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Pashkina E, Bykova M, Berishvili M, Lazarev Y, Kozlov V. Hyaluronic Acid-Based Drug Delivery Systems for Cancer Therapy. Cells 2025; 14:61. [PMID: 39851489 PMCID: PMC11764402 DOI: 10.3390/cells14020061] [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: 11/21/2024] [Revised: 01/03/2025] [Accepted: 01/04/2025] [Indexed: 01/26/2025] Open
Abstract
In recent years, hyaluronic acid (HA) has attracted increasing attention as a promising biomaterial for the development of drug delivery systems. Due to its unique properties, such as high biocompatibility, low toxicity, and modifiability, HA is becoming a basis for the creation of targeted drug delivery systems, especially in the field of oncology. Receptors for HA overexpressed in subpopulations of cancer cells, and one of them, CD44, is recognized as a molecular marker for cancer stem cells. This review examines the role of HA and its receptors in health and tumors and analyzes existing HA-based delivery systems and their use in various types of cancer. The development of new HA-based drug delivery systems will bring new opportunities and challenges to anti-cancer therapy.
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Affiliation(s)
- Ekaterina Pashkina
- Research Institute of Fundamental and Clinical Immunology, 14, Yadrintsevskaya St., 630099 Novosibirsk, Russia
- Department of Clinical Immunology, Novosibirsk State Medical University, 52, Krasny Prospect, 630091 Novosibirsk, Russia
| | - Maria Bykova
- Research Institute of Fundamental and Clinical Immunology, 14, Yadrintsevskaya St., 630099 Novosibirsk, Russia
| | - Maria Berishvili
- Research Institute of Fundamental and Clinical Immunology, 14, Yadrintsevskaya St., 630099 Novosibirsk, Russia
| | - Yaroslav Lazarev
- Research Institute of Fundamental and Clinical Immunology, 14, Yadrintsevskaya St., 630099 Novosibirsk, Russia
- Faculty of Natural Sciences, Novosibirsk State University, 2, Pirogova Street, 630090 Novosibirsk, Russia
| | - Vladimir Kozlov
- Research Institute of Fundamental and Clinical Immunology, 14, Yadrintsevskaya St., 630099 Novosibirsk, Russia
- Faculty of Natural Sciences, Novosibirsk State University, 2, Pirogova Street, 630090 Novosibirsk, Russia
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Sasaki N, Asano Y, Sorayama Y, Kamimura C, Kitano S, Irie S, Katayama R, Shimoda H, Matsusaki M. Promoting biological similarity by collagen microfibers in 3D colorectal cancer-stromal tissue: Replicating mechanical properties and cancer stem cell markers. Acta Biomater 2024; 185:161-172. [PMID: 38972624 DOI: 10.1016/j.actbio.2024.07.001] [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: 11/25/2023] [Revised: 07/02/2024] [Accepted: 07/02/2024] [Indexed: 07/09/2024]
Abstract
The extracellular matrix (ECM) of cancer tissues is rich in dense collagen, contributing to the stiffening of these tissues. Increased stiffness has been reported to promote cancer cell proliferation, invasion, metastasis, and prevent drug delivery. Replicating the structure and mechanical properties of cancer tissue in vitro is essential for developing cancer treatment drugs that target these properties. In this study, we recreated specific characteristics of cancer tissue, such as collagen density and high elastic modulus, using a colorectal cancer cell line as a model. Using our original material, collagen microfibers (CMFs), and a constructed three-dimensional (3D) cancer-stromal tissue model, we successfully reproduced an ECM highly similar to in vivo conditions. Furthermore, our research demonstrated that cancer stem cell markers expressed in the 3D cancer-stromal tissue model more closely mimic in vivo conditions than traditional two-dimensional cell cultures. We also found that CMFs might affect an impact on how cancer cells express these markers. Our 3D CMF-based model holds promise for enhancing our understanding of colorectal cancer and advancing therapeutic approaches. STATEMENT OF SIGNIFICANCE: Reproducing the collagen content and stiffness of cancer tissue is crucial in comprehending the properties of cancer and advancing anticancer drug development. Nonetheless, the use of collagen as a scaffold material has posed challenges due to its poor solubility, hindering the replication of a cancer microenvironment. In this study, we have successfully recreated cancer tissue-specific characteristics such as collagen density, stiffness, and the expression of cancer stem cell markers in three-dimensional (3D) colorectal cancer stromal tissue, utilizing a proprietary material known as collagen microfiber (CMF). CMF proves to be an ideal scaffold material for replicating cancer stromal tissue, and these 3D tissues constructed with CMFs hold promise in contributing to our understanding of cancer and the development of therapeutic drugs.
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Affiliation(s)
- Naoko Sasaki
- Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Yoshiya Asano
- Department of Neuroanatomy, Cell Biology and Histology, Graduate School of Medicine, Hirosaki University, 5 Zaifu-cho, Hirosaki, 036-8562, Japan
| | - Yukiko Sorayama
- Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Chihiro Kamimura
- Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Shiro Kitano
- Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan; TOPPAN HOLDINGS INC. TOPPAN Technical Research Institute, 4-2-3, Takanodaiminami, Sugito-cho, Kitakatsushika-gun, Saitama 345-8508, Japan
| | - Shinji Irie
- Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan; TOPPAN HOLDINGS INC. TOPPAN Technical Research Institute, 4-2-3, Takanodaiminami, Sugito-cho, Kitakatsushika-gun, Saitama 345-8508, Japan
| | - Ryohei Katayama
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Hiroshi Shimoda
- Department of Neuroanatomy, Cell Biology and Histology, Graduate School of Medicine, Hirosaki University, 5 Zaifu-cho, Hirosaki, 036-8562, Japan; Department of Anatomical Science, Graduate School of Medicine, Hirosaki University, 5 Zaifu-cho, Hirosaki, 036-8562, Japan
| | - Michiya Matsusaki
- Joint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
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3
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Ishikawa K, Suzuki H, Ohishi T, Li G, Tanaka T, Kawada M, Ohkoshi A, Kaneko MK, Katori Y, Kato Y. Anti-CD44 Variant 10 Monoclonal Antibody Exerts Antitumor Activity in Mouse Xenograft Models of Oral Squamous Cell Carcinomas. Int J Mol Sci 2024; 25:9190. [PMID: 39273139 PMCID: PMC11395228 DOI: 10.3390/ijms25179190] [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: 08/02/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
CD44 regulates cell adhesion, proliferation, survival, and stemness and has been considered a tumor therapy target. CD44 possesses the shortest CD44 standard (CD44s) and a variety of CD44 variant (CD44v) isoforms. Since the expression of CD44v is restricted in epithelial cells and carcinomas compared to CD44s, CD44v has been considered a promising target for monoclonal antibody (mAb) therapy. We previously developed an anti-CD44v10 mAb, C44Mab-18 (IgM, kappa), to recognize the variant exon 10-encoded region. In the present study, a mouse IgG2a version of C44Mab-18 (C44Mab-18-mG2a) was generated to evaluate the antitumor activities against CD44-positive cells compared with the previously established anti-pan CD44 mAb, C44Mab-46-mG2a. C44Mab-18-mG2a exhibited higher reactivity compared with C44Mab-46-mG2a to CD44v3-10-overexpressed CHO-K1 (CHO/CD44v3-10) and oral squamous cell carcinoma cell lines (HSC-2 and SAS) in flow cytometry. C44Mab-18-mG2a exerted a superior antibody-dependent cellular cytotoxicity (ADCC) against CHO/CD44v3-10. In contrast, C44Mab-46-mG2a showed a superior complement-dependent cytotoxicity (CDC) against CHO/CD44v3-10. A similar tendency was observed in ADCC and CDC against HSC-2 and SAS. Furthermore, administering C44Mab-18-mG2a or C44Mab-46-mG2a significantly suppressed CHO/CD44v3-10, HSC-2, and SAS xenograft tumor growth compared with the control mouse IgG2a. These results indicate that C44Mab-18-mG2a could be a promising therapeutic regimen for CD44v10-positive tumors.
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Affiliation(s)
- Kenichiro Ishikawa
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (K.I.); (G.L.); (T.T.); (M.K.K.)
- Department of Otolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (A.O.); (Y.K.)
| | - Hiroyuki Suzuki
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (K.I.); (G.L.); (T.T.); (M.K.K.)
| | - Tomokazu Ohishi
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, 18-24 Miyamoto, Numazu-shi 410-0301, Shizuoka, Japan;
- Institute of Microbial Chemistry (BIKAKEN), Laboratory of Oncology, Microbial Chemistry Research Foundation, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan;
| | - Guanjie Li
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (K.I.); (G.L.); (T.T.); (M.K.K.)
| | - Tomohiro Tanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (K.I.); (G.L.); (T.T.); (M.K.K.)
| | - Manabu Kawada
- Institute of Microbial Chemistry (BIKAKEN), Laboratory of Oncology, Microbial Chemistry Research Foundation, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan;
| | - Akira Ohkoshi
- Department of Otolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (A.O.); (Y.K.)
| | - Mika K. Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (K.I.); (G.L.); (T.T.); (M.K.K.)
| | - Yukio Katori
- Department of Otolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (A.O.); (Y.K.)
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (K.I.); (G.L.); (T.T.); (M.K.K.)
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Fnu G, Weber GF. Targeting the core program of metastasis with a novel drug combination. Cancer Med 2024; 13:e7291. [PMID: 38826119 PMCID: PMC11145026 DOI: 10.1002/cam4.7291] [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: 10/10/2023] [Revised: 04/29/2024] [Accepted: 05/04/2024] [Indexed: 06/04/2024] Open
Abstract
BACKGROUND We previously reported that metastases are generally characterized by a core program of gene expression that activates tissue remodeling/vascularization, alters ion homeostasis, induces the oxidative metabolism, and silences extracellular matrix interactions. This core program distinguishes metastases from their originating primary tumors as well as from their destination host tissues. Therefore, the gene products involved are potential targets for anti-metastasis drug treatment. METHODS Because the silencing of extracellular matrix interactions predisposes to anoiks in the absence of active survival mechanisms, we tested inhibitors against the other three components. RESULTS Individually, the low-specificity VEGFR blocker pazopanib (in vivo combined with marimastat), the antioxidant dimethyl sulfoxide (or the substitute atovaquone, which is approved for internal administration), and the ionic modulators bumetanide and tetrathiomolybdate inhibited soft agar colony formation by breast and pancreatic cancer cell lines. The individual candidate agents have a record of use in humans (with limited efficacy when administered individually) and are available for repurposing. In combination, the effects of these drugs were additive or synergistic. In two mouse models of cancer (utilizing 4T1 cells or B16-F10 cells), the combination treatment with these medications, applied immediately (to prevent metastasis formation) or after a delay (to suppress established metastases), dramatically reduced the occurrence of disseminated foci. CONCLUSIONS The combination of tissue remodeling inhibitors, suppressors of the oxidative metabolism, and ion homeostasis modulators has very strong promise for the treatment of metastases by multiple cancers.
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Affiliation(s)
- Gulimirerouzi Fnu
- James L. Winkle College of PharmacyUniversity of Cincinnati Academic Health CenterCincinnatiOhioUSA
| | - Georg F. Weber
- James L. Winkle College of PharmacyUniversity of Cincinnati Academic Health CenterCincinnatiOhioUSA
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5
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Pujari R, Dubey SK. Relevance of glyco-biomakers and glycan profiles in cancer stem cells. Glycobiology 2024; 34:cwad019. [PMID: 36864577 DOI: 10.1093/glycob/cwad019] [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: 09/24/2022] [Revised: 02/22/2023] [Accepted: 02/27/2023] [Indexed: 03/04/2023] Open
Abstract
Altered and aberrant glycosylation signatures have been linked to being a hallmark in a variety of human disorders including cancer. Cancer stem cells (CSCs), capable of self-renewal and differentiation, have recently been credited with a unique notion of disease genesis and implicated as the cause for initiation and recurrence of the disease in a new regime of neoplastic transformations hypothesis. Many biomarkers relating to diagnostic and prognostic intents have been discovered using the ubiquitous and abundant surface glycan patterns on CSCs. Various technological advancements have been developed to identify and determine concerns with glycosylation structure. However, the nature and purpose of the glycan moiety on these glycosylation pattern have not yet been thoroughly investigated. This review, thus, summarizes the process of glycosylation in CSCs, variations in glycosylation patterns in various stem cells, aberrant glycosylation patterns in cancer, the role of glycosylation in tumor cell adhesion, cell-matrix interactions, and signaling, as well as cancer detection and treatment. The function of carbohydrates as prospective serum biomarkers, some clinically authorized biomarkers, and potential novel biomarkers relating to cancer disease diagnosis and prognosis are also discussed in the review.
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Affiliation(s)
- Rohit Pujari
- Department of Biochemistry, C.B.S.H., G. B. Pant University of Agriculture and Technology, Pantnagar 263145, Uttarakhand, India
| | - Shiv Kumar Dubey
- Department of Biochemistry, C.B.S.H., G. B. Pant University of Agriculture and Technology, Pantnagar 263145, Uttarakhand, India
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6
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Papanastasiou AD, Peroukidis S, Sirinian C, Arkoumani E, Chaniotis D, Zizi-Sermpetzoglou A. CD44 Expression in Clear Cell Renal Cell Carcinoma (ccRCC) Correlates with Tumor Grade and Patient Survival and Is Affected by Gene Methylation. Genes (Basel) 2024; 15:537. [PMID: 38790166 PMCID: PMC11121578 DOI: 10.3390/genes15050537] [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: 04/09/2024] [Revised: 04/19/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024] Open
Abstract
Clear cell RCC (ccRCC) represents the most common type of kidney cancer, with surgery being the only potential curative treatment. Almost one-third of ccRCC patients relapse either locally or as cases of distant metastases. Several biomarkers have been employed in order to separate ccRCC patients with better prognosis or to predict treatment outcomes, with limited results. CD44 is a membrane glycoprotein with multiple roles in normal development but also cancer. Recently, the CD44 standard isoform has been implicated in tumor progression and the metastasis cascade through microenvironment interactions. Here, through CD44 immunohistochemical staining of ccRCC patient samples and TCGA data analysis, we sought to elucidate the expression patterns (mRNA and protein) of CD44 in clear cell RCC and correlate its expression with clinicopathological parameters. We were able to show that CD44 expression presents a positive association with tumor grade and overall survival, predicting a worse patient outcome in ccRCC. In addition, our data indicate that the CD44 mRNA upregulation can be attributed to reduced gene methylation, implicating epigenetic gene regulation in ccRCC development and progression.
