feng-Jun Xiao
- Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.
| | - Li-Sheng Wang
- Laboratory of Molecular Diagnosis and Regenerative Medicine, Medical Research Center, The Affiliate Hospital of Qingdao University, Qingdao, 266000, People's Republic of China.
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ALCAM regulates multiple myeloma chemoresistant side population. Cell Death Dis 2022; 13:136. [PMID: 35145058 PMCID: PMC8831486 DOI: 10.1038/s41419-022-04556-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/23/2021] [Accepted: 01/17/2022] [Indexed: 11/13/2022]
Abstract
Drug-resistance is a major problem preventing a cure in patients with multiple myeloma (MM). Previously, we demonstrated that activated-leukocyte-cell-adhesion-molecule (ALCAM) is a prognostic factor in MM and inhibits EGF/EGFR-initiated MM clonogenicity. In this study, we further showed that the ALCAM-EGF/EGFR axis regulated the MM side population (SP)-mediated drug-resistance. ALCAM-knockdown MM cells displayed an enhanced ratio of SP cells in the presence of bone marrow stromal cells (BMSCs) or with the supplement of recombinant EGF. SP MM cells were resistant to chemotherapeutics melphalan or bortezomib. Drug treatment stimulated SP-genesis. Mechanistically, EGFR, primed with EGF, activated the hedgehog pathway and promoted the SP ratio; meanwhile, ALCAM inhibited EGFR downstream pro-MM cell signaling. Further, SP MM cells exhibited an increased number of mitochondria compared to the main population. Interference of the mitochondria function strongly inhibited SP-genesis. Animal studies showed that combination therapy with both an anti-MM agent and EGFR inhibitor gefitinib achieved prolonged MM-bearing mice survival. Hence, our work identifies ALCAM as a novel negative regulator of MM drug-resistance, and EGFR inhibitors may be used to improve MM therapeutic efficacy.
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Sharma A, Joshkon A, Ladjimi A, Traboulsi W, Bachelier R, Robert S, Foucault-Bertaud A, Leroyer AS, Bardin N, Somasundaram I, Blot-Chabaud M. Soluble CD146 as a Potential Target for Preventing Triple Negative Breast Cancer MDA-MB-231 Cell Growth and Dissemination. Int J Mol Sci 2022; 23:ijms23020974. [PMID: 35055160 PMCID: PMC8780963 DOI: 10.3390/ijms23020974] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/07/2022] [Accepted: 01/08/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Triple Negative Breast Cancers (TNBC) are the most aggressive breast cancers and lead to poor prognoses. This is due to a high resistance to therapies, mainly because of the presence of Cancer Stem Cells (CSCs). Plasticity, a feature of CSCs, is acquired through the Epithelial to Mesenchymal Transition (EMT), a process that has been recently shown to be regulated by a key molecule, CD146. Of interest, CD146 is over-expressed in TNBC. Methods: The MDA-MB-231 TNBC cell line was used as a model to study the role of CD146 and its secreted soluble form (sCD146) in the development and dissemination of TNBC using in vitro and in vivo studies. Results: High expression of CD146 in a majority of MDA-MB-231 cells leads to an increased secretion of sCD146 that up-regulates the expression of EMT and CSC markers on the cells. These effects can be blocked with a specific anti-sCD146 antibody, M2J-1 mAb. M2J-1 mAb was able to reduce tumour development and dissemination in a model of cells xenografted in nude mice and an experimental model of metastasis, respectively, in part through its effects on CSC. Conclusion: We propose that M2J-1 mAb could be used as an additional therapeutic approach to fight TNBC.
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Affiliation(s)
- Akshita Sharma
- Department of Stem Cell and Regenerative Medicine, D.Y. Patil Universit, Kolhapur 416003, India; (A.S.); (I.S.)
| | - Ahmad Joshkon
- Faculty of Pharmacy, Aix-Marseille University, INSERM 1263, INRAE 1260, C2VN, 13005 Marseille, France; (A.J.); (A.L.); (W.T.); (R.B.); (S.R.); (A.F.-B.); (A.S.L.); (N.B.)
| | - Aymen Ladjimi
- Faculty of Pharmacy, Aix-Marseille University, INSERM 1263, INRAE 1260, C2VN, 13005 Marseille, France; (A.J.); (A.L.); (W.T.); (R.B.); (S.R.); (A.F.-B.); (A.S.L.); (N.B.)
| | - Waël Traboulsi
- Faculty of Pharmacy, Aix-Marseille University, INSERM 1263, INRAE 1260, C2VN, 13005 Marseille, France; (A.J.); (A.L.); (W.T.); (R.B.); (S.R.); (A.F.-B.); (A.S.L.); (N.B.)
| | - Richard Bachelier
- Faculty of Pharmacy, Aix-Marseille University, INSERM 1263, INRAE 1260, C2VN, 13005 Marseille, France; (A.J.); (A.L.); (W.T.); (R.B.); (S.R.); (A.F.-B.); (A.S.L.); (N.B.)
| | - Stéphane Robert
- Faculty of Pharmacy, Aix-Marseille University, INSERM 1263, INRAE 1260, C2VN, 13005 Marseille, France; (A.J.); (A.L.); (W.T.); (R.B.); (S.R.); (A.F.-B.); (A.S.L.); (N.B.)
| | - Alexandrine Foucault-Bertaud
- Faculty of Pharmacy, Aix-Marseille University, INSERM 1263, INRAE 1260, C2VN, 13005 Marseille, France; (A.J.); (A.L.); (W.T.); (R.B.); (S.R.); (A.F.-B.); (A.S.L.); (N.B.)
| | - Aurélie S. Leroyer
- Faculty of Pharmacy, Aix-Marseille University, INSERM 1263, INRAE 1260, C2VN, 13005 Marseille, France; (A.J.); (A.L.); (W.T.); (R.B.); (S.R.); (A.F.-B.); (A.S.L.); (N.B.)
| | - Nathalie Bardin
- Faculty of Pharmacy, Aix-Marseille University, INSERM 1263, INRAE 1260, C2VN, 13005 Marseille, France; (A.J.); (A.L.); (W.T.); (R.B.); (S.R.); (A.F.-B.); (A.S.L.); (N.B.)
| | - Indumathi Somasundaram
- Department of Stem Cell and Regenerative Medicine, D.Y. Patil Universit, Kolhapur 416003, India; (A.S.); (I.S.)
| | - Marcel Blot-Chabaud
- Faculty of Pharmacy, Aix-Marseille University, INSERM 1263, INRAE 1260, C2VN, 13005 Marseille, France; (A.J.); (A.L.); (W.T.); (R.B.); (S.R.); (A.F.-B.); (A.S.L.); (N.B.)
