|
1
|
Çakır U, Balogh P, Ferenczik A, Brodszky V, Krenács T, Kárpáti S, Sárdy M, Holló P, Fábián M. G protein-coupled estrogen receptor 1 and collagen XVII endodomain expression in human cutaneous melanomas: can they serve as prognostic factors? Pathol Oncol Res 2024; 30:1611809. [PMID: 39252786 PMCID: PMC11381273 DOI: 10.3389/pore.2024.1611809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 08/14/2024] [Indexed: 09/11/2024]
Abstract
Melanoma incidence is increasing globally. Although novel therapies have improved the survival of primary melanoma patients over the past decade, the overall survival rate for metastatic melanoma remains low. In addition to traditional prognostic factors such as Breslow thickness, ulceration, and mitotic rate, novel genetic and molecular markers have been investigated. In our study, we analyzed the expression of G-protein coupled estrogen receptor 1 (GPER1) and the endodomain of collagen XVII (COL17) in relation to clinicopathological factors in primary cutaneous melanomas with known lymph node status in both sexes, using immunohistochemistry. We found, that GPER1 expression correlated with favorable clinicopathological factors, including lower Breslow thickness, lower mitotic rate and absence of ulceration. In contrast, COL17 expression was associated with poor prognostic features, such as higher tumor thickness, higher mitotic rate, presence of ulceration and presence of regression. Melanomas positive for both GPER1 and COL17 had significantly lower mean Breslow thickness and mitotic rate compared to cases positive for COL17 only. Our data indicate that GPER1 and COL17 proteins may be of potential prognostic value in primary cutaneous melanomas.
Collapse
Affiliation(s)
- Uğur Çakır
- Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary
| | - Petra Balogh
- Queen Elizabeth Hospital, Cellular Pathology Department, University Hospitals Birmingham, Birmingham, United Kingdom
| | - Anikó Ferenczik
- Doctoral School of Economics, Business and Informatics, Corvinus University of Budapest, Budapest, Hungary
- Department of Health Policy, Institute of Social and Political Sciences, Corvinus University of Budapest, Budapest, Hungary
| | - Valentin Brodszky
- Department of Health Policy, Institute of Social and Political Sciences, Corvinus University of Budapest, Budapest, Hungary
| | - Tibor Krenács
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Sarolta Kárpáti
- Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary
| | - Miklós Sárdy
- Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary
| | - Péter Holló
- Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary
| | - Melinda Fábián
- Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary
| |
Collapse
|
|
2
|
Li X, Jin Y, Xue J. Unveiling Collagen's Role in Breast Cancer: Insights into Expression Patterns, Functions and Clinical Implications. Int J Gen Med 2024; 17:1773-1787. [PMID: 38711825 PMCID: PMC11073151 DOI: 10.2147/ijgm.s463649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 04/21/2024] [Indexed: 05/08/2024] Open
Abstract
Collagen, the predominant protein constituent of the mammalian extracellular matrix (ECM), comprises a diverse family of 28 members (I-XXVIII). Beyond its structural significance, collagen is implicated in various diseases or cancers, notably breast cancer, where it influences crucial cellular processes including proliferation, metastasis, apoptosis, and drug resistance, intricately shaping cancer progression and prognosis. In breast cancer, distinct collagens exhibit differential expression profiles, with some showing heightened or diminished levels in cancerous tissues or cells compared to normal counterparts, suggesting specific and pivotal biological functions. In this review, we meticulously analyze the expression of individual collagen members in breast cancer, utilizing Transcripts Per Million (TPM) data sourced from the GEPIA2 database. Through this analysis, we identify collagens that deviate from normal expression patterns in breast cancer, providing a comprehensive overview of their expression dynamics, functional roles, and underlying mechanisms. Our findings shed light on recent advancements in understanding the intricate interplay between these aberrantly expressed collagens and breast cancer. This exploration aims to offer valuable insights for the identification of potential biomarkers and therapeutic targets, thereby advancing the prospects of more effective interventions in breast cancer treatment.