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Affiliation(s)
| | | | - Chaido Sirinian
- Molecular Oncology Laboratory, Division of Oncology, Department of Medicine, University of Patras, 26504 Patras, Greece
| | - Elisavet Arkoumani
- Pathology Department, Tzaneion General Hospital of Piraeus, 18536 Piraeus, Greece
| | - Dimitrios Chaniotis
- Department of Biomedical Sciences, University of West Attica, 12243 Athens, Greece
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Ziranu P, Pretta A, Aimola V, Cau F, Mariani S, D’Agata AP, Codipietro C, Rizzo D, Dell’Utri V, Sanna G, Moledda G, Cadoni A, Lai E, Puzzoni M, Pusceddu V, Castagnola M, Scartozzi M, Faa G. CD44: A New Prognostic Marker in Colorectal Cancer? Cancers (Basel) 2024; 16:1569. [PMID: 38672650 PMCID: PMC11048923 DOI: 10.3390/cancers16081569] [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: 01/18/2024] [Revised: 03/19/2024] [Accepted: 04/13/2024] [Indexed: 04/28/2024] Open
Abstract
Cluster of differentiation 44 (CD44) is a non-kinase cell surface glycoprotein. It is overexpressed in several cell types, including cancer stem cells (CSCs). Cells overexpressing CD44 exhibit several CSC traits, such as self-renewal, epithelial-mesenchymal transition (EMT) capability, and resistance to chemo- and radiotherapy. The role of CD44 in maintaining stemness and the CSC function in tumor progression is accomplished by binding to its main ligand, hyaluronan (HA). The HA-CD44 complex activates several signaling pathways that lead to cell proliferation, adhesion, migration, and invasion. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. The different functional roles of CD44s and specific CD44v isoforms still need to be fully understood. The clinicopathological impact of CD44 and its isoforms in promoting tumorigenesis suggests that CD44 could be a molecular target for cancer therapy. Furthermore, the recent association observed between CD44 and KRAS-dependent carcinomas and the potential correlations between CD44 and tumor mutational burden (TMB) and microsatellite instability (MSI) open new research scenarios for developing new strategies in cancer treatment. This review summarises current research regarding the different CD44 isoform structures, their roles, and functions in supporting tumorigenesis and discusses its therapeutic implications.
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Affiliation(s)
- Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Valentina Aimola
- Division of Pathology, Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy; (V.A.); (F.C.)
| | - Flaviana Cau
- Division of Pathology, Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy; (V.A.); (F.C.)
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Alessandra Pia D’Agata
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Claudia Codipietro
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Daiana Rizzo
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Veronica Dell’Utri
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Giorgia Sanna
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Giusy Moledda
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Andrea Cadoni
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Massimo Castagnola
- Proteomics Laboratory, Centro Europeo di Ricerca sul Cervello, IRCCS Fondazione Santa Lucia, 00013 Rome, Italy;
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Gavino Faa
- Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy;
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
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8
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Pronoy TUH, Islam F, Gopalan V, Lam AKY. Surface Markers for the Identification of Cancer Stem Cells. Methods Mol Biol 2024; 2777:51-69. [PMID: 38478335 DOI: 10.1007/978-1-0716-3730-2_4] [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] [Indexed: 03/26/2024]
Abstract
Cancer stem cells have genetic and functional characteristics which can turn them resistant to standard cancer therapeutic targets. Identification of these cells is challenging and is done mainly by detecting the expression of antigens specific to stem cells. Currently, there is a significant number of surface markers available which can detect cancer stem cells by directly targeting the specific antigens present in cells. These markers possess differential expression patterns and sub-localizations in cancer stem cells compared to nonneoplastic and somatic cells. In addition to these biomarkers, multiple analytical methods and techniques, including functional assays, cell sorting, filtration approaches, and xenotransplantation methods, are used to identify cancer stem cells. This chapter will overview the functional significance of cancer stem cells, their biological correlations, specific markers, and detection methods.
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Affiliation(s)
- Tasfik Ul Haque Pronoy
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
| | - Farhadul Islam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
| | - Vinod Gopalan
- Cancer Molecular Pathology, School of Medicine and Dentistry, Griffith University, Gold Coast, QLD, Australia
| | - Alfred King-Yin Lam
- Cancer Molecular Pathology, School of Medicine and Dentistry, Griffith University, Gold Coast, QLD, Australia.
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9
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Baro B, Kim CY, Lin C, Kongsomboonvech AK, Tetard M, Peterson NA, Salinas ND, Tolia NH, Egan ES. Plasmodium falciparum exploits CD44 as a coreceptor for erythrocyte invasion. Blood 2023; 142:2016-2028. [PMID: 37832027 PMCID: PMC10783654 DOI: 10.1182/blood.2023020831] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 09/08/2023] [Accepted: 09/30/2023] [Indexed: 10/15/2023] Open
Abstract
The malaria parasite Plasmodium falciparum invades and replicates asexually within human erythrocytes. CD44 expressed on erythrocytes was previously identified as an important host factor for P falciparum infection through a forward genetic screen, but little is known about its regulation or function in these cells, nor how it may be used by the parasite. We found that CD44 can be efficiently deleted from primary human hematopoietic stem cells using CRISPR/Cas9 genome editing, and that the efficiency of ex vivo erythropoiesis to enucleated cultured red blood cells (cRBCs) is not affected by lack of CD44. However, the rate of P falciparum invasion was reduced in CD44-null cRBCs relative to isogenic wild-type control cells, validating CD44 as an important host factor for this parasite. We identified 2 P falciparum invasion ligands as binding partners for CD44, erythrocyte binding antigen 175 (EBA-175) and EBA-140 and demonstrated that their ability to bind to human erythrocytes relies primarily on their canonical receptors, glycophorin A and glycophorin C, respectively. We further show that EBA-175 induces phosphorylation of erythrocyte cytoskeletal proteins in a CD44-dependent manner. Our findings support a model in which P falciparum exploits CD44 as a coreceptor during invasion of human erythrocytes, stimulating CD44-dependent phosphorylation of host cytoskeletal proteins that alter host cell deformability and facilitate parasite entry.
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Affiliation(s)
- Barbara Baro
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Chi Yong Kim
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Carrie Lin
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | | | - Marilou Tetard
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | | | - Nichole D. Salinas
- Host-Pathogen Interactions and Structural Vaccinology Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Niraj H. Tolia
- Host-Pathogen Interactions and Structural Vaccinology Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Elizabeth S. Egan
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA
- Chan Zuckerberg Biohub–San Francisco, San Francisco, CA
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10
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Yang SJ, Pai JA, Yao CJ, Huang CH, Chen JL, Wang CH, Chen KC, Shieh MJ. SN38-loaded nanomedicine mediates chemo-radiotherapy against CD44-expressing cancer growth. Cancer Nanotechnol 2023. [DOI: 10.1186/s12645-022-00151-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Abstract
Background
Chemo-radiotherapy is the combined chemotherapy and radiotherapy on tumor treatment to obtain the local radiosensitization and local cytotoxicity of the tumor and to control the microscopic metastatic disease.
Methods
In this study, 7-ethyl-10-hydroxycamptothecin (SN38) molecules could be successfully loaded into human serum albumin (HSA)–hyaluronic acid (HA) nanoparticles (SH/HA NPs) by the hydrophobic side groups of amino acid in HSA.
Results
HSA could be used to increase the biocompatibility and residence time of the nanoparticles in the blood, whereas HA could improve the benefits and overall treatment effect on CD44-expressing colorectal cancer (CRC), and reduce drug side effects. In addition to its role as a chemotherapeutic agent, SN38 could be used as a radiosensitizer, able to arrest the cell cycle, and allowing cells to stay in the G2/M stage, to improve the sensitivity of tumor cells to radiation. In vivo results demonstrated that SH/HA NPs could accumulate in the tumor and produce significant tumor suppression, with no adverse effects observed when combined with γ-ray irradiation. This SH/HA NPs-medicated chemo-radiotherapy could induce an anti-tumor immune response to inhibit the growth of distal tumors, and produce an abscopal effect.
Conclusions
Therefore, this SN38-loaded and HA-incorporated nanoparticle combined with radiotherapy may be a promising therapeutic artifice for CRC in the future.
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11
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Fnu G, Weber GF. Osteopontin induces mitochondrial biogenesis in deadherent cancer cells. Oncotarget 2023; 14:957-969. [PMID: 38039408 PMCID: PMC10691814 DOI: 10.18632/oncotarget.28540] [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: 08/10/2023] [Accepted: 11/16/2023] [Indexed: 12/03/2023] Open
Abstract
Metastasizing cells display a unique metabolism, which is very different from the Warburg effect that arises in primary tumors. Over short time frames, oxidative phosphorylation and ATP generation are prominent. Over longer time frames, mitochondrial biogenesis becomes a pronounced feature and aids metastatic success. It has not been known whether or how these two phenomena are connected. We hypothesized that Osteopontin splice variants, which synergize to increase ATP levels in deadherent cells, also increase the mitochondrial mass via the same signaling mechanisms. Here, we report that autocrine Osteopontin does indeed stimulate an increase in mitochondrial size, with the splice variant -c being more effective than the full-length form -a. Osteopontin-c achieves this via its receptor CD44v, jointly with the upregulation and co-ligation of the chloride-dependent cystine-glutamate transporter SLC7A11. The signaling proceeds through activation of the known mitochondrial biogenesis inducer PGC-1 (which acts as a transcription coactivator). Peroxide is an important intermediate in this cascade, but surprisingly acts upstream of PGC-1 and is likely produced as a consequence of SLC7A11 recruitment and activation. In vivo, suppression of the biogenesis-inducing mechanisms leads to a reduction in disseminated tumor mass. This study confirms a functional connection between the short-term oxidative metabolism and the longer-term mitochondrial biogenesis in cancer metastasis - both are induced by Osteopontin-c. The results imply possible mechanisms and targets for treating cancer metastasis.
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Affiliation(s)
- Gulimirerouzi Fnu
- University of Cincinnati Academic Health Center, James L. Winkle College of Pharmacy, Cincinnati, OH 45229, USA
| | - Georg F. Weber
- University of Cincinnati Academic Health Center, James L. Winkle College of Pharmacy, Cincinnati, OH 45229, USA
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12
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van Loon K, van Breest Smallenburg ME, Huijbers EJM, Griffioen AW, van Beijnum JR. Extracellular vimentin as a versatile immune suppressive protein in cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188985. [PMID: 37717859 DOI: 10.1016/j.bbcan.2023.188985] [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: 06/15/2023] [Revised: 08/24/2023] [Accepted: 08/29/2023] [Indexed: 09/19/2023]
Abstract
The interest in finding new targets in the tumor microenvironment for anti-cancer therapy has increased rapidly over the years. More specifically, the tumor-associated blood vessels are a promising target. We recently found that the intermediate filament protein vimentin is externalized by endothelial cells of the tumor vasculature. Extracellular vimentin was shown to sustain angiogenesis by mimicking VEGF and supporting cell migration, as well as endothelial cell anergy, the unresponsiveness of the endothelium to proinflammatory cytokines. The latter hampers immune cell infiltration and subsequently provides escape from tumor immunity. Other studies showed that extracellular vimentin plays a role in sustained systemic and local inflammation. Here we will review the reported roles of extracellular vimentin with a particular emphasis on its involvement in the interactions between immune cells and the endothelium in the tumor microenvironment. To this end, we discuss the different ways by which extracellular vimentin modulates the immune system. Moreover, we review how this protein can alter immune cell-vessel wall adhesion by altering the expression of adhesion proteins, attenuating immune cell infiltration into the tumor parenchyma. Finally, we discuss how vimentin-targeting therapy can reverse endothelial cell anergy and promote immune infiltration, supporting anti-tumor immunity.
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Affiliation(s)
- Karlijn van Loon
- Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Mathilda E van Breest Smallenburg
- Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Elisabeth J M Huijbers
- Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; CimCure BV, Amsterdam, the Netherlands
| | - Arjan W Griffioen
- Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; CimCure BV, Amsterdam, the Netherlands
| | - Judy R van Beijnum
- Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam University Medical Center, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; CimCure BV, Amsterdam, the Netherlands.
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13
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Babu AK, Raja MKMM, Zehravi M, Mohammad BD, Anees MI, Prasad C, Yahya BA, Sultana R, Sharma R, Singh J, Khan KA, Siddiqui FA, Khan SL, Emran TB. An overview of polymer surface coated synthetic quantum dots as therapeutics and sensors applications. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 184:1-12. [PMID: 37652186 DOI: 10.1016/j.pbiomolbio.2023.08.004] [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: 05/11/2023] [Revised: 08/01/2023] [Accepted: 08/27/2023] [Indexed: 09/01/2023]
Abstract
Quantum dots (QDs) are a class of remarkable materials that have garnered significant attention since their initial discovery. It is noteworthy to mention that it took approximately a decade for these materials to be successfully implemented in practical applications. While QDs have demonstrated notable optical properties, it is important to note that these attributes alone have not rendered them a feasible substitute for traditional organic dyes. Furthermore, it is worth noting that the substance under investigation exhibited inherent toxicity and instability in its initial state, primarily due to the presence of a heavy metal core. In the initial stages of research, it was observed that the integration of nanocomposites had a positive impact on the properties of QDs. The discovery of these nanocomposites was motivated by the remarkable properties exhibited by biocomposites found in nature. Recent discoveries have shed light on the potential utilization of QDs as a viable strategy for drug delivery, offering a promising avenue to enhance the efficacy of current pharmaceuticals and pave the way for the creation of innovative therapeutic approaches. The primary objective of this review was to elucidate the distinctive characteristics that render QDs highly suitable for utilization as nanocarriers. In this study, we will delve into the multifaceted applications of QDs as sensing nanoprobes and their utilization in diverse drug delivery systems. The focus of our investigation was directed toward the utilization of QD/polymer composites in sensing applications, with particular emphasis on their potential as chemical sensors, biosensors, and physical sensors.