- Correspondence: ; Tel.: +33-4-91-83-56-85
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Luo H, Zhang D, Wang F, Wang Q, Wu Y, Gou M, Hu Y, Zhang W, Huang J, Gong Y, Pan L, Li T, Zhao P, Zhang D, Qu Y, Liu Z, Jiang T, Dai Y, Guo T, Zhu J, Ye L, Zhang L, Liu W, Yi Q, Zheng Y. ALCAM-EGFR interaction regulates myelomagenesis. Blood Adv 2021; 5:5269-5282. [PMID: 34592762 PMCID: PMC9152994 DOI: 10.1182/bloodadvances.2021004695] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 07/28/2021] [Indexed: 02/05/2023] Open
Abstract
Multiple myeloma, a plasma cell malignancy in the bone marrow, remains largely incurable with currently available therapeutics. In this study, we discovered that the activated leukocyte cell adhesion molecule (ALCAM) interacted with epidermal growth factor receptor (EGFR), and regulated myelomagenesis. ALCAM was a negative regulator of myeloma clonogenicity. ALCAM expression was positively correlated with patients' survival. ALCAM-knockdown myeloma cells displayed enhanced colony formation in the presence of bone marrow stromal cells (BMSCs). BMSCs supported myeloma colony formation by secreted epidermal growth factor (EGF), which bound with its receptor (EGFR) on myeloma cells and activated Mek/Erk cell signaling, PI3K/Akt cell signaling, and hedgehog pathway. ALCAM could also bind with EGFR, block EGF from binding to EGFR, and abolish EGFR-initiated cell signaling. Hence, our study identifies ALCAM as a novel negative regulator of myeloma pathogenesis.
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Affiliation(s)
- Hongmei Luo
- Department of Hematology, West China Hospital
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, China
| | - Dan Zhang
- Department of Hematology, West China Hospital
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, China
| | - Fangfang Wang
- Department of Hematology, West China Hospital
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, China
| | - Qiang Wang
- Center for Translational Research in Hematological Malignancies, Cancer Center, Houston Methodist Hospital, Houston, TX
| | - Yu Wu
- Department of Hematology, West China Hospital
| | - Maling Gou
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, China
| | - Yiguo Hu
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, China
| | | | - Jingcao Huang
- Department of Hematology, West China Hospital
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, China
| | - Yuping Gong
- Department of Hematology, West China Hospital
| | - Ling Pan
- Department of Hematology, West China Hospital
| | - Tianshu Li
- Center for Translational Research in Hematological Malignancies, Cancer Center, Houston Methodist Hospital, Houston, TX
| | - Pan Zhao
- Department of Hematology, West China Hospital
| | | | - Ying Qu
- Department of Hematology, West China Hospital
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, China
| | - Zhigang Liu
- Department of Hematology, West China Hospital
| | - Tao Jiang
- Department of Hematology, West China Hospital
| | - Yang Dai
- Department of Hematology, West China Hospital
| | | | - Jiang Zhu
- Department of Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Lingqun Ye
- Center for Translational Research in Hematological Malignancies, Cancer Center, Houston Methodist Hospital, Houston, TX
| | - Li Zhang
- Department of Hematology, West China Hospital
| | | | - Qing Yi
- Center for Translational Research in Hematological Malignancies, Cancer Center, Houston Methodist Hospital, Houston, TX
| | - Yuhuan Zheng
- Department of Hematology, West China Hospital
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, China
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Rapanotti MC, Cugini E, Nuccetelli M, Terrinoni A, Di Raimondo C, Lombardo P, Costanza G, Cosio T, Rossi P, Orlandi A, Campione E, Bernardini S, Blot-Chabaud M, Bianchi L. MCAM/MUC18/CD146 as a Multifaceted Warning Marker of Melanoma Progression in Liquid Biopsy. Int J Mol Sci 2021; 22:12416. [PMID: 34830300 PMCID: PMC8623757 DOI: 10.3390/ijms222212416] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/09/2021] [Accepted: 11/10/2021] [Indexed: 12/26/2022] Open
Abstract
Human malignant melanoma shows a high rate of mortality after metastasization, and its incidence is continuously rising worldwide. Several studies have suggested that MCAM/MUC18/CD146 plays an important role in the progression of this malignant disease. MCAM/MUC18/CD146 is a typical single-spanning transmembrane glycoprotein, existing as two membrane isoforms, long and short, and an additional soluble form, sCD146. We previously documented that molecular MCAM/MUC18/CD146 expression is strongly associated with disease progression. Recently, we showed that MCAM/MUC18/CD146 and ABCB5 can serve as melanoma-specific-targets in the selection of highly primitive circulating melanoma cells, and constitute putative proteins associated with disease spreading progression. Here, we analyzed CD146 molecular expression at onset or at disease recurrence in an enlarged melanoma case series. For some patients, we also performed the time courses of molecular monitoring. Moreover, we explored the role of soluble CD146 in different cohorts of melanoma patients at onset or disease progression, rather than in clinical remission, undergoing immune therapy or free from any clinical treatment. We showed that MCAM/MUC18/CD146 can be considered as: (1) a membrane antigen suitable for identification and enrichment in melanoma liquid biopsy; (2) a highly effective molecular "warning" marker for minimal residual disease monitoring; and (3) a soluble protein index of inflammation and putative response to therapeutic treatments.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- CD146 Antigen/blood
- CD146 Antigen/chemistry
- CD146 Antigen/genetics
- Disease Progression
- Female
- Follow-Up Studies
- Gene Expression
- Gene Expression Regulation, Neoplastic
- Humans
- Liquid Biopsy
- Longitudinal Studies
- Male
- Melanoma/blood
- Melanoma/genetics
- Melanoma/pathology
- Middle Aged
- Neoplasm Recurrence, Local/blood
- Neoplasm Recurrence, Local/genetics
- Neoplasm, Residual/blood
- Neoplasm, Residual/genetics
- Neoplastic Cells, Circulating/metabolism
- Skin Neoplasms/blood
- Skin Neoplasms/genetics
- Skin Neoplasms/pathology
- Solubility
- Young Adult
- Melanoma, Cutaneous Malignant
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Affiliation(s)
- Maria Cristina Rapanotti
- Department of Onco-Haematology, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy
- Department of Laboratory Medicine, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (E.C.); (M.N.); (A.T.); (G.C.); (S.B.)
| | - Elisa Cugini
- Department of Laboratory Medicine, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (E.C.); (M.N.); (A.T.); (G.C.); (S.B.)
| | - Marzia Nuccetelli
- Department of Laboratory Medicine, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (E.C.); (M.N.); (A.T.); (G.C.); (S.B.)
| | - Alessandro Terrinoni
- Department of Laboratory Medicine, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (E.C.); (M.N.); (A.T.); (G.C.); (S.B.)