Collapse
Affiliation(s)
- Xia Li
- Department of Molecular Diagnosis, Northern Jiangsu People’s Hospital, Yangzhou, People’s Republic of China
| | - Yue Jin
- Department of Molecular Diagnosis, Northern Jiangsu People’s Hospital, Yangzhou, People’s Republic of China
| | - Jian Xue
- Department of Emergency Medicine, Yizheng People’s Hospital, Yangzhou, People’s Republic of China
| |
Collapse
|
|
3
|
Kashiwagi R, Funayama R, Aoki S, Matsui A, Klein S, Sato Y, Suzuki T, Murakami K, Inoue K, Iseki M, Masuda K, Mizuma M, Naito H, Duda DG, Unno M, Nakayama K. Collagen XVII regulates tumor growth in pancreatic cancer through interaction with the tumor microenvironment. Cancer Sci 2023; 114:4286-4298. [PMID: 37688308 PMCID: PMC10637054 DOI: 10.1111/cas.15952] [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: 04/01/2023] [Revised: 08/15/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
Expression of the gene for collagen XVII (COL17A1) in tumor tissue is positively or negatively associated with patient survival depending on cancer type. High COL17A1 expression is thus a favorable prognostic marker for breast cancer but unfavorable for pancreatic cancer. This study explored the effects of COL17A1 expression on pancreatic tumor growth and their underlying mechanisms. Analysis of published single-cell RNA-sequencing data for human pancreatic cancer tissue revealed that COL17A1 was expressed predominantly in cancer cells rather than surrounding stromal cells. Forced expression of COL17A1 did not substantially affect the proliferation rate of the mouse pancreatic cancer cell lines KPC and AK4.4 in vitro. However, in mouse homograft tumor models in which KPC or AK4.4 cells were injected into syngeneic C57BL/6 or FVB mice, respectively, COL17A1 expression promoted or suppressed tumor growth, respectively, suggesting that the effect of COL17A1 on tumor growth was influenced by the tumor microenvironment. RNA-sequencing analysis of tumor tissue revealed effects of COL17A1 on gene expression profiles (including the expression of genes related to cell proliferation, the immune response, Wnt signaling, and Hippo signaling) that differed between C57BL/6-KPC and FVB-AK4.4 tumors. Our data thus suggest that COL17A1 promotes or suppresses cancer progression in a manner dependent on the interaction of tumor cells with the tumor microenvironment.
Collapse
Affiliation(s)
- Ryosuke Kashiwagi
- Department of Cell ProliferationART, Graduate School of Medicine, Tohoku UniversitySendaiJapan
- Department of SurgeryGraduate School of Medicine, Tohoku UniversitySendaiJapan
| | - Ryo Funayama
- Department of Cell ProliferationART, Graduate School of Medicine, Tohoku UniversitySendaiJapan
| | - Shuichi Aoki
- Department of SurgeryGraduate School of Medicine, Tohoku UniversitySendaiJapan
| | - Aya Matsui
- Department of Vascular Physiology, Graduate School of Medical ScienceKanazawa UniversityKanazawaJapan
| | - Sebastian Klein
- PathologyUniversity Hospital CologneCologneGermany
- Radiation Oncology/Steele Laboratories for Tumor BiologyMassachusetts General HospitalBostonMassachusettsUSA
| | - Yukihiro Sato
- Department of Cell ProliferationART, Graduate School of Medicine, Tohoku UniversitySendaiJapan
- Department of SurgeryGraduate School of Medicine, Tohoku UniversitySendaiJapan
| | - Tsubasa Suzuki
- Department of Cell ProliferationART, Graduate School of Medicine, Tohoku UniversitySendaiJapan
| | - Keigo Murakami
- Department of Investigative Pathology, Graduate School of MedicineTohoku UniversitySendaiJapan
| | - Koetsu Inoue
- Department of SurgeryGraduate School of Medicine, Tohoku UniversitySendaiJapan
| | - Masahiro Iseki
- Department of SurgeryGraduate School of Medicine, Tohoku UniversitySendaiJapan
| | - Kunihiro Masuda
- Department of SurgerySouth Miyagi Medical CenterShibata‐gunJapan
| | - Masamichi Mizuma
- Department of SurgeryGraduate School of Medicine, Tohoku UniversitySendaiJapan
| | - Hisamichi Naito
- Department of Vascular Physiology, Graduate School of Medical ScienceKanazawa UniversityKanazawaJapan
| | - Dan G. Duda
- Radiation Oncology/Steele Laboratories for Tumor BiologyMassachusetts General HospitalBostonMassachusettsUSA
| | - Michiaki Unno
- Department of SurgeryGraduate School of Medicine, Tohoku UniversitySendaiJapan
| | - Keiko Nakayama
- Department of Cell ProliferationART, Graduate School of Medicine, Tohoku UniversitySendaiJapan
| |
Collapse
|
|
4
|