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Affiliation(s)
- Ancha Kishore Babu
- Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, KPJ Healthcare University College, 71800, Nilai, Malaysia
| | - M K Mohan Maruga Raja
- Parul Institute of Pharmacy & Research, Parul University, Vadodara, Gujarat, 391110, India
| | - Mehrukh Zehravi
- Department of Clinical Pharmacy Girls Section, Prince Sattam Bin Abdul Aziz University, Al-Kharj, 11942, Saudi Arabia
| | - Badrud Duza Mohammad
- Department of Pharmaceutical Chemistry, G R T Institute of Pharmaceutical Education and Research, GRT Mahalakshmi Nagar, Tiruttani 631209, Tamil Nadu, India
| | - Mohammed Imran Anees
- Y. B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Aurangabad, Maharashtra, 431003, India
| | | | - Barrawaz Aateka Yahya
- Y. B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Aurangabad, Maharashtra, 431003, India
| | - Rokeya Sultana
- Yenepoya Pharmacy College and Research Centre, Yenepoya (Deemed to Be University), Deralakatte, 575022, Mangalore, India
| | - Rohit Sharma
- Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India.
| | - Jay Singh
- Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India
| | - Khalid Ali Khan
- Unit of Bee Research and Honey Production, Research Center for Advanced Materials Science (RCAMS), King Khalid University, P.O. Box 9004, Abha, 61413, Saudi Arabia; Applied College, King Khalid University, P. O. Box 9004, Abha, 61413, Saudi Arabia
| | - Falak A Siddiqui
- Department of Pharmaceutical Chemistry, N.B.S. Institute of Pharmacy, Ausa, 413520, Maharashtra, India; Department of Pharmaceutical Chemistry, School of Pharmacy, Anurag University, Hyderabad, India
| | - Sharuk L Khan
- Department of Pharmaceutical Chemistry, N.B.S. Institute of Pharmacy, Ausa, 413520, Maharashtra, India; Department of Pharmaceutical Chemistry, School of Pharmacy, Anurag University, Hyderabad, India.
| | - Talha Bin Emran
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School & Legorreta Cancer Center, Brown University, Providence, RI 02912, USA; Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, 1207, Bangladesh.
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14
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Liu B, Song A, Gui P, Wang J, Pan Y, Li C, Li S, Zhang Y, Jiang T, Xu Y, Pei D, Song J. Long noncoding RNA LINC01594 inhibits the CELF6-mediated splicing of oncogenic CD44 variants to promote colorectal cancer metastasis. Cell Death Dis 2023; 14:427. [PMID: 37452042 PMCID: PMC10349055 DOI: 10.1038/s41419-023-05924-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 06/16/2023] [Accepted: 06/23/2023] [Indexed: 07/18/2023]
Abstract
Long noncoding RNAs (lncRNAs) play critical roles in tumorigenesis and tumor metastasis. However, the underlying mechanisms of lncRNAs in colorectal cancer (CRC) need further exploration. By using data from The Cancer Genome Atlas (TCGA) and GEO databases, we identified a novel CRC-related lncRNA, LINC01594, that is significantly upregulated in CRC and associated with poor prognosis. In vitro and in vivo, gain- and loss-of-function experiments demonstrated that LINC01594 promotes metastasis in CRC. LINC01594 functions as a DNMT1 scaffold, increasing the level of CELF6 promoter methylation. LINC01594 also competitively binds the transcription factor p53, decreasing CELF6 expression. This inhibited the exon skipping of CD44 V4-V7 induced by CELF6. In summary, this study highlights a novel CRC biomarker and therapeutic target, LINC01594, and the findings suggest that the LINC01594-CELF6-CD44 axis might serve as a biomarker and therapeutic target in CRC.
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Affiliation(s)
- Bowen Liu
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University. No. 99, Huaihai West Road, Quanshan District, Xuzhou, 221006, China
- Institute of Digestive Diseases, Xuzhou Medical University. No. 84, Huaihai West Road, Quanshan District, Xuzhou, 221002, China
| | - Angxi Song
- Institute of Digestive Diseases, Xuzhou Medical University. No. 84, Huaihai West Road, Quanshan District, Xuzhou, 221002, China
| | - Pengkun Gui
- Institute of Digestive Diseases, Xuzhou Medical University. No. 84, Huaihai West Road, Quanshan District, Xuzhou, 221002, China
| | - Jin Wang
- Department of Pathology, Xuzhou Medical University. No. 209, Tongshan Road, Yunlong District, Xuzhou, 221004, China
| | - Yaojie Pan
- Department of Medical Oncology, Zhejiang Provincial People's Hospital. No. 158, Shangtang Road, Xiacheng District, Zhejiang, 310000, China
| | - Chao Li
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University. No. 99, Huaihai West Road, Quanshan District, Xuzhou, 221006, China
- Institute of Digestive Diseases, Xuzhou Medical University. No. 84, Huaihai West Road, Quanshan District, Xuzhou, 221002, China
| | - Shuai Li
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University. No. 99, Huaihai West Road, Quanshan District, Xuzhou, 221006, China
- Institute of Digestive Diseases, Xuzhou Medical University. No. 84, Huaihai West Road, Quanshan District, Xuzhou, 221002, China
| | - Yi Zhang
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University. No. 99, Huaihai West Road, Quanshan District, Xuzhou, 221006, China
- Institute of Digestive Diseases, Xuzhou Medical University. No. 84, Huaihai West Road, Quanshan District, Xuzhou, 221002, China
| | - Tao Jiang
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University. No. 99, Huaihai West Road, Quanshan District, Xuzhou, 221006, China
- Institute of Digestive Diseases, Xuzhou Medical University. No. 84, Huaihai West Road, Quanshan District, Xuzhou, 221002, China
| | - Yixin Xu
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University. No. 99, Huaihai West Road, Quanshan District, Xuzhou, 221006, China
- Institute of Digestive Diseases, Xuzhou Medical University. No. 84, Huaihai West Road, Quanshan District, Xuzhou, 221002, China
| | - Dongsheng Pei
- Department of Pathology, Xuzhou Medical University. No. 209, Tongshan Road, Yunlong District, Xuzhou, 221004, China.
| | - Jun Song
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University. No. 99, Huaihai West Road, Quanshan District, Xuzhou, 221006, China.
- Institute of Digestive Diseases, Xuzhou Medical University. No. 84, Huaihai West Road, Quanshan District, Xuzhou, 221002, China.
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15
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Suzuki H, Goto N, Tanaka T, Ouchida T, Kaneko MK, Kato Y. Development of a Novel Anti-CD44 Variant 8 Monoclonal Antibody C 44Mab-94 against Gastric Carcinomas. Antibodies (Basel) 2023; 12:45. [PMID: 37489367 PMCID: PMC10366929 DOI: 10.3390/antib12030045] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/28/2023] [Accepted: 07/03/2023] [Indexed: 07/26/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. GC with peritoneal metastasis exhibits a poor prognosis due to the lack of effective therapy. A comprehensive analysis of malignant ascites identified the genomic alterations and significant amplifications of cancer driver genes, including CD44. CD44 and its splicing variants are overexpressed in tumors, and play crucial roles in the acquisition of invasiveness, stemness, and resistance to treatments. Therefore, the development of CD44-targeted monoclonal antibodies (mAbs) is important for GC diagnosis and therapy. In this study, we immunized mice with CD44v3-10-overexpressed PANC-1 cells and established several dozens of clones that produce anti-CD44v3-10 mAbs. One of the clones (C44Mab-94; IgG1, kappa) recognized the variant-8-encoded region and peptide, indicating that C44Mab-94 is a specific mAb for CD44v8. Furthermore, C44Mab-94 could recognize CHO/CD44v3-10 cells, oral squamous cell carcinoma cell line (HSC-3), or GC cell lines (MKN45 and NUGC-4) in flow cytometric analyses. C44Mab-94 could detect the exogenous CD44v3-10 and endogenous CD44v8 in western blotting and stained the formalin-fixed paraffin-embedded gastric cancer cells. These results indicate that C44Mab-94 is useful for detecting CD44v8 in a variety of experimental methods and is expected to become usefully applied to GC diagnosis and therapy.
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Affiliation(s)
- Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Nohara Goto
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Tomohiro Tanaka
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Tsunenori Ouchida
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Mika K Kaneko
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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16
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Razi S, Haghparast A, Chodari Khameneh S, Ebrahimi Sadrabadi A, Aziziyan F, Bakhtiyari M, Nabi-Afjadi M, Tarhriz V, Jalili A, Zalpoor H. The role of tumor microenvironment on cancer stem cell fate in solid tumors. Cell Commun Signal 2023; 21:143. [PMID: 37328876 PMCID: PMC10273768 DOI: 10.1186/s12964-023-01129-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 04/15/2023] [Indexed: 06/18/2023] Open
Abstract
In the last few decades, the role of cancer stem cells in initiating tumors, metastasis, invasion, and resistance to therapies has been recognized as a potential target for tumor therapy. Understanding the mechanisms by which CSCs contribute to cancer progression can help to provide novel therapeutic approaches against solid tumors. In this line, the effects of mechanical forces on CSCs such as epithelial-mesenchymal transition, cellular plasticity, etc., the metabolism pathways of CSCs, players of the tumor microenvironment, and their influence on the regulating of CSCs can lead to cancer progression. This review focused on some of these mechanisms of CSCs, paving the way for a better understanding of their regulatory mechanisms and developing platforms for targeted therapies. While progress has been made in research, more studies will be required in the future to explore more aspects of how CSCs contribute to cancer progression. Video Abstract.
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Affiliation(s)
- Sara Razi
- Vira Pioneers of Modern Science (VIPOMS), Tehran, Iran
| | | | | | - Amin Ebrahimi Sadrabadi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACER, Tehran, Iran
- Cytotech and Bioinformatics Research Group, Tehran, Iran
| | - Fatemeh Aziziyan
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Maryam Bakhtiyari
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Vahideh Tarhriz
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, P.O. Box 5163639888, Tabriz, Iran.
| | - Arsalan Jalili
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACER, Tehran, Iran.
- Parvaz Research Ideas Supporter Institute, Tehran, Iran.
| | - Hamidreza Zalpoor
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran.
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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17
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Kudo Y, Suzuki H, Tanaka T, Kaneko MK, Kato Y. Development of a Novel Anti-CD44 Variant 5 Monoclonal Antibody C 44Mab-3 for Multiple Applications against Pancreatic Carcinomas. Antibodies (Basel) 2023; 12:antib12020031. [PMID: 37218897 DOI: 10.3390/antib12020031] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/24/2023] [Accepted: 04/10/2023] [Indexed: 05/24/2023] Open
Abstract
Pancreatic cancer exhibits a poor prognosis due to the lack of early diagnostic biomarkers and the resistance to conventional chemotherapy. CD44 has been known as a cancer stem cell marker and plays tumor promotion and drug resistance roles in various cancers. In particular, the splicing variants are overexpressed in many carcinomas and play essential roles in the cancer stemness, invasiveness or metastasis, and resistance to treatments. Therefore, the understanding of each CD44 variant's (CD44v) function and distribution in carcinomas is essential for the establishment of CD44-targeting tumor therapy. In this study, we immunized mice with CD44v3-10-overexpressed Chinese hamster ovary (CHO)-K1 cells and established various anti-CD44 monoclonal antibodies (mAbs). One of the established clones (C44Mab-3; IgG1, kappa) recognized peptides of the variant-5-encoded region, indicating that C44Mab-3 is a specific mAb for CD44v5. Moreover, C44Mab-3 reacted with CHO/CD44v3-10 cells or pancreatic cancer cell lines (PK-1 and PK-8) by flow cytometry. The apparent KD of C44Mab-3 for CHO/CD44v3-10 and PK-1 was 1.3 × 10-9 M and 2.6 × 10-9 M, respectively. C44Mab-3 could detect the exogenous CD44v3-10 and endogenous CD44v5 in Western blotting and stained the formalin-fixed paraffin-embedded pancreatic cancer cells but not normal pancreatic epithelial cells in immunohistochemistry. These results indicate that C44Mab-3 is useful for detecting CD44v5 in various applications and is expected to be useful for the application of pancreatic cancer diagnosis and therapy.
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Affiliation(s)
- Yuma Kudo
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
| | - Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
| | - Tomohiro Tanaka
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
| | - Mika K Kaneko
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
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18
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Baro-Sastre B, Kim CY, Lin C, Kongsomboonvech AK, Tetard M, Salinas ND, Tolia NH, Egan ES. Plasmodium falciparum exploits CD44 as a co-receptor for erythrocyte invasion. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.12.536503. [PMID: 37090581 PMCID: PMC10120705 DOI: 10.1101/2023.04.12.536503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
The malaria parasite Plasmodium falciparum invades and replicates asexually within human erythrocytes. CD44 expressed on erythrocytes was previously identified as an important host factor for P. falciparum infection through a forward genetic screen, but little is known about its regulation or function in these cells, nor how it may be utilized by the parasite. We found that CD44 can be efficiently deleted from primary human hematopoietic stem cells using CRISPR/Cas9 genome editing, and that the efficiency of ex-vivo erythropoiesis to enucleated cultured red blood cells (cRBCs) is not impacted by lack of CD44. However, the rate of P. falciparum invasion was substantially reduced in CD44-null cRBCs relative to isogenic wild-type (WT) control cells, validating CD44 as an important host factor for this parasite. We identified two P. falciparum invasion ligands as binding partners for CD44, Erythrocyte Binding Antigen-175 (EBA-175) and EBA-140, and demonstrated that their ability to bind to human erythrocytes relies primarily on their canonical receptors-glycophorin A and glycophorin C, respectively. We further show that EBA-175 induces phosphorylation of erythrocyte cytoskeletal proteins in a CD44-dependent manner. Our findings support a model where P. falciparum exploits CD44 as a co-receptor during invasion of human erythrocytes, stimulating CD44-dependent phosphorylation of host cytoskeletal proteins that alter host cell deformability and facilitate parasite entry.