| | - Cosimo Di Raimondo
- Dermatology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.D.R.); (P.L.); (T.C.); (E.C.); (L.B.)
| | - Paolo Lombardo
- Dermatology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.D.R.); (P.L.); (T.C.); (E.C.); (L.B.)
| | - Gaetana Costanza
- Department of Laboratory Medicine, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (E.C.); (M.N.); (A.T.); (G.C.); (S.B.)
| | - Terenzio Cosio
- Dermatology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.D.R.); (P.L.); (T.C.); (E.C.); (L.B.)
| | - Piero Rossi
- Department of Surgery Sciences, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - Augusto Orlandi
- Anatomic Pathology, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - Elena Campione
- Dermatology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.D.R.); (P.L.); (T.C.); (E.C.); (L.B.)
| | - Sergio Bernardini
- Department of Laboratory Medicine, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (E.C.); (M.N.); (A.T.); (G.C.); (S.B.)
| | - Marcel Blot-Chabaud
- Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1076, Aix-Marseille University, UFR Pharmacy, 13005 Marseille, France;
| | - Luca Bianchi
- Dermatology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (C.D.R.); (P.L.); (T.C.); (E.C.); (L.B.)
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Kaczmarczyk JA, Roberts RR, Luke BT, Chan KC, Van Wagoner CM, Felder RA, Saul RG, Simona C, Blonder J. Comparative microsomal proteomics of a model lung cancer cell line NCI-H23 reveals distinct differences between molecular profiles of 3D and 2D cultured cells. Oncotarget 2021; 12:2022-2038. [PMID: 34611477 PMCID: PMC8487723 DOI: 10.18632/oncotarget.28072] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/31/2021] [Indexed: 12/11/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths in the USA and worldwide. Yet, about 95% of new drug candidates validated in preclinical phase eventually fail in clinical trials. Such a high attrition rate is attributed mostly to the inability of conventional two-dimensionally (2D) cultured cancer cells to mimic native three-dimensional (3D) growth of malignant cells in human tumors. To ascertain phenotypical differences between these two distinct culture conditions, we carried out a comparative proteomic analysis of a membrane fraction obtained from 3D- and 2D-cultured NSCLC model cell line NCI-H23. This analysis revealed a map of 1,166 (24%) protein species regulated in culture dependent manner, including differential regulation of a subset of cell surface-based CD molecules. We confirmed exclusive expression of CD99, CD146 and CD239 in 3D culture. Furthermore, label-free quantitation, targeting KRas proteoform-specific peptides, revealed upregulation of both wild type and monoallelic KRas4BG12C mutant at the surface of 3D cultured cells. In order to reduce the high attrition rate of new drug candidates, the results of this study strongly suggests exploiting base-line molecular profiling of a large number of patient-derived NSCLC cell lines grown in 2D and 3D culture, prior to actual drug candidate testing.
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Affiliation(s)
- Jan A. Kaczmarczyk
- Antibody Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Rhonda R. Roberts
- Antibody Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Brian T. Luke
- Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - King C. Chan
- Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
- Current address: The Center for Cell Clearance, University of Virginia, Charlottesville, VA 22908, USA
| | - Carly M. Van Wagoner
- Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
- Current address: The Center for Cell Clearance, University of Virginia, Charlottesville, VA 22908, USA
| | - Robin A. Felder
- Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Richard G. Saul
- Antibody Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Colantonio Simona
- Antibody Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Josip Blonder
- Antibody Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
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An Y, Wei N, Cheng X, Li Y, Liu H, Wang J, Xu Z, Sun Z, Zhang X. MCAM abnormal expression and clinical outcome associations are highly cancer dependent as revealed through pan-cancer analysis. Brief Bioinform 2021; 21:709-718. [PMID: 30815677 DOI: 10.1093/bib/bbz019] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 01/28/2019] [Accepted: 01/29/2019] [Indexed: 12/30/2022] Open
Abstract
MCAM (CD146) is a cell surface adhesion molecule that has been reported to promote cancer development, progression and metastasis and is considered as a potential tumor biomarker and therapeutic target. However, inconsistent reports exist, and its clinical value is yet to be confirmed. Here we took advantage of several large genomic data collections (Genotype-Tissue Expression, The Cancer Genome Atlas and Cancer Cell Line Encyclopedia) and comprehensively analyzed MCAM expression in thousands of normal and cancer samples and cell lines along with their clinical phenotypes and drug response information. Our results show that MCAM is very highly expressed in large vessel tissues while majority of tissues have low or minimal expression. Its expression is dramatically increased in a few tumors but significantly decreased in most other tumors relative to their pairing normal tissues. Increased MCAM expression is associated with a higher tumor stage and worse patient survival for some less common tumors but not for major ones. Higher MCAM expression in primary tumors may be complicated by tumor-associated or normal stromal blood vessels yet its significance may differ from the one from cancer cells. MCAM expression is weakly associated with the response to a few small molecular drugs and the association with targeted anti-BRAF agents suggests its involvement in that pathway which warrants further investigation.
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Affiliation(s)
- Yunxia An
- Department of Respiratory Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Nan Wei
- Department of Respiratory Medicine, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
| | - Xiangsong Cheng
- Department of Respiratory Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ying Li
- Department of Respiratory Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Haiyang Liu
- Department of Respiratory Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jia Wang
- Department of Respiratory Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhiwei Xu
- Department of Respiratory Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhifu Sun
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Xiaoju Zhang
- Department of Respiratory Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Wu GJ. Enforced Expression of METCAM/MUC18 Decreases In Vitro Motility and Invasiveness and Tumorigenesis and In Vivo Tumorigenesis of Human Ovarian Cancer BG-1 Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1330:125-137. [PMID: 34339034 DOI: 10.1007/978-3-030-73359-9_8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2023]
Abstract
OBJECTIVES We tested if METCAM/MUC18 overexpression also plays a suppressor role in another human ovarian cancer cell line, BG-1, in addition to the SK-OV3 cell line. METHODS Human ovarian cancer BG-1 cells were transfected with METCAM/MUC18 cDNA and G418-resistant clones expressing different levels of METCAM/MUC18 were isolated. These clones were used to test the effects of enforced expression of METCAM/MUC18 on in vitro motility, invasiveness, and anchorage-independent colony formation (in vitro tumorigenesis), and in vivo tumorigenesis after SC injection and after IP injection in female athymic nude mice. RESULTS Overexpression of METCAM/MUC18 reduced in vitro motility and invasiveness of BG-1 cells and anchorage-independent colony formation (in vitro tumor formation). Higher expression of METCAM/MUC18 in BG-1 cells significantly reduced in vivo tumor proliferation of the BG-1 cells after IP injection (orthotopic route) of the clones in female nude mice, though it did not significantly affect in vivo tumor proliferation after SC injection (non-orthotopic route). CONCLUSION Similar to SK-OV3 cells, METCAM/MUC18 also plays a suppressor role in the progression of BG-1 cells in a xenograft mouse model.