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19
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Suzuki H, Ozawa K, Tanaka T, Kaneko MK, Kato Y. Development of a Novel Anti-CD44 Variant 7/8 Monoclonal Antibody, C44Mab-34, for Multiple Applications against Oral Carcinomas. Biomedicines 2023; 11:biomedicines11041099. [PMID: 37189717 DOI: 10.3390/biomedicines11041099] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/29/2023] [Accepted: 04/03/2023] [Indexed: 04/08/2023] Open
Abstract
Cluster of differentiation 44 (CD44) has been investigated as a cancer stem cell (CSC) marker as it plays critical roles in tumor malignant progression. The splicing variants are overexpressed in many carcinomas, especially squamous cell carcinomas, and play critical roles in the promotion of tumor metastasis, the acquisition of CSC properties, and resistance to treatments. Therefore, each CD44 variant (CD44v) function and distribution in carcinomas should be clarified for the establishment of novel tumor diagnosis and therapy. In this study, we immunized mouse with a CD44 variant (CD44v3–10) ectodomain and established various anti-CD44 monoclonal antibodies (mAbs). One of the established clones (C44Mab-34; IgG1, kappa) recognized a peptide that covers both variant 7- and variant 8-encoded regions, indicating that C44Mab-34 is a specific mAb for CD44v7/8. Moreover, C44Mab-34 reacted with CD44v3–10-overexpressed Chinese hamster ovary-K1 (CHO) cells or the oral squamous cell carcinoma (OSCC) cell line (HSC-3) by flow cytometry. The apparent KD of C44Mab-34 for CHO/CD44v3–10 and HSC-3 was 1.4 × 10−9 and 3.2 × 10−9 M, respectively. C44Mab-34 could detect CD44v3–10 in Western blotting and stained the formalin-fixed paraffin-embedded OSCC in immunohistochemistry. These results indicate that C44Mab-34 is useful for detecting CD44v7/8 in various applications and is expected to be useful in the application of OSCC diagnosis and therapy.
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Affiliation(s)
- Hiroyuki Suzuki
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
| | - Kazuki Ozawa
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
| | - Tomohiro Tanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
| | - Mika K. Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
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20
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Development of a Novel Anti-CD44 Variant 6 Monoclonal Antibody C 44Mab-9 for Multiple Applications against Colorectal Carcinomas. Int J Mol Sci 2023; 24:ijms24044007. [PMID: 36835416 PMCID: PMC9965047 DOI: 10.3390/ijms24044007] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/02/2023] [Accepted: 02/14/2023] [Indexed: 02/18/2023] Open
Abstract
CD44 is a cell surface glycoprotein, and its isoforms are produced by the alternative splicing with the standard and variant exons. The CD44 variant exon-containing isoforms (CD44v) are overexpressed in carcinomas. CD44v6 is one of the CD44v, and its overexpression predicts poor prognosis in colorectal cancer (CRC) patients. CD44v6 plays critical roles in CRC adhesion, proliferation, stemness, invasiveness, and chemoresistance. Therefore, CD44v6 is a promising target for cancer diagnosis and therapy for CRC. In this study, we established anti-CD44 monoclonal antibodies (mAbs) by immunizing mice with CD44v3-10-overexpressed Chinese hamster ovary (CHO)-K1 cells. We then characterized them using enzyme-linked immunosorbent assay, flow cytometry, western blotting, and immunohistochemistry. One of the established clones (C44Mab-9; IgG1, kappa) reacted with a peptide of the variant 6-encoded region, indicating that C44Mab-9 recognizes CD44v6. Furthermore, C44Mab-9 reacted with CHO/CD44v3-10 cells or CRC cell lines (COLO201 and COLO205) by flow cytometry. The apparent dissociation constant (KD) of C44Mab-9 for CHO/CD44v3-10, COLO201, and COLO205 was 8.1 × 10-9 M, 1.7 × 10-8 M, and 2.3 × 10-8 M, respectively. C44Mab-9 detected the CD44v3-10 in western blotting, and partially stained the formalin-fixed paraffin-embedded CRC tissues in immunohistochemistry. Collectively, C44Mab-9 is useful for detecting CD44v6 in various applications.
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21
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Zhang H, Cao H, Luo H, Zhang N, Wang Z, Dai Z, Wu W, Liu G, Xie Z, Cheng Q, Cheng Y. RUNX1/CD44 axis regulates the proliferation, migration, and immunotherapy of gliomas: A single-cell sequencing analysis. Front Immunol 2023; 14:1086280. [PMID: 36776876 PMCID: PMC9909339 DOI: 10.3389/fimmu.2023.1086280] [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: 11/01/2022] [Accepted: 01/10/2023] [Indexed: 01/27/2023] Open
Abstract
Background Glioma is one of the most common, primary, and lethal adult brain tumors because of its extreme aggressiveness and poor prognosis. Several recent studies relevant to the immune function of CD44, a transmembrane glycoprotein as a significant hyaluronic acid receptor, have achieved great success, revealing the critical role of CD44 in immune infiltration in gliomas. The overexpression of CD44 has been verified to correlate with cancer aggressiveness and migration, while the clinical and immune features of CD44 expression have not yet been thoroughly characterized in gliomas. Methods Molecular and clinical data of glioma collected from publicly available genomic databases were analyzed. Results CD44 was up-expressed in malignant gliomas, notably in the 1p/19q non-codeletion cases, isocitrate dehydrogenase (IDH) wild-type, and mesenchymal subtypes in GBM samples. CD44 expression level strongly correlates with stromal and immune cells, mainly infiltrating the glioma microenvironment by single-cell sequencing analysis. Meanwhile, CD44 can be a promising biomarker in predicting immunotherapy responses and mediating the expression of PD-L1. Finally, RUNX1/CD44 axis could promote the proliferation and migration of gliomas. Conclusions Therefore, CD44 was responsible for glioma growth and progression. It could potentially lead to a novel target for glioma immunotherapy or a prognostic biomarker.
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Affiliation(s)
- Hao Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Hui Cao
- Department of Psychiatry, Brain Hospital of Hunan Province, The Second People's Hospital of Hunan Province, Changsha, China.,The School of Clinical Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Hong Luo
- Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Nan Zhang
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Zeyu Wang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Ziyu Dai
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Wantao Wu
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Guodong Liu
- Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Zongyi Xie
- Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yuan Cheng
- Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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22
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Schorr C, Perna F. Targets for chimeric antigen receptor T-cell therapy of acute myeloid leukemia. Front Immunol 2022; 13:1085978. [PMID: 36605213 PMCID: PMC9809466 DOI: 10.3389/fimmu.2022.1085978] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 11/30/2022] [Indexed: 12/24/2022] Open
Abstract
Acute Myeloid Leukemia (AML) is an aggressive myeloid malignancy associated with high mortality rates (less than 30% 5-year survival). Despite advances in our understanding of the molecular mechanisms underpinning leukemogenesis, standard-of-care therapeutic approaches have not changed over the last couple of decades. Chimeric Antigen Receptor (CAR) T-cell therapy targeting CD19 has shown remarkable clinical outcomes for patients with acute lymphoblastic leukemia (ALL) and is now an FDA-approved therapy. Targeting of myeloid malignancies that are CD19-negative with this promising technology remains challenging largely due to lack of alternate target antigens, complex clonal heterogeneity, and the increased recognition of an immunosuppressive bone marrow. We carefully reviewed a comprehensive list of AML targets currently being used in both proof-of-concept pre-clinical and experimental clinical settings. We analyzed the expression profile of these molecules in leukemic as well normal tissues using reliable protein databases and data reported in the literature and we provide an updated overview of the current clinical trials with CAR T-cells in AML. Our study represents a state-of-art review of the field and serves as a potential guide for selecting known AML-associated targets for adoptive cellular therapies.
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Affiliation(s)
- Christopher Schorr
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States,Department of Biomedical Engineering, Purdue University Weldon School of Biomedical Engineering, West Lafayette, IN, United States
| | - Fabiana Perna
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States,*Correspondence: Fabiana Perna,
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23
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Guo Q, Yang C, Gao F. The state of CD44 activation in cancer progression and therapeutic targeting. FEBS J 2022; 289:7970-7986. [PMID: 34478583 DOI: 10.1111/febs.16179] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 07/20/2021] [Accepted: 09/02/2021] [Indexed: 01/14/2023]
Abstract
CD44, a non-kinase transmembrane glycoprotein, is ubiquitously expressed on various types of cells, especially cancer stem cells (CSCs), and has been implicated in cancer onset and aggressiveness. The major ligand for the CD44, hyaluronan (HA), binds to and interacts with CD44, which in turn triggers downstream signaling cascades, thereby promoting cellular behaviors such as proliferation, motility, invasiveness and chemoresistance. The CD44-HA interaction is cell-specific and strongly affected by the state of CD44 activation. Therefore, the binding of HA to CD44 is essential for the activation of CD44 during which the detailed regulatory mechanism needs to be clarified. Different CD44 activation states distribute in human carcinoma and normal tissue; however, whether CD44 activation is a critical requirement for tumor initiation, progression and notorious CSC properties remains to be clarified. A deeper understanding of the regulation of CD44 activation may facilitate the development of novel targeted drugs in the future. Here, we review the current findings concerning the states of CD44 activation on the cell surface, the underlying regulatory mechanisms of CD44 activation, the known role for CD44 activation in tumor progression and CSC hallmarks, as well as the potential of HA-coated nanoparticle for targeting activated CD44 for cancer therapy.
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Affiliation(s)
- Qian Guo
- Department of Molecular Biology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Cuixia Yang
- Department of Molecular Biology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.,Department of Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Feng Gao
- Department of Molecular Biology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.,Department of Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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24
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Gao S, Wu X, Lou X, Cui W. Identification of a prognostic risk-scoring model and risk signatures based on glycosylation-associated cluster in breast cancer. Front Genet 2022; 13:960567. [PMID: 36338982 PMCID: PMC9630632 DOI: 10.3389/fgene.2022.960567] [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: 06/03/2022] [Accepted: 08/24/2022] [Indexed: 11/24/2022] Open
Abstract
Breast cancer is a heterogeneous disease whose subtypes represent different histological origins, prognoses, and therapeutic sensitivity. But there remains a strong need for more specific biomarkers and broader alternatives for personalized treatment. Our study classified breast cancer samples from The Cancer Genome Atlas (TCGA) into three groups based on glycosylation-associated genes and then identified differentially expressed genes under different glycosylation patterns to construct a prognostic model. The final prognostic model containing 23 key molecules achieved exciting performance both in the TCGA training set and testing set GSE42568 and GSE58812. The risk score also showed a significant difference in predicting overall clinical survival and immune infiltration analysis. This work helped us to understand the heterogeneity of breast cancer from another perspective and indicated that the identification of risk scores based on glycosylation patterns has potential clinical implications and immune-related value for breast cancer.
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Affiliation(s)
- Shengnan Gao
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/ State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinjie Wu
- Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
- Department of Orthopedic Surgery, China-Japan Friendship Hospital, Beijing, China
- Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Xiaoying Lou
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/ State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Cui
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/ State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Wei Cui,
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25
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Hyaluronic Acid-Based Nanomaterials Applied to Cancer: Where Are We Now? Pharmaceutics 2022; 14:pharmaceutics14102092. [PMID: 36297526 PMCID: PMC9609123 DOI: 10.3390/pharmaceutics14102092] [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: 08/25/2022] [Revised: 09/23/2022] [Accepted: 09/26/2022] [Indexed: 11/05/2022] Open
Abstract
Cancer cells normally develop the ability to rewire or reprogram themselves to become resistant to treatments that were previously effective. Despite progress in understanding drug resistance, knowledge gaps remain regarding the underlying biological causes of drug resistance and the design of cancer treatments to overcome it. So, resistance acquisition remains a major problem in cancer treatment. Targeted therapeutics are considered the next generation of cancer therapy because they overcome many limitations of traditional treatments. Numerous tumor cells overexpress several receptors that have a high binding affinity for hyaluronic acid (HA), while they are poorly expressed in normal body cells. HA and its derivatives have the advantage of being biocompatible and biodegradable and may be conjugated with a variety of drugs and drug carriers for developing various formulations as anticancer therapies such as micelles, nanogels, and inorganic nanoparticles. Due to their stability in blood circulation and predictable delivery patterns, enhanced tumor-selective drug accumulation, and decreased toxicity to normal tissues, tumor-targeting nanomaterial-based drug delivery systems have been shown to represent an efficacious approach for the treatment of cancer. In this review, we aim to provide an overview of some in vitro and in vivo studies related to the potential of HA as a ligand to develop targeted nanovehicles for future biomedical applications in cancer treatment.
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26
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Antoszczak M, Müller S, Cañeque T, Colombeau L, Dusetti N, Santofimia-Castaño P, Gaillet C, Puisieux A, Iovanna JL, Rodriguez R. Iron-Sensitive Prodrugs That Trigger Active Ferroptosis in Drug-Tolerant Pancreatic Cancer Cells. J Am Chem Soc 2022; 144:11536-11545. [PMID: 35696539 DOI: 10.1021/jacs.2c03973] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Persister cancer cells represent rare populations of cells resistant to therapy. Cancer cells can exploit epithelial-mesenchymal plasticity to adopt a drug-tolerant state that does not depend on genetic alterations. Small molecules that can interfere with cell plasticity or kill cells in a cell state-dependent manner are highly sought after. Salinomycin has been shown to kill cancer cells in the mesenchymal state by sequestering iron in lysosomes, taking advantage of the iron addiction of this cell state. Here, we report the chemo- and stereoselective synthesis of a series of structurally complex small molecule chimeras of salinomycin derivatives and the iron-reactive dihydroartemisinin. We show that these chimeras accumulate in lysosomes and can react with iron to release bioactive species, thereby inducing ferroptosis in drug-tolerant pancreatic cancer cells and biopsy-derived organoids of pancreatic ductal adenocarcinoma. This work paves the way toward the development of new cancer medicines acting through active ferroptosis.