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Affiliation(s)
- Guang-Jer Wu
- Department of Microbiology & Immunology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. .,Department of Bioscience Technology and Center for Biomedical Technology, Chung Yuan Christian University, Taoyuan City, Taiwan.
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Wang W, Sindrewicz-Goral P, Chen C, Duckworth CA, Pritchard DM, Rhodes JM, Yu LG. Appearance of peanut agglutinin in the blood circulation after peanut ingestion promotes endothelial secretion of metastasis-promoting cytokines. Carcinogenesis 2021; 42:1079-1088. [PMID: 34223877 PMCID: PMC8643467 DOI: 10.1093/carcin/bgab059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 06/07/2021] [Accepted: 07/02/2021] [Indexed: 11/18/2022] Open
Abstract
Peanut agglutinin (PNA) is a carbohydrate-binding protein in peanuts that accounts for ~0.15% peanut weight. PNA is highly resistant to cooking and digestion and is rapidly detectable in the blood after peanut consumption. Our previous studies have shown that circulating PNA mimics the actions of endogenous galactoside-binding protein galectin-3 by interaction with tumour cell-associated MUC1 and promotes circulating tumour cell metastatic spreading. The present study shows that circulating PNA interacts with micro- as well as macro-vascular endothelial cells and induces endothelial secretion of cytokines MCP-1 (CCL2) and IL-6 in vitro and in vivo. The increased secretion of these cytokines autocrinely/paracrinely enhances the expression of endothelial cell surface adhesion molecules including integrins, VCAM and selectin, leading to increased tumour cell-endothelial adhesion and endothelial tubule formation. Binding of PNA to endothelial surface MCAM (CD146), via N-linked glycans, and subsequent activation of PI3K-AKT-PREAS40 signalling is here shown responsible for PNA-induced secretion of MCP-1 and IL-6 by vascular endothelium. Thus, in addition to its influence on promoting tumour cell spreading by interaction with tumour cell-associated MUC1, circulating PNA might also influence metastasis by enhancing the secretion of metastasis-promoting MCP-1 and IL-6 from the vascular endothelium.
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Affiliation(s)
- Weikun Wang
- The Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, United Kingdom
| | - Paulina Sindrewicz-Goral
- The Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, United Kingdom
| | - Chen Chen
- The Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, United Kingdom
| | - Carrie A Duckworth
- The Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, United Kingdom
| | - David Mark Pritchard
- The Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, United Kingdom
| | - Jonathan M Rhodes
- The Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, United Kingdom
| | - Lu-Gang Yu
- The Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, United Kingdom
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Ferreira CA, Kang L, Li C, Kamkaew A, Barrett KE, Aluicio-Sarduy E, Yang Y, Engle JW, Jiang D, Cai W. ImmunoPET of the differential expression of CD146 in breast cancer. Am J Cancer Res 2021; 11:1586-1599. [PMID: 33948375 PMCID: PMC8085863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 01/20/2021] [Indexed: 06/12/2023] Open
Abstract
With advancement in antibody engineering, the development and characterization of new cancer-specific molecular targets are in the forefront of this PET-antibody combination "revolution". Overexpression of CD146 in different types of tumors, including breast tumor, has been associated with tumor progression and poor prognosis. Non-invasive detection of CD146 with a monoclonal antibody may provide a noninvasive diagnostic tool with high specificity and accountability. METHODS Herein, we have developed a CD146-specific monoclonal antibody (YY146), radiolabeled it with 52Mn and 89Zr and identified its capability in acting as a non-invasive imaging agent that specific targets CD146 in different murine breast cancer models. CD146 expression was first screened in different breast tumor cell lines through Western Blot and confirmed its binding ability to YY146 using Flow Cytometry. Serial immunoPET images were carried out after intravenous administration of 52Mn or 89Zr labeled YY146. In addition, we also performed in vivo fluorescence imaging in animals injected with YY146 conjugated with Cy5.5. RESULTS Western Blot results show that MDA-MB-435 cell line had greater levels of CD146 expression when compared to the other cell lines investigated. Flow cytometry confirmed binding ability of YY146. PET images revealed well correlated uptake between tumor uptake and CD146 expression levels, confirmed by biodistribution studies and fluorescence imaging. CONCLUSION PET imaging, for up to 7 days, of mice bearing three different breast tumors were carried out and revealed radiotracer uptake in tumors that strongly (r2 = 0.98, P < 0.01), correlated with CD146 expression levels, as confirmed by in vitro and ex vivo studies.
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Affiliation(s)
- Carolina A Ferreira
- Department of Biomedical Engineering, University of Wisconsin-MadisonMadison, WI, USA
| | - Lei Kang
- Department of Nuclear Medicine, Peking University First HospitalBeijing, China
- Department of Radiology and Medical Physics, University of Wisconsin-MadisonWI, USA
| | - Cuicui Li
- Department of Nuclear Medicine, Peking University First HospitalBeijing, China
| | - Anyanee Kamkaew
- Department of Radiology and Medical Physics, University of Wisconsin-MadisonWI, USA
| | - Kendall E Barrett
- Department of Radiology and Medical Physics, University of Wisconsin-MadisonWI, USA
| | | | - Yunan Yang
- Department of Radiology and Medical Physics, University of Wisconsin-MadisonWI, USA
| | - Jonathan W Engle
- Department of Radiology and Medical Physics, University of Wisconsin-MadisonWI, USA
| | - Dawei Jiang
- Department of Radiology and Medical Physics, University of Wisconsin-MadisonWI, USA
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, China
| | - Weibo Cai
- Department of Biomedical Engineering, University of Wisconsin-MadisonMadison, WI, USA
- Department of Radiology and Medical Physics, University of Wisconsin-MadisonWI, USA
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Chen X, Yan H, Liu D, Xu Q, Duan H, Feng J, Yan X, Xie C. Structure basis for AA98 inhibition on the activation of endothelial cells mediated by CD146. iScience 2021; 24:102417. [PMID: 33997697 PMCID: PMC8093899 DOI: 10.1016/j.isci.2021.102417] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 02/10/2021] [Accepted: 04/08/2021] [Indexed: 12/27/2022] Open
Abstract
CD146 is an adhesion molecule that plays important roles in angiogenesis, cancer metastasis, and immune response. It exists as a monomer or dimer on the cell surface. AA98 is a monoclonal antibody that binds to CD146, which abrogates the activation of CD146-mediated signaling pathways and shows inhibitory effects on tumor growth. However, how AA98 inhibits the function of CD146 remains unclear. Here, we describe a crystal structure of the CD146/AA98 Fab complex at a resolution of 2.8 Å. Monomeric CD146 is stabilized by AA98 Fab binding to the junction region of CD146 domains 4 and 5. A higher-affinity AA98 variant (here named HA98) was thus rationally designed. Better binding to CD146 and prominent inhibition on cell migration were achieved with HA98. Further experiments on xenografted melanoma in mice with HA98 revealed superior inhibitory effects on tumor growth to those of AA98, which suggested future applications of this antibody in cancer therapy.