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Affiliation(s)
- Michał Antoszczak
- Department of Chemical Biology, Institut Curie, CNRS UMR 3666, INSERM U1143, PSL Université, 26 rue d'Ulm, 75005 Paris, France
| | - Sebastian Müller
- Department of Chemical Biology, Institut Curie, CNRS UMR 3666, INSERM U1143, PSL Université, 26 rue d'Ulm, 75005 Paris, France
| | - Tatiana Cañeque
- Department of Chemical Biology, Institut Curie, CNRS UMR 3666, INSERM U1143, PSL Université, 26 rue d'Ulm, 75005 Paris, France
| | - Ludovic Colombeau
- Department of Chemical Biology, Institut Curie, CNRS UMR 3666, INSERM U1143, PSL Université, 26 rue d'Ulm, 75005 Paris, France
| | - Nelson Dusetti
- CRCM, CNRS UMR 7258, INSERM U1068, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288 Marseille, France
| | - Patricia Santofimia-Castaño
- CRCM, CNRS UMR 7258, INSERM U1068, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288 Marseille, France
| | - Christine Gaillet
- Department of Chemical Biology, Institut Curie, CNRS UMR 3666, INSERM U1143, PSL Université, 26 rue d'Ulm, 75005 Paris, France
| | - Alain Puisieux
- Department of Chemical Biology, Institut Curie, CNRS UMR 3666, INSERM U1143, PSL Université, 26 rue d'Ulm, 75005 Paris, France
| | - Juan Lucio Iovanna
- CRCM, CNRS UMR 7258, INSERM U1068, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288 Marseille, France
| | - Raphaël Rodriguez
- Department of Chemical Biology, Institut Curie, CNRS UMR 3666, INSERM U1143, PSL Université, 26 rue d'Ulm, 75005 Paris, France
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27
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Li Y, Zhao W, Wang Y, Wang H, Liu S. Extracellular vesicle-mediated crosstalk between pancreatic cancer and stromal cells in the tumor microenvironment. J Nanobiotechnology 2022; 20:208. [PMID: 35501802 PMCID: PMC9063273 DOI: 10.1186/s12951-022-01382-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 03/17/2022] [Indexed: 01/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) interacts closely with the tumor microenvironment (TME). The TME is remodeled by crosstalk between pancreatic cancer cells and stromal cells, and is critical for cancer progression. Extracellular vesicles (EVs), including exosomes and microvesicles, help facilitate an exchange of information both within the TME and to distant organs. EVs have also been identified as potential diagnostic biomarkers, therapeutic targets, and drug carriers for pancreatic cancer treatment. Thus, understanding the selective packaging of EVs cargo and its mechanistic impact will increase our understanding of cancer biology. In this review, we collect and analyze recent findings of the pancreatic cancer-stromal cell interactions mediated by EVs and the mechanisms involved in cancer-related immunity and chemoresistance. These studies demonstrate the vital role of EVs in pancreatic cancer reprogramming and TME remodeling. We also summarize the EVs identified as potential PDAC diagnostic biomarkers and possible therapeutic targets. This greater understanding is a promising avenue for transitioning EVs from bench to bedside.
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Affiliation(s)
- Ying Li
- Department of Blood Transfusion, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenjing Zhao
- Central Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Yanli Wang
- Department of Operating Room, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Haiyan Wang
- Department of Blood Transfusion, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shanglong Liu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
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28
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Store-Operated Calcium Entry and Its Implications in Cancer Stem Cells. Cells 2022; 11:cells11081332. [PMID: 35456011 PMCID: PMC9032688 DOI: 10.3390/cells11081332] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/04/2022] [Accepted: 04/12/2022] [Indexed: 12/25/2022] Open
Abstract
Tumors are composed by a heterogeneous population of cells. Among them, a sub-population of cells, termed cancer stem cells, exhibit stemness features, such as self-renewal capabilities, disposition to differentiate to a more proliferative state, and chemotherapy resistance, processes that are all mediated by Ca2+. Ca2+ homeostasis is vital for several physiological processes, and alterations in the patterns of expressions of the proteins and molecules that modulate it have recently become a cancer hallmark. Store-operated Ca2+ entry is a major mechanism for Ca2+ entry from the extracellular medium in non-excitable cells that leads to increases in the cytosolic Ca2+ concentration required for several processes, including cancer stem cell properties. Here, we focus on the participation of STIM, Orai, and TRPC proteins, the store-operated Ca2+ entry key components, in cancer stem cell biology and tumorigenesis.
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29
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Furumoto H, Kato T, Wakiyama H, Furusawa A, Choyke PL, Kobayashi H. Endoscopic Applications of Near-Infrared Photoimmunotherapy (NIR-PIT) in Cancers of the Digestive and Respiratory Tracts. Biomedicines 2022; 10:846. [PMID: 35453596 PMCID: PMC9027987 DOI: 10.3390/biomedicines10040846] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 12/11/2022] Open
Abstract
Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed and promising therapy that specifically destroys target cells by irradiating antibody-photo-absorber conjugates (APCs) with NIR light. APCs bind to target molecules on the cell surface, and when exposed to NIR light, cause disruption of the cell membrane due to the ligand release reaction and dye aggregation. This leads to rapid cell swelling, blebbing, and rupture, which leads to immunogenic cell death (ICD). ICD activates host antitumor immunity, which assists in killing still viable cancer cells in the treated lesion but is also capable of producing responses in untreated lesions. In September 2020, an APC and laser system were conditionally approved for clinical use in unresectable advanced head and neck cancer in Japan, and are now routine in appropriate patients. However, most tumors have been relatively accessible in the oral cavity or neck. Endoscopes offer the opportunity to deliver light deeper within hollow organs of the body. In recent years, the application of endoscopic therapy as an alternative to surgery for the treatment of cancer has expanded, providing significant benefits to inoperable patients. In this review, we will discuss the potential applications of endoscopic NIR-PIT, especially in thoracic and gastrointestinal cancers.
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Affiliation(s)
| | | | | | | | | | - Hisataka Kobayashi
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; (H.F.); (T.K.); (H.W.); (A.F.); (P.L.C.)
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30
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Qiu S, Iimori M, Edahiro K, Fujimoto Y, Matsuoka K, Oki E, Maehara Y, Mori M, Kitao H. A CD44 variant is essential for Slug-dependent vimentin gene expression to acquire TGF-β1-induced tumor cell motility. Cancer Sci 2022; 113:2654-2667. [PMID: 35363934 PMCID: PMC9357650 DOI: 10.1111/cas.15353] [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: 11/14/2021] [Revised: 03/02/2022] [Accepted: 03/07/2022] [Indexed: 11/28/2022] Open
Abstract
CD44 is a widely expressed polymorphic adhesion molecule that has pleiotropic functions in development and tumor progression. Its mRNA undergoes alternative splicing to generate multiple variant (CD44v) isoforms, although the function of each CD44v isoform is not fully elucidated. Here, we show that CD44v plays an important role in the induction of vimentin expression upon transforming growth factor‐β1 (TGF‐β1)‐induced epithelial–mesenchymal transition (EMT). Among multiple CD44v isoforms expressed in NUGC3 gastric cancer cells, CD44v8‐10 and CD44v3,8‐10 are involved in the acquisition of migratory and invasive properties associated with TGF‐β1‐induced EMT, and only CD44v3,8‐10 induces the transcription of vimentin mediated by the EMT transcription factor Slug. In primary tumor specimens obtained from patients with gastric cancer, CD44‐containing variant exon 9 (CD44v9) expression and EMT features [E‐cadherin(−)vimentin(+)] were significantly correlated, and EMT features in the cells expressing CD44v9 were associated with tumor invasion depth, lymph node metastasis, and pStage, which indicate invasive and metastatic properties, and poor prognosis. These results indicate that certain CD44v isoforms promote tumor cell motility and metastasis in gastric cancer in association with EMT features, and CD44v3,8‐10 may contribute to these clinical characteristics.
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Affiliation(s)
- Shichao Qiu
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Makoto Iimori
- Department of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Keitaro Edahiro
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshiaki Fujimoto
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiko Maehara
- Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan
| | - Masaki Mori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Graduate School of Medicine, Tokai University School of Medicine, Kanagawa, Japan
| | - Hiroyuki Kitao
- Department of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
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Trouvilliez S, Cicero J, Lévêque R, Aubert L, Corbet C, Van Outryve A, Streule K, Angrand PO, Völkel P, Magnez R, Brysbaert G, Mysiorek C, Gosselet F, Bourette R, Adriaenssens E, Thuru X, Lagadec C, de Ruyck J, Orian-Rousseau V, Le Bourhis X, Toillon RA. Direct interaction of TrkA/CD44v3 is essential for NGF-promoted aggressiveness of breast cancer cells. J Exp Clin Cancer Res 2022; 41:110. [PMID: 35346305 PMCID: PMC8962522 DOI: 10.1186/s13046-022-02314-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 03/03/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND CD44 is a multifunctional membrane glycoprotein. Through its heparan sulfate chain, CD44 presents growth factors to their receptors. We have shown that CD44 and Tropomyosin kinase A (TrkA) form a complex following nerve growth factor (NGF) induction. Our study aimed to understand how CD44 and TrkA interact and the consequences of inhibiting this interaction regarding the pro-tumoral effect of NGF in breast cancer. METHODS After determining which CD44 isoforms (variants) are involved in forming the TrkA/CD44 complex using proximity ligation assays, we investigated the molecular determinants of this interaction. By molecular modeling, we isolated the amino acids involved and confirmed their involvement using mutations. A CD44v3 mimetic peptide was then synthesized to block the TrkA/CD44v3 interaction. The effects of this peptide on the growth, migration and invasion of xenografted triple-negative breast cancer cells were assessed. Finally, we investigated the correlations between the expression of the TrkA/CD44v3 complex in tumors and histo-pronostic parameters. RESULTS We demonstrated that isoform v3 (CD44v3), but not v6, binds to TrkA in response to NGF stimulation. The final 10 amino acids of exon v3 and the TrkA H112 residue are necessary for the association of CD44v3 with TrkA. Functionally, the CD44v3 mimetic peptide impairs not only NGF-induced RhoA activation, clonogenicity, and migration/invasion of breast cancer cells in vitro but also tumor growth and metastasis in a xenograft mouse model. We also detected TrkA/CD44v3 only in cancerous cells, not in normal adjacent tissues. CONCLUSION Collectively, our results suggest that blocking the CD44v3/TrkA interaction can be a new therapeutic option for triple-negative breast cancers.
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Affiliation(s)
- Sarah Trouvilliez
- University Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France
| | - Julien Cicero
- University Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France
- University Artois, UR 2465, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), F-62300, Lens, France
| | - Romain Lévêque
- University Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France
| | - Léo Aubert
- University Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France
| | - Cyril Corbet
- University Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France
| | - Alexandre Van Outryve
- University Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France
| | - Karolin Streule
- Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, 76344, Eggenstein-Leopoldshafen, Germany
| | - Pierre-Olivier Angrand
- University Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France
| | - Pamela Völkel
- University Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France
| | - Romain Magnez
- University Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France
| | - Guillaume Brysbaert
- University Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000, Lille, France
| | - Caroline Mysiorek
- University Artois, UR 2465, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), F-62300, Lens, France
| | - Fabien Gosselet
- University Artois, UR 2465, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), F-62300, Lens, France
| | - Roland Bourette
- University Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France
| | - Eric Adriaenssens
- University Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France
| | - Xavier Thuru
- University Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France
| | - Chann Lagadec
- University Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France
| | - Jérôme de Ruyck
- University Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000, Lille, France
| | - Véronique Orian-Rousseau
- Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, 76344, Eggenstein-Leopoldshafen, Germany
| | - Xuefen Le Bourhis
- University Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France
| | - Robert-Alain Toillon
- University Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France.
- Université de Lille, Faculté des Sciences et Technologies, UMR CNRS 9020- INSERM U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Bâtiment SN3, 3ème étage, Cité scientifique, 59655, Villeneuve d'Ascq, France.
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CD44 Variant Exon 6 Isoform Expression as a Potential Predictor of Lymph Node Metastasis in Invasive Breast Carcinoma of No Special Type. Int J Breast Cancer 2021; 2021:1586367. [PMID: 34925920 PMCID: PMC8683235 DOI: 10.1155/2021/1586367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 11/19/2021] [Accepted: 11/25/2021] [Indexed: 12/12/2022] Open
Abstract
Background Invasive breast carcinoma of no special type (IBC-NST) is the most widespread invasive carcinoma subtype causing primarily regional metastases of the lymphatic node (LNM). The capacity of CD44 variant exon 6 (CD44v6) expression as an LNM predictor biomarker in IBC-NST was explored. Methods We conducted a cross-sectional research with 48 paraffin blocks containing IBC-NST primary tumors that were divided into two groups by LNM. The assessment has been carried out in terms of age, tumor size, tumor grade, lymphovascular invasion (LVI), and CD44v6 expression. The expression of CD44v6 was analyzed on the grounds of immunohistochemical (IHC) staining, while other data were taken from archives. Statistical analysis is carried out by univariate, multivariate, and AUROC. Results CD44v6 exhibits a dominant expression in IBC-NST tumor cells. Univariate analysis revealed a significant association between CD44v6 and LNM status (p = 0.001). Multiple logistic regression results showed that CD44v6 expression and LVI were significantly associated with LNM with OR 10.7 (95% CI: 2.43 to 47.08) and 6.22 (95% CI: 1.4 to 27.88), respectively. CD44v6 expression was able to discriminate against LNM with AUROC 0.863 ± 0.053 (95% CI: 0.759 to 0.967) at the H-score cut-off 133.889 (75% sensitivity and 83.3% specificity). Conclusion CD44v6 expression and LVI are potential predictors of LNM in IBC-NST. The H-score cut-off of the CD44v6 expression can also be used as a threshold for classification in further investigation.
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Soliman F, Ye L, Jiang W, Hargest R. Targeting Hyaluronic Acid and Peritoneal Dissemination in Colorectal Cancer. Clin Colorectal Cancer 2021; 21:e126-e134. [PMID: 34955378 DOI: 10.1016/j.clcc.2021.11.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 10/30/2021] [Accepted: 11/22/2021] [Indexed: 11/03/2022]
Abstract
Peritoneal metastasis (PM) from colorectal cancer (CRC) carries a significant mortality rate for patients and treatment is challenging. The development of PM is a multistep process involving detachment, adhesion, invasion and colonization of the peritoneal cavity. Cytoreductive surgery and HIPEC (hyperthermic intraperitoneal chemotherapy) for PM from CRC has some benefit but overall survival is poor and recurrence rates are high. Treatments to prevent the development of peritoneal metastasis could have the potential to improve CRC survival and disease-free outcomes. The ability of cancer cells to invade the peritoneum and become established as metastatic tumors is influenced by a multifactorial process. Hyaluronic acid (HA) has been shown to coat the mesothelial cells of the peritoneum and has been demonstrated to be utilized in various malignancies as part of the metastatic process in peritoneal dissemination. CD44, RHAMM (CD168) and ICAM-1 have all been shown to be binding partners for HA. Targeting HA-mediated binding may prevent adhesion to distant sites within the peritoneum through suppression of interaction of these molecules. Here we review the current literature and discuss key molecules involved with PM dissemination, with the potential to target these mechanisms in the delivery of future treatments.