Structural analysis elucidated how mAb AA98 inhibited CD146-mediated EC activation AA98-stabilized CD146 in monomer thus inhibited activation of EC Higher affinity monoclonal antibody HA98 was rationally designed for cancer treatment
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Affiliation(s)
- Xuehui Chen
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.,State Key Laboratory of Membrane Biology, Laboratory of Molecular Biophysics, School of Life Sciences, Peking University, Beijing 100871, China
| | - Huiwen Yan
- Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Dan Liu
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Qingji Xu
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hongxia Duan
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Jing Feng
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Xiyun Yan
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Can Xie
- State Key Laboratory of Membrane Biology, Laboratory of Molecular Biophysics, School of Life Sciences, Peking University, Beijing 100871, China.,High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Science Island, Hefei, Anhui 230031, PR China.,International Magnetobiology Frontier Research Center, Science Island, Hefei 230031, China
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Wu Z, Liu J, Chen G, Du J, Cai H, Chen X, Ye G, Luo Y, Luo Y, Zhang L, Duan H, Liu Z, Yang S, Sun H, Cui Y, Sun L, Zhang H, Shi G, Wei T, Liu P, Yan X, Feng J, Bu P. CD146 is a Novel ANGPTL2 Receptor that Promotes Obesity by Manipulating Lipid Metabolism and Energy Expenditure. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2004032. [PMID: 33747748 PMCID: PMC7967059 DOI: 10.1002/advs.202004032] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/18/2020] [Indexed: 05/08/2023]
Abstract
Obesity and its related complications pose an increasing threat to human health; however, targetable obesity-related membrane receptors are not yet elucidated. Here, the membrane receptor CD146 is demonstrated to play an essential role in obesity. In particular, CD146 acts as a new adipose receptor for angiopoietin-like protein 2 (ANGPTL2), which is thought to act on endothelial cells to activate adipose inflammation. ANGPTL2 binds to CD146 to activate cAMP response element-binding protein (CREB), which then upregulates CD146 during adipogenesis and adipose inflammation. CD146 is present in preadipocytes and mature adipocytes, where it is mediated by its ligands ANGPTL2 and galectin-1. In preadipocytes, CD146 ablation suppresses adipogenesis, whereas the loss of CD146 in mature adipocytes suppresses lipid accumulation and enhances energy expenditure. Moreover, anti-CD146 antibodies inhibit obesity by disrupting the interactions between CD146 and its ligands. Together, these findings demonstrate that ANGPTL2 directly affects adipocytes via CD146 to promote obesity, suggesting that CD146 can be a potential target for treating obesity.
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Joshkon A, Heim X, Dubrou C, Bachelier R, Traboulsi W, Stalin J, Fayyad-Kazan H, Badran B, Foucault-Bertaud A, Leroyer AS, Bardin N, Blot-Chabaud M. Role of CD146 (MCAM) in Physiological and Pathological Angiogenesis-Contribution of New Antibodies for Therapy. Biomedicines 2020; 8:biomedicines8120633. [PMID: 33352759 PMCID: PMC7767164 DOI: 10.3390/biomedicines8120633] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/14/2020] [Accepted: 12/16/2020] [Indexed: 02/07/2023] Open
Abstract
The fundamental role of cell adhesion molecules in mediating various biological processes as angiogenesis has been well-documented. CD146, an adhesion molecule of the immunoglobulin superfamily, and its soluble form, constitute major players in both physiological and pathological angiogenesis. A growing body of evidence shows soluble CD146 to be significantly elevated in the serum or interstitial fluid of patients with pathologies related to deregulated angiogenesis, as autoimmune diseases, obstetric and ocular pathologies, and cancers. To block the undesirable effects of this molecule, therapeutic antibodies have been developed. Herein, we review the multifaceted functions of CD146 in physiological and pathological angiogenesis and summarize the interest of using monoclonal antibodies for therapeutic purposes.
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Affiliation(s)
- Ahmad Joshkon
- Hematology Department, Center for CardioVascular and Nutrition Research C2VN, Faculty of Pharmacy, Timone Campus, Aix-Marseille University, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche Pour L’agriculture, L’alimentation et L’environnement (INRAE), 13005 Marseille, France; (X.H.); (C.D.); (R.B.); (W.T.); (J.S.); (A.F.-B.); (A.S.L.); (N.B.); (M.B.-C.)
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Science, Lebanese University, Hadath 1104, Lebanon; (H.F.-K.); (B.B.)
- Correspondence:
| | - Xavier Heim
- Hematology Department, Center for CardioVascular and Nutrition Research C2VN, Faculty of Pharmacy, Timone Campus, Aix-Marseille University, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche Pour L’agriculture, L’alimentation et L’environnement (INRAE), 13005 Marseille, France; (X.H.); (C.D.); (R.B.); (W.T.); (J.S.); (A.F.-B.); (A.S.L.); (N.B.); (M.B.-C.)
- Service d’immunologie, Pôle de Biologie, Hôpital de la Conception, Assistance Publique Hôpitaux de Marseille (AP-HM), 13005 Marseille, France
| | - Cléa Dubrou
- Hematology Department, Center for CardioVascular and Nutrition Research C2VN, Faculty of Pharmacy, Timone Campus, Aix-Marseille University, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche Pour L’agriculture, L’alimentation et L’environnement (INRAE), 13005 Marseille, France; (X.H.); (C.D.); (R.B.); (W.T.); (J.S.); (A.F.-B.); (A.S.L.); (N.B.); (M.B.-C.)
| | - Richard Bachelier
- Hematology Department, Center for CardioVascular and Nutrition Research C2VN, Faculty of Pharmacy, Timone Campus, Aix-Marseille University, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche Pour L’agriculture, L’alimentation et L’environnement (INRAE), 13005 Marseille, France; (X.H.); (C.D.); (R.B.); (W.T.); (J.S.); (A.F.-B.); (A.S.L.); (N.B.); (M.B.-C.)
| | - Wael Traboulsi
- Hematology Department, Center for CardioVascular and Nutrition Research C2VN, Faculty of Pharmacy, Timone Campus, Aix-Marseille University, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche Pour L’agriculture, L’alimentation et L’environnement (INRAE), 13005 Marseille, France; (X.H.); (C.D.); (R.B.); (W.T.); (J.S.); (A.F.-B.); (A.S.L.); (N.B.); (M.B.-C.)
| | - Jimmy Stalin
- Hematology Department, Center for CardioVascular and Nutrition Research C2VN, Faculty of Pharmacy, Timone Campus, Aix-Marseille University, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche Pour L’agriculture, L’alimentation et L’environnement (INRAE), 13005 Marseille, France; (X.H.); (C.D.); (R.B.); (W.T.); (J.S.); (A.F.-B.); (A.S.L.); (N.B.); (M.B.-C.)
| | - Hussein Fayyad-Kazan
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Science, Lebanese University, Hadath 1104, Lebanon; (H.F.-K.); (B.B.)
| | - Bassam Badran
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Science, Lebanese University, Hadath 1104, Lebanon; (H.F.-K.); (B.B.)
| | - Alexandrine Foucault-Bertaud
- Hematology Department, Center for CardioVascular and Nutrition Research C2VN, Faculty of Pharmacy, Timone Campus, Aix-Marseille University, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche Pour L’agriculture, L’alimentation et L’environnement (INRAE), 13005 Marseille, France; (X.H.); (C.D.); (R.B.); (W.T.); (J.S.); (A.F.-B.); (A.S.L.); (N.B.); (M.B.-C.)
| | - Aurelie S. Leroyer
- Hematology Department, Center for CardioVascular and Nutrition Research C2VN, Faculty of Pharmacy, Timone Campus, Aix-Marseille University, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche Pour L’agriculture, L’alimentation et L’environnement (INRAE), 13005 Marseille, France; (X.H.); (C.D.); (R.B.); (W.T.); (J.S.); (A.F.-B.); (A.S.L.); (N.B.); (M.B.-C.)
| | - Nathalie Bardin
- Hematology Department, Center for CardioVascular and Nutrition Research C2VN, Faculty of Pharmacy, Timone Campus, Aix-Marseille University, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche Pour L’agriculture, L’alimentation et L’environnement (INRAE), 13005 Marseille, France; (X.H.); (C.D.); (R.B.); (W.T.); (J.S.); (A.F.-B.); (A.S.L.); (N.B.); (M.B.-C.)
- Service d’immunologie, Pôle de Biologie, Hôpital de la Conception, Assistance Publique Hôpitaux de Marseille (AP-HM), 13005 Marseille, France
| | - Marcel Blot-Chabaud
- Hematology Department, Center for CardioVascular and Nutrition Research C2VN, Faculty of Pharmacy, Timone Campus, Aix-Marseille University, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche Pour L’agriculture, L’alimentation et L’environnement (INRAE), 13005 Marseille, France; (X.H.); (C.D.); (R.B.); (W.T.); (J.S.); (A.F.-B.); (A.S.L.); (N.B.); (M.B.-C.)
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Zondler L, Herich S, Kotte P, Körner K, Schneider-Hohendorf T, Wiendl H, Schwab N, Zarbock A. MCAM/CD146 Signaling via PLCγ1 Leads to Activation of β 1-Integrins in Memory T-Cells Resulting in Increased Brain Infiltration. Front Immunol 2020; 11:599936. [PMID: 33381120 PMCID: PMC7767877 DOI: 10.3389/fimmu.2020.599936] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 11/13/2020] [Indexed: 12/11/2022] Open
Abstract
Multiple sclerosis is a chronic auto-inflammatory disease of the central nervous system affecting patients worldwide. Neuroinflammation in multiple sclerosis is mainly driven by peripheral immune cells which invade the central nervous system and cause neurodegenerative inflammation. To enter the target tissue, immune cells have to overcome the endothelium and transmigrate into the tissue. Numerous molecules mediate this process and, as they determine the tissue invasiveness of immune cells, display great therapeutic potential. Melanoma cell adhesion molecule (MCAM) is a membrane-anchored glycoprotein expressed by a subset of T-cells and MCAM+ T-cells have been shown to contribute to neuroinflammation in multiple sclerosis. The role of the MCAM molecule for brain invasion, however, remained largely unknown. In order to investigate the role of the MCAM molecule on T-cells, we used different in vitro and in vivo assays, including ex vivo flow chambers, biochemistry and microscopy experiments of the mouse brain. We demonstrate that MCAM directly mediates adhesion and that the engagement of MCAM induces intracellular signaling leading to β1-integrin activation on human T-cells. Furthermore, we show that MCAM engagement triggers the phosphorylation of PLCγ1 which is required for integrin activation and thus amplification of the cellular adhesive potential. To confirm the physiological relevance of our findings in vivo, we demonstrate that MCAM plays an important role in T-cell recruitment into the mouse brain. In conclusion, our data demonstrate that MCAM expressed on T-cells acts as an adhesion molecule and a signaling receptor that may trigger β1-integrin activation via PLCγ1 upon engagement.
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Affiliation(s)
- Lisa Zondler
- Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany
| | - Sebastian Herich
- Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany
| | - Petra Kotte
- Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany
| | - Katharina Körner
- Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany
| | - Tilman Schneider-Hohendorf
- Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany
| | - Heinz Wiendl
- Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany
| | - Nicholas Schwab
- Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany
| | - Alexander Zarbock
- Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany
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CD146/sCD146 in the Pathogenesis and Monitoring of Angiogenic and Inflammatory Diseases. Biomedicines 2020; 8:biomedicines8120592. [PMID: 33321883 PMCID: PMC7764286 DOI: 10.3390/biomedicines8120592] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/04/2020] [Accepted: 12/04/2020] [Indexed: 12/19/2022] Open
Abstract
CD146 is a cell adhesion molecule expressed on endothelial cells, as well as on other cells such as mesenchymal stem cells and Th17 lymphocytes. This protein also exists in a soluble form, whereby it can be detected in biological fluids, including the serum or the cerebrospinal fluid (CSF). Some studies have highlighted the significance of CD146 and its soluble form in angiogenesis and inflammation, having been shown to contribute to the pathogenesis of many inflammatory autoimmune diseases, such as systemic sclerosis, mellitus diabetes, rheumatoid arthritis, inflammatory bowel diseases, and multiple sclerosis. In this review, we will focus on how CD146 and sCD146 contribute to the pathogenesis of the aforementioned autoimmune diseases and discuss the relevance of considering it as a biomarker in these pathologies.