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Affiliation(s)
- Faris Soliman
- Cardiff China Medical Research Collaborative, Division of Cancer and Genetics, School of Medicine, Cardiff University; Cardiff and Vale University Health Board.
| | - Lin Ye
- Cardiff China Medical Research Collaborative, Division of Cancer and Genetics, School of Medicine, Cardiff University
| | - Wenguo Jiang
- Cardiff China Medical Research Collaborative, Division of Cancer and Genetics, School of Medicine, Cardiff University
| | - Rachel Hargest
- Cardiff China Medical Research Collaborative, Division of Cancer and Genetics, School of Medicine, Cardiff University; Cardiff and Vale University Health Board
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34
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Takei J, Asano T, Suzuki H, Kaneko MK, Kato Y. Epitope Mapping of the Anti-CD44 Monoclonal Antibody (C 44Mab-46) Using Alanine-Scanning Mutagenesis and Surface Plasmon Resonance. Monoclon Antib Immunodiagn Immunother 2021; 40:219-226. [PMID: 34678095 DOI: 10.1089/mab.2021.0028] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
CD44 is a type I transmembrane protein expressed in various kinds of normal cancer cells, including pancreatic, breast, and oral cancers. CD44 is associated with cancer progression, metastases, and treatment resistance. CD44 consists of 20 exons, and various isoforms exist due to alternative splicing of the central 10 exons. Some splicing variants show cancer-specific expression patterns and are related to prognosis of patients with cancer. Therefore, CD44 targeting therapy has been attracting attention. In a previous study, we established an anti-CD44 monoclonal antibody, C44Mab-46 (IgG1, kappa), useful for flow cytometry, Western blotting, and immunohistochemistry by immunizing mice with CD44v3-10 ectodomain. This study investigated the binding epitope of C44Mab-46 using enzyme-linked immunosorbent assay (ELISA) and the surface plasmon resonance (SPR) with the synthesized peptide. ELISA results using deletion mutants showed that C44Mab-46 reacted with the amino acids (aa) of 161-180 aa of CD44. Further examination of the C44Mab-46 epitope using ELISA with point mutants in 161-180 aa of CD44 demonstrates that the C44Mab-46 epitope comprised Thr174, Asp177, and Val178. The SPR with point mutants in 161-180 aa of CD44 demonstrated that the C44Mab-46 epitope comprises Thr174, Asp175, Asp176, Asp177, and Val178. Together, the C44Mab-46 epitope was determined to be located in exon 5 of CD44.
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Affiliation(s)
- Junko Takei
- Department of Antibody Drug Development, and Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Teizo Asano
- Department of Antibody Drug Development, and Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mika K Kaneko
- Department of Antibody Drug Development, and Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yukinari Kato
- Department of Antibody Drug Development, and Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
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35
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Chaudhry GES, Akim A, Naveed Zafar M, Safdar N, Sung YY, Muhammad TST. Understanding Hyaluronan Receptor (CD44) Interaction, HA-CD44 Activated Potential Targets in Cancer Therapeutics. Adv Pharm Bull 2021; 11:426-438. [PMID: 34513617 PMCID: PMC8421618 DOI: 10.34172/apb.2021.050] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 07/14/2020] [Accepted: 07/15/2020] [Indexed: 12/11/2022] Open
Abstract
Cancer is a complex mechanism involving a series of cellular events. The glycoproteins such as hyaluronan (HA) are a significant element of extracellular matrix (ECM), involve in the onset of cancer developmental process. The pivotal roles of HA in cancer progression depend on dysregulated expression in various cancer. HA, also gain attention due to consideration as a primary ligand of CD44 receptor. The CD44, complex transmembrane receptor protein, due to alternative splicing in the transcription process, various CD44 isoforms predominantly exist. The overexpression of distinct CD44 isoforms (CD44v) standard (CD44s) depends on the tumour type and stage. The receptor proteins, CD44 engage in a variety of biological processes, including cell growth, apoptosis, migration, and angiogenesis. HA-CD44 interaction trigger survival pathways that result in cell proliferation, invasion ultimately complex metastasis. The interaction and binding of ligand-receptor HA-CD44 regulate the downstream cytoskeleton pathways involve in cell survival or cell death. Thus, targeting HA, CD44 (variant and standard) isoform, and HA-CD44 binding consider as an attractive and useful approach towards cancer therapeutics. The use of various inhibitors of HA, hyaluronidases (HYALs), and utilizing targeted Nano-delivery of anticancer agents and antibodies against CD44, peptides gives promising results in vitro and in vivo. However, they are in clinical trials with favourable and unfavourable outcomes, which reflects the need for various modifications in targeting agents and a better understanding of potential targets in tumour progression pathways.
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Affiliation(s)
- Gul-E-Saba Chaudhry
- Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030 Kuala Terengganu, Malaysia
| | - Abdah Akim
- Department of Biomedical Sciences, Universiti Putra Malaysia, Seri Kembangan, Selangor, Malaysia
| | | | - Naila Safdar
- Department of Environmental Sciences, Fatima Jinnah University, Rawalpindi, Pakistan
| | - Yeong Yik Sung
- Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030 Kuala Terengganu, Malaysia
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Asano T, Kaneko MK, Kato Y. Development of a Novel Epitope Mapping System: RIEDL Insertion for Epitope Mapping Method. Monoclon Antib Immunodiagn Immunother 2021; 40:162-167. [PMID: 34424761 DOI: 10.1089/mab.2021.0023] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
To clarify the binding region of monoclonal antibodies (mAbs) to target molecules, it is very essential to understand the pharmacological function of each mAb. Although deletion mutants and point mutants are usefully utilized for epitope mapping, we often experience the difficulty of determining the mAb epitope against membrane proteins. We aimed to develop a novel method to determine the binding region of mAbs using epitope tag system. We first checked the reactivity of an anti-CD44 mAb (C44Mab-5) to several deletion mutants of CD44. We then employed the RIEDL tag system ("RIEDL" peptide and LpMab-7 mAb). We inserted the "RIEDL" peptide into the CD44 protein from the 21st to 41st amino acid (AA). The transfectants produced were stained by LpMab-7 and C44Mab-5 in flow cytometry. C44Mab-5 did not react with 30th-361st AA of the deletion mutant of CD44. Furthermore, the reaction of C44Mab-5 to RIEDL tag-inserted CD44 from 25th to 36th AA was lost, although LpMab-7 detected most of the RIEDL tag-inserted CD44 from 21st to 41st AA. The epitope of C44Mab-5 for CD44 was determined to be the peptide from 25th to 36th AA of CD44 using RIEDL insertion for epitope mapping (REMAP) method. The REMAP method might be useful for determining the critical epitope of functional mAbs against many target molecules.
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Affiliation(s)
- Teizo Asano
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mika K Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
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37
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Marofi F, Rahman HS, Al-Obaidi ZMJ, Jalil AT, Abdelbasset WK, Suksatan W, Dorofeev AE, Shomali N, Chartrand MS, Pathak Y, Hassanzadeh A, Baradaran B, Ahmadi M, Saeedi H, Tahmasebi S, Jarahian M. Novel CAR T therapy is a ray of hope in the treatment of seriously ill AML patients. Stem Cell Res Ther 2021; 12:465. [PMID: 34412685 PMCID: PMC8377882 DOI: 10.1186/s13287-021-02420-8] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/26/2021] [Indexed: 12/20/2022] Open
Abstract
Acute myeloid leukemia (AML) is a serious, life-threatening, and hardly curable hematological malignancy that affects the myeloid cell progenies and challenges patients of all ages but mostly occurs in adults. Although several therapies are available including chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), and receptor-antagonist drugs, the 5-year survival of patients is quietly disappointing, less than 30%. alloHSCT is the major curative approach for AML with promising results but the treatment has severe adverse effects such as graft-versus-host disease (GVHD). Therefore, as an alternative, more efficient and less harmful immunotherapy-based approaches such as the adoptive transferring T cell therapy are in development for the treatment of AML. As such, chimeric antigen receptor (CAR) T cells are engineered T cells which have been developed in recent years as a breakthrough in cancer therapy. Interestingly, CAR T cells are effective against both solid tumors and hematological cancers such as AML. Gradually, CAR T cell therapy found its way into cancer therapy and was widely used for the treatment of hematologic malignancies with successful results particularly with somewhat better results in hematological cancer in comparison to solid tumors. The AML is generally fatal, therapy-resistant, and sometimes refractory disease with a disappointing low survival rate and weak prognosis. The 5-year survival rate for AML is only about 30%. However, the survival rate seems to be age-dependent. Novel CAR T cell therapy is a light at the end of the tunnel. The CD19 is an important target antigen in AML and lymphoma and the CAR T cells are engineered to target the CD19. In addition, a lot of research goes on the discovery of novel target antigens with therapeutic efficacy and utilizable for generating CAR T cells against various types of cancers. In recent years, many pieces of research on screening and identification of novel AML antigen targets with the goal of generation of effective anti-cancer CAR T cells have led to new therapies with strong cytotoxicity against cancerous cells and impressive clinical outcomes. Also, more recently, an improved version of CAR T cells which were called modified or smartly reprogrammed CAR T cells has been designed with less unwelcome effects, less toxicity against normal cells, more safety, more specificity, longer persistence, and proliferation capability. The purpose of this review is to discuss and explain the most recent advances in CAR T cell-based therapies targeting AML antigens and review the results of preclinical and clinical trials. Moreover, we will criticize the clinical challenges, side effects, and the different strategies for CAR T cell therapy.
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Affiliation(s)
- Faroogh Marofi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Heshu Sulaiman Rahman
- College of Medicine, University of Sulaimani, Sulaimaniyah, Iraq.,Department of Medical Laboratory Sciences, Komar University of Science and Technology, Chaq-Chaq Qularaise, Sulaimaniyah, Iraq
| | - Zaid Mahdi Jaber Al-Obaidi
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Alkafeel, Najaf, 54001, Iraq.,Department of Chemistry and Biochemistry, College of Medicine, University of Kerbala, Karbala, 56001, Iraq
| | | | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia.,Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, 10210, Thailand
| | | | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Yashwant Pathak
- Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA.,Department of Pharmaceutics, Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
| | - Ali Hassanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Saeedi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Safa Tahmasebi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mostafa Jarahian
- German Cancer Research Center, Toxicology and Chemotherapy, No. 2, Floor 4 Unit (G401), 69120, Heidelberg, Germany.
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Kalantar H, Rashidi M, Kalantar M, Tavallaei M, Hosseini SM. Anticancer Effects of Valproic Acid via Regulation of Epigenetic Mechanisms in Non-small-cell Lung Cancer A549 Cell Line. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2021; 20:133-140. [PMID: 34400947 PMCID: PMC8170755 DOI: 10.22037/ijpr.2019.111945.13442] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Epigenetic mechanisms are the most important factors contributing to both the development and metastasis of cancer cells. We aimed to scrutinize the role of epigenetic alternations of genes involved in cancer metastasis, including CD44v6 (metastasis indicator) and Nm23-H1 (a novel tumor suppressor), in the A549 lung cancer cell line. The A549 cells were cultured in the DMEM medium. Valproic acid (VPA) was used as a histone deacetylase inhibitor. Caspase-3 activity was assessed by adding DEVD-pNA substrate to the cell lysate. Gene expression was determined by real-time PCR. Finally, protein expression was assessed by western blot. The results showed that VA significantly decreased the expression of the CD44v6 gene and its protein level. This was further accompanied by lower expressions of MMP-2 and MMP-9 genes. On the other hand, the expression of Nm23-H1 and its protein were significantly increased in the cells accompanied by higher activity of caspase-3 (P ˂ 0.05). Our results showed that epigenetic regulation of CD44v6, Nm23-H1, MMP-2, and MMP-9 might be involved in the pathogenesis and metastasis of lung cancer. Therefore, the use of histone deacetylase inhibitors can be effective in the suppression of metastases and the treatment of these tumors.
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Affiliation(s)
- Hadi Kalantar
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohsen Rashidi
- Department of Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | | | - Mahmoud Tavallaei
- Human Genetics Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Sayed Mostafa Hosseini
- Human Genetics Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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39
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Bruno B, Wäsch R, Engelhardt M, Gay F, Giaccone L, D'Agostino M, Rodríguez-Lobato LG, Danhof S, Gagelmann N, Kröger N, Popat R, Van de Donk NWCJ, Terpos E, Dimopoulos MA, Sonneveld P, Einsele H, Boccadoro M. European Myeloma Network perspective on CAR T-Cell therapies for multiple myeloma. Haematologica 2021; 106:2054-2065. [PMID: 33792221 PMCID: PMC8327729 DOI: 10.3324/haematol.2020.276402] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 03/11/2021] [Indexed: 12/12/2022] Open
Abstract
Chimeric antigen receptor (CAR) T cells (CAR-T) have dramatically changed the treatment landscape of B-cell malignancies, providing a potential cure for relapsed/refractory patients. Long-term responses in patients with acute lymphoblastic leukemia and non Hodgkin lymphomas have encouraged further development in myeloma. In particular, B-cell maturation antigen (BCMA)-targeted CAR-T have established very promising results in heavily pre-treated patients. Moreover, CAR-T targeting other antigens (i.e., SLAMF7 and CD44v6) are currently under investigation. However, none of these current autologous therapies have been approved, and despite high overall response rates across studies, main issues such as long-term outcome, toxicities, treatment resistance, and management of complications limit as yet their widespread use. Here, we critically review the most important pre-clinical and clinical findings, recent advances in CAR-T against myeloma, as well as discoveries in the biology of a still incurable disease, that, all together, will further improve safety and efficacy in relapsed/refractory patients, urgently in need of novel treatment options.
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Affiliation(s)
- Benedetto Bruno
- Department of Molecular Biotechnology and Health Sciences, University of Torino and Department of Oncology, Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Presidio Molinette, Torino, Italy; Division of Hematology and Medical Oncology, Perlmutter Cancer Center, Grossman School of Medicine, NYU Langone Health, New York, NY.
| | - Ralph Wäsch
- Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg
| | - Monika Engelhardt
- Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg
| | - Francesca Gay
- Department of Molecular Biotechnology and Health Sciences, University of Torino and Department of Oncology, Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Presidio Molinette, Torino
| | - Luisa Giaccone
- Department of Molecular Biotechnology and Health Sciences, University of Torino and Department of Oncology, Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Presidio Molinette, Torino
| | - Mattia D'Agostino
- Department of Molecular Biotechnology and Health Sciences, University of Torino and Department of Oncology, Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Presidio Molinette, Torino
| | - Luis-Gerardo Rodríguez-Lobato
- Unit of Amyloidosis and Multiple Myeloma, Department of Hematology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Division of Medicine II, University Hospital Würzburg, Würzburg
| | - Sophia Danhof
- Division of Medicine II, University Hospital Würzburg, Würzburg
| | - Nico Gagelmann
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Nicolaus Kröger
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Rakesh Popat
- Department of Hematology, University College London Hospitals, London
| | - Niels W C J Van de Donk
- Department of Hematology, Amsterdam University Medical Centers, Cancer Center Amsterdam, Location VUmc, Amsterdam
| | - Evangelos Terpos
- Stem Cell Transplantation Unit, Plasma Cell Dyscrasias Unit, Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens
| | - Meletios A Dimopoulos
- Stem Cell Transplantation Unit, Plasma Cell Dyscrasias Unit, Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens
| | | | - Hermann Einsele
- Division of Medicine II, University Hospital Würzburg, Würzburg
| | - Mario Boccadoro
- Department of Molecular Biotechnology and Health Sciences, University of Torino and Department of Oncology, Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Presidio Molinette, Torino
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Asano T, Kaneko MK, Takei J, Tateyama N, Kato Y. Epitope Mapping of the Anti-CD44 Monoclonal Antibody (C 44Mab-46) Using the REMAP Method. Monoclon Antib Immunodiagn Immunother 2021; 40:156-161. [PMID: 34283655 DOI: 10.1089/mab.2021.0012] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
CD44 functions as a major hyaluronan receptor on most cell types, with roles in cell adhesion, migration, proliferation, differentiation, and survival. The CD44 gene comprises 20 exons, with alternative splicing producing many different isoforms. CD44 variant isoforms exhibit tissue-specific expression patterns and have been studied as therapeutic targets for several cancers; therefore, anti-CD44 monoclonal antibodies (mAbs) are useful for investigating CD44 expression in various cancers. Previously, we established an anti-CD44 mAb, C44Mab-46 (IgG1, κ), by immunizing mice with the CD44v3-10 ectodomain. Although C44Mab-46 recognized all CD44 isoforms, the binding epitope of C44Mab-46 has not been determined. In this study, we first checked the reactivity of C44Mab-46 to several CD44v3-10 deletion mutants such as dN79, dN124, dN147, and dN224. We found the N-terminus of the C44Mab-46-binding epitope between residues 147 and 224 of CD44v3-10. We next investigated this epitope using a novel mapping system: RIEDL insertion for epitope mapping (REMAP) method. We constructed 31 CD44 standard (CD44s) mutants where the RIEDL tag was inserted into the expected epitope region in CD44s. We observed that the C44Mab-46 epitope constituted five amino acids: 174-TDDDV-178 of CD44s. Thus, the REMAP method could be used to determine mAb binding epitopes for membrane proteins.
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Affiliation(s)
- Teizo Asano
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mika K Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Junko Takei
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Nami Tateyama
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
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41
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Affolter A, Lammert A, Kern J, Scherl C, Rotter N. Precision Medicine Gains Momentum: Novel 3D Models and Stem Cell-Based Approaches in Head and Neck Cancer. Front Cell Dev Biol 2021; 9:666515. [PMID: 34307351 PMCID: PMC8296983 DOI: 10.3389/fcell.2021.666515] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 04/30/2021] [Indexed: 12/12/2022] Open
Abstract
Despite the current progress in the development of new concepts of precision medicine for head and neck squamous cell carcinoma (HNSCC), in particular targeted therapies and immune checkpoint inhibition (CPI), overall survival rates have not improved during the last decades. This is, on the one hand, caused by the fact that a significant number of patients presents with late stage disease at the time of diagnosis, on the other hand HNSCC frequently develop therapeutic resistance. Distinct intratumoral and intertumoral heterogeneity is one of the strongest features in HNSCC and has hindered both the identification of specific biomarkers and the establishment of targeted therapies for this disease so far. To date, there is a paucity of reliable preclinical models, particularly those that can predict responses to immune CPI, as these models require an intact tumor microenvironment (TME). The "ideal" preclinical cancer model is supposed to take both the TME as well as tumor heterogeneity into account. Although HNSCC patients are frequently studied in clinical trials, there is a lack of reliable prognostic biomarkers allowing a better stratification of individuals who might benefit from new concepts of targeted or immunotherapeutic strategies. Emerging evidence indicates that cancer stem cells (CSCs) are highly tumorigenic. Through the process of stemness, epithelial cells acquire an invasive phenotype contributing to metastasis and recurrence. Specific markers for CSC such as CD133 and CD44 expression and ALDH activity help to identify CSC in HNSCC. For the majority of patients, allocation of treatment regimens is simply based on histological diagnosis and on tumor location and disease staging (clinical risk assessments) rather than on specific or individual tumor biology. Hence there is an urgent need for tools to stratify HNSCC patients and pave the way for personalized therapeutic options. This work reviews the current literature on novel approaches in implementing three-dimensional (3D) HNSCC in vitro and in vivo tumor models in the clinical daily routine. Stem-cell based assays will be particularly discussed. Those models are highly anticipated to serve as a preclinical prediction platform for the evaluation of stable biomarkers and for therapeutic efficacy testing.
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Affiliation(s)
- Annette Affolter
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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42
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Yang C, Lin J, Liang H, Xue L, Kwart A, Jiang M, Zhao J, Ren H, Jiang X, Munshi NC. CD44 v5 domain inhibition represses the polarization of Th2 cells by interfering with the IL-4/IL-4R signaling pathway. Immunol Cell Biol 2021; 100:21-32. [PMID: 34219288 DOI: 10.1111/imcb.12491] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 07/02/2021] [Accepted: 07/02/2021] [Indexed: 11/29/2022]
Abstract
The balance between Th1 and Th2 cells is critical for both innate and acquired immune reactions. But the precise mechanisms of T helper cells differentiations are still unclear. As an important T cell activation molecular, CD44 participates in the Th1 and Th2 differentiation. We demonstrated that CD44 variant exon-v5 is highly expressed by induced human Th2 cells. In order to investigate the role of CD44v5 domain in Th2 cell differentiation, we treated human CD4+ T cells with CD44v5 antibody and observed that the levels of pSTAT6 and GATA3 and the secretion of IL-4 were significantly decreased after the treatment. We also further found that the inhibition of Th2 differentiation was caused by the IL-4Rα degradation, CD44v5 domain co-localized with IL-4Rα on cell surface, the degradation of IL-4Rα increased after CD44v5 blocking or ablating. Our results indicated that CD44v5 antibody treatment interrupted the interaction between CD44v5 and IL-4Rα, but the CD44v5 domain blockage would not spoil the co-localization between IL4R expression and TCR and the immunological synapse formation, similar results were also found in CD44v5 deficient CD4+ T cells. In conclusion, we revealed the function of CD44v5 domain in Th2 cell differentiation, blocking or ablating CD44v5 domain could accelerate IL-4Rα degradation and then induce the Th2 cell inhibition.
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Affiliation(s)
- Chun Yang
- Department of Clinical Laboratory, the 4thHospital of Harbin Medical University, Harbin, China.,Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.,LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jianhong Lin
- Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.,LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Hongyan Liang
- Department of Clinical Laboratory, the 4thHospital of Harbin Medical University, Harbin, China
| | - Li Xue
- Department of Clinical Laboratory, the 4thHospital of Harbin Medical University, Harbin, China.,Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.,LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Ariel Kwart
- Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.,LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Meng Jiang
- Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.,Department of General surgery, the 4th Hospital of Harbin Medical University, Harbin, China
| | - Jianjun Zhao
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Huan Ren
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Xiaofeng Jiang
- Department of Clinical Laboratory, the 4thHospital of Harbin Medical University, Harbin, China
| | - Nikhil C Munshi
- Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.,LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.,VA Boston Healthcare System, Boston, MA, USA
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43
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Kim CJ, Terado T, Tambe Y, Mukaisho KI, Kageyama S, Kawauchi A, Inoue H. Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis. Int J Oncol 2021; 59:40. [PMID: 33982789 PMCID: PMC8131085 DOI: 10.3892/ijo.2021.5220] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 04/19/2021] [Indexed: 12/13/2022] Open
Abstract
The phosphorylation of pyruvate dehydrogenase (PDH) by pyruvate dehydrogenase kinase (PDK) 4 inhibits its ability to induce a glycolytic shift. PDK4 expression is upregulated in various types of human cancer. Because PDK4 regulation is critical for metabolic changes in cancer cells, it is an attractive target for cancer therapy given its ability to shift glucose metabolism. It was previously shown that a novel PDK4 inhibitor, cryptotanshinone (CPT), suppressed the three‑dimensional (3D)‑spheroid formation of pancreatic and colorectal cancer cells. In the present study, the effects of CPT on the invasiveness of bladder cancer cells were investigated. CPT significantly suppressed the invasiveness and 3D‑spheroid formation of T24 and J82 bladder cancer cells. CPT also suppressed the phosphorylation of PDH and β‑catenin, as well as the expression of N‑cadherin, which are all critical for inducing epithelial‑mesenchymal transition (EMT). The knockdown of β‑catenin or PDK4 using specific small interfering RNAs suppressed N‑cadherin expression and invasiveness in T24 cells. An mTOR inhibitor also suppressed the phosphorylation of β‑catenin and N‑cadherin expression. Furthermore, CPT injection significantly suppressed pancreatic tumor growth and peritoneal dissemination of highly metastatic SUIT‑2 pancreatic cancer cells in a mouse orthotopic pancreatic cancer model, without evident toxicity. Moreover, immunohistochemistry analyses demonstrated decreased β‑catenin expression in CPT‑treated pancreatic tumors compared with control tumors. Taken together, these results indicate that CPT reduced the invasiveness and metastasis of bladder cancer cells by suppressing EMT via the mTOR/β‑catenin/N‑cadherin pathway.
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Affiliation(s)
- Chul Jang Kim
- Department of Urology, Kohka Public Hospital, Minakuchi-cho, Kohka, Shiga 528-0074, Japan
- Department of Urology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Tokio Terado
- Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Yukihiro Tambe
- Division of Microbiology and Infectious Diseases, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Ken-Ichi Mukaisho
- Division of Human Pathology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Susumu Kageyama
- Department of Urology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Akihiro Kawauchi
- Department of Urology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Hirokazu Inoue
- Division of Microbiology and Infectious Diseases, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
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44
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Structural Constraint of Osteopontin Facilitates Efficient Binding to CD44. Biomolecules 2021; 11:biom11060813. [PMID: 34070790 PMCID: PMC8228714 DOI: 10.3390/biom11060813] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/26/2021] [Accepted: 05/27/2021] [Indexed: 11/21/2022] Open
Abstract
Since the original description in 1996, the interaction between the cytokine osteopontin (OPN) and the homing receptor CD44 has been extensively studied in cancer, inflammation, bone remodeling, and various other conditions. Alternative splicing and extensive posttranslational modifications by both binding partners, as well as the possibility for lateral recruitment of additional membrane receptors or soluble co-ligands into a complex have left the exact molecular requirements for high-affinity OPN-CD44 binding unresolved. We now report that there is a moderate engagement between the unmodified molecules, which results in curved double-reciprocal plots for OPN titration, suggesting the existence of two binding sites or two binding conformations. Structural constraint of OPN, by immobilization or by addition of heparin, is required for its strong ligation of CD44. Prior literature provides evidence that heparin binding to OPN prompts the unfolding of a core element in the protein. This conformational adjustment may be essential for efficient CD44 interaction. The integrin α9β1 seems to compete with the OPN-CD44 engagement, while the integrin αVβ3 reflects additive binding, suggesting that the CD44 contact sites on OPN are downstream of the RGD motif but overlap with the SVVYGLR domain. Hyaluronate has no effect, placing the relevant domain on CD44 downstream of the N-terminus.
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45
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Maiti A, Okano I, Oshi M, Okano M, Tian W, Kawaguchi T, Katsuta E, Takabe K, Yan L, Patnaik SK, Hait NC. Altered Expression of Secreted Mediator Genes That Mediate Aggressive Breast Cancer Metastasis to Distant Organs. Cancers (Basel) 2021; 13:cancers13112641. [PMID: 34072157 PMCID: PMC8199412 DOI: 10.3390/cancers13112641] [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: 04/17/2021] [Revised: 05/11/2021] [Accepted: 05/21/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Heterogeneity is the characteristic of breast tumors, making it difficult to understand the molecular mechanism. Alteration of gene expression in the primary tumor versus the metastatic lesion remains challenging for getting any specific targeted therapy. To better understand how gene expression profile changes during metastasis, we compare the primary tumor and distant metastatic tumor gene expression using primary breast tumors compared with its metastatic variant in animal models. Our RNA sequencing data from cells revealed that parental cell and the metastatic variant cell are different in gene expression while gene signature significantly altered during metastasis to distant organs than primary breast tumors. We found that secreted mediators encoding genes (ANGPTL7, MMP3, LCN2, S100A8, and ESM1) are correlated with poor prognosis in the clinical setting as divulged from METABRIC and TCGA-BRCA cohort data analysis. Abstract Due to the heterogeneous nature of breast cancer, metastasis organotropism has been poorly understood. This study assessed the specific cancer-related gene expression changes occurring with metastatic breast cancer recurrence to distant organs compared with non-metastatic breast cancer. We found that several secreted mediators encoding genes notably, LCN2 and S100A8 overexpressed at the distant metastatic site spine (LCN2, 5-fold; S100A8, 6-fold) and bone (LCN2, 5-fold; S100A8, 3-fold) vs. primary tumors in the syngeneic implantation/tumor-resection metastasis mouse model. In contrast, the ESM-1 encoding gene is overexpressed in the primary tumors and markedly downregulated at distant metastatic sites. Further digging into TCAGA-BRCA, SCAN-B, and METABRIC cohorts data analysis revealed that LCN2, S100A8, and ESM-1 mediators encoding individual gene expression scores were strongly associated with disease-specific survival (DSS) in the METABRIC cohort (hazard ratio (HR) > 1, p < 0.0004). The gene expression scores predicted worse clinically aggressive tumors, such as high Nottingham histological grade and advanced cancer staging. Higher gene expression score of ESM-1 gene was strongly associated with worse overall survival (OS) in the triple-negative breast cancer (TNBC) and hormonal receptor (HR)-positive/HER2-negative subtype in METABRIC cohort, HER2+ subtype in TCGA-BRCA and SCAN-B breast cancer cohorts. Our data suggested that mediators encoding genes with prognostic and predictive values may be clinically useful for breast cancer spine, bone, and lung metastasis, particularly in more aggressive subtypes such as TNBC and HER2+ breast cancer.