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Wang Z, Xu Q, Zhang N, Du X, Xu G, Yan X. CD146, from a melanoma cell adhesion molecule to a signaling receptor. Signal Transduct Target Ther 2020; 5:148. [PMID: 32782280 PMCID: PMC7421905 DOI: 10.1038/s41392-020-00259-8] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 06/14/2020] [Accepted: 06/18/2020] [Indexed: 12/11/2022] Open
Abstract
CD146 was originally identified as a melanoma cell adhesion molecule (MCAM) and highly expressed in many tumors and endothelial cells. However, the evidence that CD146 acts as an adhesion molecule to mediate a homophilic adhesion through the direct interactions between CD146 and itself is still lacking. Recent evidence revealed that CD146 is not merely an adhesion molecule, but also a cellular surface receptor of miscellaneous ligands, including some growth factors and extracellular matrixes. Through the bidirectional interactions with its ligands, CD146 is actively involved in numerous physiological and pathological processes of cells. Overexpression of CD146 can be observed in most of malignancies and is implicated in nearly every step of the development and progression of cancers, especially vascular and lymphatic metastasis. Thus, immunotherapy against CD146 would provide a promising strategy to inhibit metastasis, which accounts for the majority of cancer-associated deaths. Therefore, to deepen the understanding of CD146, we review the reports describing the newly identified ligands of CD146 and discuss the implications of these findings in establishing novel strategies for cancer therapy.
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Affiliation(s)
- Zhaoqing Wang
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
| | - Qingji Xu
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
- College of Life Science, University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Nengwei Zhang
- Department of Gastrointestinal Hepatobiliary Tumor Surgery, Beijing Shijitan Hospital, Capital Medical University, 100038, Beijing, China
| | - Xuemei Du
- Departments of Pathology, Beijing Shijitan Hospital, Capital Medical University, 100038, Beijing, China
| | - Guangzhong Xu
- Department of Gastrointestinal Hepatobiliary Tumor Surgery, Beijing Shijitan Hospital, Capital Medical University, 100038, Beijing, China
| | - Xiyun Yan
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
- College of Life Science, University of Chinese Academy of Sciences, 100049, Beijing, China.
- Nanozyme Medical Center, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
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Chen J, Dang Y, Feng W, Qiao C, Liu D, Zhang T, Wang Y, Tian D, Fan D, Nie Y, Wu K, Xia L. SOX18 promotes gastric cancer metastasis through transactivating MCAM and CCL7. Oncogene 2020; 39:5536-5552. [PMID: 32616889 DOI: 10.1038/s41388-020-1378-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 06/06/2020] [Accepted: 06/23/2020] [Indexed: 02/07/2023]
Abstract
The therapeutic strategies for advanced gastric cancer (GC) remain unsatisfying and limited. Therefore, it is still imperative to fully elucidate the mechanisms underlying GC metastasis. Here, we report a novel role of SRY-box transcription factor 18 (SOX18), a member of the SOX family, in promoting GC metastasis. The elevated expression of SOX18 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in human GC. SOX18 expression was an independent and significant risk factor for the recurrence and survival in GC patients. Up-regulation of SOX18 promoted GC invasion and metastasis, whereas down-regulation of SOX18 decreased GC invasion and metastasis. Melanoma cell adhesion molecule (MCAM) and C-C motif chemokine ligand 7 (CCL7) are direct transcriptional targets of SOX18. Knockdown of MCAM and CCL7 significantly decreased SOX18-mediated GC invasion and metastasis, while the stable overexpression of MCAM and CCL7 reversed the decrease in cell invasion and metastasis that was induced by the inhibition of SOX18. A mechanistic investigation indicated that the upregulation of SOX18 that was mediated by the CCL7-CCR1 pathway relied on the ERK/ELK1 pathway. SOX18 knockdown significantly reduced CCL7-enhanced GC invasion and metastasis. Furthermore, BX471, a specific CCR1 inhibitor, significantly reduced the SOX18-mediated GC invasion and metastasis. In human GC tissues, SOX18 expression was positively correlated with CCL7 and MCAM expression, and patients with positive coexpression of SOX18/CCL7 or SOX18/MCAM had the worst prognosis. In conclusion, we defined a CCL7-CCR1-SOX18 positive feedback loop that played a pivotal role in GC metastasis, and targeting this pathway may be a promising therapeutic option for the clinical management of GC.
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Affiliation(s)
- Jie Chen
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Yunzhi Dang
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Weibo Feng
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Chenyang Qiao
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Danfei Liu
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Tongyue Zhang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Yijun Wang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Dean Tian
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Daiming Fan
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Yongzhan Nie
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Kaichun Wu
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Limin Xia
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
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Gan GL, Liu J, Chen WJ, Ye QQ, Xu Y, Wu HT, Li W. The Diverse Roles of the Mucin Gene Cluster Located on Chromosome 11p15.5 in Colorectal Cancer. Front Cell Dev Biol 2020; 8:514. [PMID: 32695780 PMCID: PMC7338833 DOI: 10.3389/fcell.2020.00514] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 05/28/2020] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC), the third most common malignant tumor in the world, shows multiple complex and pathologies based on the impaired structure and function of the intestinal mucosal barrier. Goblet cells secrete mucins, which are involved in the formation of the intestinal mucosal barrier and not only lubricate and protect the intestinal mucosa but also participate in the processes of cell adhesion, intercellular signal transduction, and immune regulation. It is accepted that the disordered expression and dysfunction of mucins are associated with the occurrence and development of CRC. This article focuses on the secretory mucins encoded by a gene cluster located on chromosome 11p15.5 and systematically reviews their composition, regulation, function, and role in CRC, to deepen the understanding of the pathogeneses of CRC and to provide a new basis and ideas for the treatment of CRC.
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Affiliation(s)
- Guo-Lian Gan
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Jing Liu
- Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Shantou University Medical College, Shantou, China
- Department of Physiology/Cancer Research Center, Shantou University Medical College, Shantou, China
| | - Wen-Jia Chen
- Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Shantou University Medical College, Shantou, China
- Department of Physiology/Cancer Research Center, Shantou University Medical College, Shantou, China
| | - Qian-Qian Ye
- Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Shantou University Medical College, Shantou, China
- Department of Physiology/Cancer Research Center, Shantou University Medical College, Shantou, China
| | - Ya Xu
- Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Shantou University Medical College, Shantou, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Wei Li
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
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Intratumoral Gene Electrotransfer of Plasmid DNA Encoding shRNA against Melanoma Cell Adhesion Molecule Radiosensitizes Tumors by Antivascular Effects and Activation of an Immune Response. Vaccines (Basel) 2020; 8:vaccines8010135. [PMID: 32204304 PMCID: PMC7157247 DOI: 10.3390/vaccines8010135] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 03/17/2020] [Accepted: 03/17/2020] [Indexed: 12/12/2022] Open
Abstract
In this study, radiotherapy was combined with the gene electrotransfer (GET) of plasmid encoding shRNA against melanoma cell adhesion molecule (pMCAM) with dual action, which was a vascular-targeted effect mediated by the silencing of MCAM and an immunological effect mediated by the presence of plasmid DNA in the cytosol-activating DNA sensors. The effects and underlying mechanisms of therapy were evaluated in more immunogenic B16F10 melanoma and less immunogenic TS/A carcinoma. The silencing of MCAM potentiated the effect of irradiation (IR) in both tumor models. Combined therapy resulted in 81% complete responses (CR) in melanoma and 27% CR in carcinoma. Moreover, after the secondary challenge of cured mice, 59% of mice were resistant to challenge with melanoma cells, and none were resistant to carcinoma. Combined therapy reduced the number of blood vessels; induced hypoxia, apoptosis, and necrosis; and reduced cell proliferation in both tumor models. In addition, the significant increase of infiltrating immune cells was observed in both tumor models but more so in melanoma, where the expression of IL-12 and TNF-α was determined as well. Our results indicate that the combined therapy exerts both antiangiogenic and immune responses that contribute to the antitumor effect. However, tumor immunological status is crucial for a sufficient immune system contribution to the overall antitumor effect.