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Affiliation(s)
- Aparna Maiti
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (I.O.); (M.O.); (M.O.); (T.K.); (E.K.); (K.T.)
- Department of Molecular & Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Correspondence: (A.M.); (N.C.H.); Tel.: +1-(716)-845-3505 (A.M.); +1-(716)-845-8527 (N.C.H.); Fax: +1-(716)-845-1668 (N.C.H.)
| | - Ichiro Okano
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (I.O.); (M.O.); (M.O.); (T.K.); (E.K.); (K.T.)
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (I.O.); (M.O.); (M.O.); (T.K.); (E.K.); (K.T.)
| | - Maiko Okano
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (I.O.); (M.O.); (M.O.); (T.K.); (E.K.); (K.T.)
| | - Wanqing Tian
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (W.T.); (L.Y.)
| | - Tsutomu Kawaguchi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (I.O.); (M.O.); (M.O.); (T.K.); (E.K.); (K.T.)
| | - Eriko Katsuta
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (I.O.); (M.O.); (M.O.); (T.K.); (E.K.); (K.T.)
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (I.O.); (M.O.); (M.O.); (T.K.); (E.K.); (K.T.)
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (W.T.); (L.Y.)
| | - Santosh K. Patnaik
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Nitai C. Hait
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (I.O.); (M.O.); (M.O.); (T.K.); (E.K.); (K.T.)
- Department of Molecular & Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Correspondence: (A.M.); (N.C.H.); Tel.: +1-(716)-845-3505 (A.M.); +1-(716)-845-8527 (N.C.H.); Fax: +1-(716)-845-1668 (N.C.H.)
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46
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Fontanella RA, Sideri S, Di Stefano C, Catizone A, Di Agostino S, Angelini DF, Guerrera G, Battistini L, Battafarano G, Del Fattore A, Campese AF, Padula F, De Cesaris P, Filippini A, Riccioli A. CD44v8-10 is a marker for malignant traits and a potential driver of bone metastasis in a subpopulation of prostate cancer cells. Cancer Biol Med 2021; 18:j.issn.2095-3941.2020.0495. [PMID: 34018387 PMCID: PMC8330537 DOI: 10.20892/j.issn.2095-3941.2020.0495] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 03/08/2021] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Bone metastasis is a clinically important outcome of prostate carcinoma (PC). We focused on the phenotypic and functional characterization of a particularly aggressive phenotype within the androgen-independent bone metastasis-derived PC3 cell line. These cells, originated from the spontaneous conversion of a CD44-negative subpopulation, stably express the CD44v8-10 isoform (CD44v8-10pos) and display stem cell-like features and a marked invasive phenotype in vitro that is lost upon CD44v8-10 silencing. METHODS Flow cytometry, enzyme-linked immunoassay, immunofluorescence, and Western blot were used for phenotypic and immunologic characterization. Real-time quantitative polymerase chain reaction and functional assays were used to assess osteomimicry. RESULTS Analysis of epithelial-mesenchymal transition markers showed that CD44v8-10pos PC3 cells surprisingly display epithelial phenotype and can undergo osteomimicry, acquiring bone cell phenotypic and behavioral traits. Use of specific siRNA evidenced the ability of CD44v8-10 variant to confer osteomimetic features, hence the potential to form bone-specific metastasis. Moreover, the ability of tumors to activate immunosuppressive mechanisms which counteract effective immune responses is a sign of the aggressiveness of a tumor. Here we report that CD44v8-10pos cells express programmed death ligand 1, a negative regulator of anticancer immunity, and secrete exceptionally high amounts of interleukin-6, favoring osteoclastogenesis and immunosuppression in bone microenvironment. Notably, we identified a novel pathway activated by CD44v8-10, involving tafazzin (TAZ) and likely the Wnt/TAZ axis, known to play a role in upregulating osteomimetic genes. CONCLUSIONS CD44v8-10 could represent a marker of a more aggressive bone metastatic PC population exerting a driver role in osteomimicry in bone. A novel link between TAZ and CD44v8-10 is also shown.
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Affiliation(s)
- Rosaria A. Fontanella
- Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Unit of Histology and Medical Embryology, Sapienza University, Rome 00161, Italy
| | - Silvia Sideri
- Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Unit of Histology and Medical Embryology, Sapienza University, Rome 00161, Italy
| | - Chiara Di Stefano
- Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Unit of Histology and Medical Embryology, Sapienza University, Rome 00161, Italy
| | - Angiolina Catizone
- Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Unit of Histology and Medical Embryology, Sapienza University, Rome 00161, Italy
| | - Silvia Di Agostino
- Department of Health Sciences School of Medicine – “Magna Graecia” University of Catanzaro, Catanzaro 88100, Italy
| | | | | | | | - Giulia Battafarano
- Bone Physiopathology Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS, Rome 00146, Italy
| | - Andrea Del Fattore
- Bone Physiopathology Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS, Rome 00146, Italy
| | | | - Fabrizio Padula
- Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Unit of Histology and Medical Embryology, Sapienza University, Rome 00161, Italy
| | - Paola De Cesaris
- Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila 67100, Italy
| | - Antonio Filippini
- Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Unit of Histology and Medical Embryology, Sapienza University, Rome 00161, Italy
| | - Anna Riccioli
- Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Unit of Histology and Medical Embryology, Sapienza University, Rome 00161, Italy
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47
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Lusche DF, Wessels DJ, Reis RJ, Forrest CC, Thumann AR, Soll DR. New monoclonal antibodies that recognize an unglycosylated, conserved, extracellular region of CD44 in vitro and in vivo, and can block tumorigenesis. PLoS One 2021; 16:e0250175. [PMID: 33891595 PMCID: PMC8064539 DOI: 10.1371/journal.pone.0250175] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 03/31/2021] [Indexed: 12/13/2022] Open
Abstract
CD44 is a transmembrane glycoprotein that binds to hyaluronic acid, plays roles in a number of cellular processes and is expressed in a variety of cell types. It is up-regulated in stem cells and cancer. Anti-CD44 monoclonal antibodies affect cell motility and aggregation, and repress tumorigenesis and metastasis. Here we describe four new anti-CD44 monoclonal antibodies originating from B cells of a mouse injected with a plasmid expressing CD44 isoform 12. The four monoclonal antibodies bind to the terminal, extracellular, conserved domain of CD44 isoforms. Based on differences in western blot patterns of cancer cell lysates, the four anti-CD44 mAbs separated into three distinct categories that include P4G9, P3D2, and P3A7, and P3G4. Spot assay analysis with peptides generated in Escherichia coli support the conclusion that the monoclonal antibodies recognize unglycosylated sequences in the N-terminal conserved region between amino acid 21-220, and analyses with a peptide generated in human embryonic kidney 293 cells, demonstrate that these monoclonal antibodies bind to these peptides only after deglycosylation. Western blots with lysates from three cancer cell lines demonstrate that several CD44 isoforms are unglycosylated in the anti-CD44 target regions. The potential utility of the monoclonal antibodies in blocking tumorigenesis was tested by co-injection of cells of the breast cancer-derived tumorigenic cell line MDA-MB-231 with the anti-CD44 monoclonal antibody P3D2 into the mammary fat pads of mice. All five control mice injected with MDA-MB-231 cells plus anti-IgG formed palpable tumors, while only one of the six test mice injected with MDA-MB-231 cells plus P3D2 formed a tiny tumor, while the remaining five were tumor-free, indicating that the four anti-CD44 mAbs may be useful therapeutically.
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Affiliation(s)
- Daniel F. Lusche
- Developmental Studies Hybridoma Bank, Department of Biology, University of Iowa, Iowa City, Iowa, United States of America
| | - Deborah J. Wessels
- Developmental Studies Hybridoma Bank, Department of Biology, University of Iowa, Iowa City, Iowa, United States of America
| | - Ryan J. Reis
- Developmental Studies Hybridoma Bank, Department of Biology, University of Iowa, Iowa City, Iowa, United States of America
| | - Cristopher C. Forrest
- Developmental Studies Hybridoma Bank, Department of Biology, University of Iowa, Iowa City, Iowa, United States of America
| | - Alexis R. Thumann
- Developmental Studies Hybridoma Bank, Department of Biology, University of Iowa, Iowa City, Iowa, United States of America
| | - David R. Soll
- Developmental Studies Hybridoma Bank, Department of Biology, University of Iowa, Iowa City, Iowa, United States of America
- * E-mail:
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48
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Gorelova A, Berman M, Al Ghouleh I. Endothelial-to-Mesenchymal Transition in Pulmonary Arterial Hypertension. Antioxid Redox Signal 2021; 34:891-914. [PMID: 32746619 PMCID: PMC8035923 DOI: 10.1089/ars.2020.8169] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 07/23/2020] [Indexed: 12/14/2022]
Abstract
Endothelial-to-mesenchymal transition (EndMT) is a process that encompasses extensive transcriptional reprogramming of activated endothelial cells leading to a shift toward mesenchymal cellular phenotypes and functional responses. Initially observed in the context of embryonic development, in the last few decades EndMT is increasingly recognized as a process that contributes to a variety of pathologies in the adult organism. Within the settings of cardiovascular biology, EndMT plays a role in various diseases, including atherosclerosis, heart valvular disease, cardiac fibrosis, and myocardial infarction. EndMT is also being progressively implicated in development and progression of pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH). This review covers the current knowledge about EndMT in PH and PAH, and provides comprehensive overview of seminal discoveries. Topics covered include evidence linking EndMT to factors associated with PAH development, including hypoxia responses, inflammation, dysregulation of bone-morphogenetic protein receptor 2 (BMPR2), and redox signaling. This review amalgamates these discoveries into potential insights for the identification of underlying mechanisms driving EndMT in PH and PAH, and discusses future directions for EndMT-based therapeutic strategies in disease management.
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Affiliation(s)
- Anastasia Gorelova
- Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Mariah Berman
- Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Imad Al Ghouleh
- Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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49
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Li K, Wang Z. Splicing factor SRSF2-centric gene regulation. Int J Biol Sci 2021; 17:1708-1715. [PMID: 33994855 PMCID: PMC8120470 DOI: 10.7150/ijbs.58888] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 04/04/2021] [Indexed: 01/14/2023] Open
Abstract
Serine/arginine-rich splicing factor 2 (SRSF2) is a splicing factor that is widely expressed in a variety of mammalian cell types. Increasing evidence has confirmed that SRSF2 plays vital roles in a number of biological and pathological processes. Therefore, it is important to understand how its expression is regulated, and how it regulates the expression of its target genes. Recently, we found that SRSF2 expression could be upregulated by herpes simplex virus-1 (HSV-1) infection, and that altered SRSF2 expression, in turn, epigenetically regulates the transcription of HSV-1 genes. Further studies on T cell exhaustion demonstrated that upregulated SRSF2 in exhausted T cells elevated the levels of multiple immune checkpoint molecules by associating with the acyl-transferases, P300 and CBP, and by altering histone modification near the transcription start sites of these genes, thereby influencing signal transducer and activator of transcription 3 binding to these gene promoters. These findings suggest that SRSF2 acts as an important sensor and effector during disease progression. Here, we discuss the molecules that regulate SRSF2 gene expression and their associated mechanisms, and the mechanisms via which SRSF2 regulates the expression of target genes, thus providing novel insights into the central role of SRSF2 in gene regulation.
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Affiliation(s)
- Kun Li
- Department of Nuclear Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China
| | - Ziqiang Wang
- Department of Nuclear Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China.,Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250062, China
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50
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Derakhshani A, Rostami Z, Safarpour H, Shadbad MA, Nourbakhsh NS, Argentiero A, Taefehshokr S, Tabrizi NJ, Kooshkaki O, Astamal RV, Singh PK, Taefehshokr N, Alizadeh N, Silvestris N, Baradaran B. From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy. Molecules 2021; 26:2278. [PMID: 33920054 PMCID: PMC8071039 DOI: 10.3390/molecules26082278] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 04/09/2021] [Accepted: 04/09/2021] [Indexed: 12/19/2022] Open
Abstract
Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.
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Affiliation(s)
- Afshin Derakhshani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran; (A.D.); (M.A.S.); (S.T.); (N.J.T.); (R.V.A.); (N.A.)
- IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
| | - Zeinab Rostami
- Student Research Committee, Birjand University of Medical Sciences, Birjand 97178-53577, Iran; (Z.R.); (O.K.)
| | - Hossein Safarpour
- Cellular & Molecular Research Center, Birjand University of Medical Sciences, Birjand 97178-53577, Iran;
| | - Mahdi Abdoli Shadbad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran; (A.D.); (M.A.S.); (S.T.); (N.J.T.); (R.V.A.); (N.A.)
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz 51666-14766, Iran
| | | | | | - Sina Taefehshokr
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran; (A.D.); (M.A.S.); (S.T.); (N.J.T.); (R.V.A.); (N.A.)
| | - Neda Jalili Tabrizi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran; (A.D.); (M.A.S.); (S.T.); (N.J.T.); (R.V.A.); (N.A.)
| | - Omid Kooshkaki
- Student Research Committee, Birjand University of Medical Sciences, Birjand 97178-53577, Iran; (Z.R.); (O.K.)
| | - Reza Vaezi Astamal
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran; (A.D.); (M.A.S.); (S.T.); (N.J.T.); (R.V.A.); (N.A.)
| | - Pankaj Kumar Singh
- Principal Research Technologist, Department of Radiation Oncology, Mayo Clinic, 4500 San Pablo Rd S, Jacksonville, FL 32224, USA;
| | - Nima Taefehshokr
- Department of Microbiology and Immunology, Center for Human Immunology, The University of Western Ontario, London, ON N6A 5C1, Canada;
| | - Nazila Alizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran; (A.D.); (M.A.S.); (S.T.); (N.J.T.); (R.V.A.); (N.A.)
| | - Nicola Silvestris
- IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran; (A.D.); (M.A.S.); (S.T.); (N.J.T.); (R.V.A.); (N.A.)
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 51666-14766, Iran
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