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49
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Tomonobu N, Kinoshita R, Sakaguchi M. S100 Soil Sensor Receptors and Molecular Targeting Therapy Against Them in Cancer Metastasis. Transl Oncol 2020; 13:100753. [PMID: 32193075 PMCID: PMC7078545 DOI: 10.1016/j.tranon.2020.100753] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 02/25/2020] [Accepted: 02/27/2020] [Indexed: 12/12/2022] Open
Abstract
The molecular mechanisms underlying the ‘seed and soil’ theory are unknown. S100A8/A9 (a heterodimer complex of S100A8 and S100A9 proteins that exhibits a ‘soil signal’) is a ligand for Toll-like receptor 4, causing distant melanoma cells to approach the lung as a ‘seeding’ site. Unknown soil sensors for S100A8/A9 may exist, e.g., extracellular matrix metalloproteinase inducer, neuroplastin, activated leukocyte cell adhesion molecule, and melanoma cell adhesion molecule. We call these receptor proteins ‘novel S100 soil sensor receptors (novel SSSRs).’ Here we review and summarize a crucial role of the S100A8/A9-novel SSSRs' axis in cancer metastasis. The binding of S100A8/A9 to individual SSSRs is important in cancer metastasis via upregulations of the epithelial-mesenchymal transition, cellular motility, and cancer cell invasiveness, plus the formation of an inflammatory immune suppressive environment in metastatic organ(s). These metastatic cellular events are caused by the SSSR-featured signal transductions we identified that provide cancer cells a driving force for metastasis. To deprive cancer cells of these metastatic forces, we developed novel biologics that prevent the interaction of S100A8/A9 with SSSRs, followed by the efficient suppression of S100A8/A9-mediated lung-tropic metastasis in vivo.
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Affiliation(s)
- Nahoko Tomonobu
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama 700-8558, Japan.
| | - Rie Kinoshita
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama 700-8558, Japan.
| | - Masakiyo Sakaguchi
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama 700-8558, Japan.
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50
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Stalin J, Traboulsi W, Vivancos-Stalin L, Nollet M, Joshkon A, Bachelier R, Guillet B, Lacroix R, Foucault-Bertaud A, Leroyer AS, Dignat-George F, Bardin N, Blot-Chabaud M. Therapeutic targeting of soluble CD146/MCAM with the M2J-1 monoclonal antibody prevents metastasis development and procoagulant activity in CD146-positive invasive tumors. Int J Cancer 2020; 147:1666-1679. [PMID: 32022257 DOI: 10.1002/ijc.32909] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/20/2019] [Accepted: 01/22/2020] [Indexed: 12/17/2022]
Abstract
Initially discovered in human melanoma, CD146/MCAM is expressed on many tumors and is correlated with cancer progression and metastasis. However, targeting CD146 remains challenging since it is also expressed on other cell types, as vessel cells, where it displays important physiological functions. We previously demonstrated that CD146 is shed as a soluble form (sCD146) that vectorizes the effects of membrane CD146 on tumor angiogenesis, growth and survival. We thus generated a novel monoclonal antibody, the M2J-1 mAb, which specifically targets sCD146, but not membrane CD146, and counteracts these effects. In our study, we analyzed the effects of sCD146 on the dissemination and the associated procoagulant phenotype in two highly invasive human CD146-positive cancer cell lines (ovarian and melanoma). Results show that sCD146 induced epithelial to mesenchymal transition, favored the generation of cancer stem cells and increased the membrane expression of tissue factor. Treatment of cancer cells with sCD146 in two experimental models (subcutaneous xenografting and intracardiac injection of cancer cells in nude mice) led to increased tumor dissemination and procoagulant activity. The M2J-1 mAb drastically reduced metastasis but also procoagulant activity, in particular by decreasing the number of circulating tumor microparticles, and blocked the relevant signaling pathways as demonstrated by RNA expression profiling experiments. Thus, our findings demonstrate that sCD146 mediates important pro-metastatic and procoagulant effects in two CD146-positive tumors. Targeting sCD146 with the newly generated M2J-1 mAb could constitute an innovative strategy for preventing dissemination and thromboembolism in many CD146-positive tumors.
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Affiliation(s)
- Jimmy Stalin
- INSERM, INRAE, C2VN, UFR Pharmacie, Aix-Marseille University, Marseille, France
| | - Wael Traboulsi
- INSERM, INRAE, C2VN, UFR Pharmacie, Aix-Marseille University, Marseille, France
| | | | - Marie Nollet
- INSERM, INRAE, C2VN, UFR Pharmacie, Aix-Marseille University, Marseille, France
| | - Ahmad Joshkon
- INSERM, INRAE, C2VN, UFR Pharmacie, Aix-Marseille University, Marseille, France
| | - Richard Bachelier
- INSERM, INRAE, C2VN, UFR Pharmacie, Aix-Marseille University, Marseille, France
| | - Benjamin Guillet
- INSERM, INRAE, C2VN, UFR Pharmacie, Aix-Marseille University, Marseille, France.,CERIMED (European Center of Research in Medical Imaging), Aix-Marseille University, Marseille, France
| | - Romaric Lacroix
- INSERM, INRAE, C2VN, UFR Pharmacie, Aix-Marseille University, Marseille, France.,AP-HM, La Conception Hospital, Marseille, France
| | | | - Aurélie S Leroyer
- INSERM, INRAE, C2VN, UFR Pharmacie, Aix-Marseille University, Marseille, France
| | - Françoise Dignat-George
- INSERM, INRAE, C2VN, UFR Pharmacie, Aix-Marseille University, Marseille, France.,AP-HM, La Conception Hospital, Marseille, France
| | - Nathalie Bardin
- INSERM, INRAE, C2VN, UFR Pharmacie, Aix-Marseille University, Marseille, France.,AP-HM, La Conception Hospital, Marseille, France
| | - Marcel Blot-Chabaud
- INSERM, INRAE, C2VN, UFR Pharmacie, Aix-Marseille University, Marseille, France
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