Crespo-Bravo M, Thorlacius-Ussing J, Nissen NI, Pedersen RS, Boisen MK, Liljefors M, Johansen AZ, Johansen JS, Karsdal MA, Willumsen N. Levels of type XVII collagen (BP180) ectodomain are elevated in circulation from patients with multiple cancer types and is prognostic for patients with metastatic colorectal cancer. BMC Cancer 2023; 23:949. [PMID: 37803411 PMCID: PMC10557271 DOI: 10.1186/s12885-023-11470-5] [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: 06/22/2023] [Accepted: 10/02/2023] [Indexed: 10/08/2023] Open
Abstract
BACKGROUND Collagens are the major components of the extracellular matrix (ECM) and are known to contribute to tumor progression and metastasis. There are 28 different types of collagens each with unique functions in maintaining tissue structure and function. Type XVII collagen (BP180) is a type II transmembrane protein that provides stable adhesion between epithelial cells and the underlying basement membrane. Aberrant expression and ectodomain shedding of type XVII collagen have been associated with epithelial damage, tumor invasiveness, and metastasis in multiple tumor types and may consequently be used as a potential (non-invasive) biomarker in cancer and treatment target. METHOD An ELISA targeting the type XVII collagen ectodomain (PRO-C17) was developed for use in serum. PRO-C17 was measured in a cohort of patients with 11 different cancer types (n = 214) and compared to healthy controls (n = 23) (cohort 1). Based on the findings from cohort 1, PRO-C17 and its association with survival was explored in patients with metastatic colorectal cancer (mCRC) treated with bevacizumab in combination with chemotherapy (n = 212) (cohort 2). RESULTS PRO-C17 was robust and specific towards the ectodomain of type XVII collagen. In cohort 1, PRO-C17 levels were elevated (p < 0.05) in serum from patients with CRC, kidney, ovarian, bladder, breast, and head and neck cancer compared to healthy controls. PRO-C17 was especially good at discriminating between CRC patients and healthy controls with an AUROC of 0.904. In cohort 2, patients with mCRC and high levels (tertile 3) of PRO-C17 had shorter overall survival (OS) with a median OS of 390 days compared to 539 days for patients with low levels of PRO-C17. When evaluated by multivariate Cox regression analysis, high PRO-C17 was predictive for poor OS independent of risk factors and the tumor fibrosis biomarker PRO-C3. CONCLUSION PRO-C17 measures the ectodomain of type XVII collagen in serum and is a promising non-invasive biomarker that can aid in understanding tumor heterogeneity as well as elaborate on the role of collagen XVII in tumor progression. Moreover, the findings in the study proposes PRO-C17 as novel biomarker of epithelial damage in specific cancer types including CRC.
Collapse
Affiliation(s)
- Marina Crespo-Bravo
- Nordic Bioscience A/S, Herlev, 2730, Denmark.
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark.
| | | | | | - Rasmus S Pedersen
- Nordic Bioscience A/S, Herlev, 2730, Denmark
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
| | - Mogens K Boisen
- Department of Oncology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, 2730, Denmark
| | - Maria Liljefors
- Department of Clinical Science, Intervention and Technology, Karolinska University Hospital Huddinge, Stockholm, 141 57, Sweden
| | - Astrid Z Johansen
- Department of Oncology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, 2730, Denmark
| | - Julia S Johansen
- Department of Oncology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, 2730, Denmark
- Department of Medicine, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Copenhagen, 2730, 2900, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
| | | | | |
Collapse
|
|
5
|
Ewald CY, Nyström A. Mechanotransduction through hemidesmosomes during aging and longevity. J Cell Sci 2023; 136:jcs260987. [PMID: 37522320 DOI: 10.1242/jcs.260987] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/01/2023] Open
Abstract
Hemidesmosomes are structural protein complexes localized at the interface of tissues with high mechanical demand and shear forces. Beyond tissue anchoring, hemidesmosomes have emerged as force-modulating structures important for translating mechanical cues into biochemical and transcriptional adaptation (i.e. mechanotransduction) across tissues. Here, we discuss the recent insights into the roles of hemidesmosomes in age-related tissue regeneration and aging in C. elegans, mice and humans. We highlight the emerging concept of preserved dynamic mechanoregulation of hemidesmosomes in tissue maintenance and healthy aging.
Collapse
Affiliation(s)
- Collin Y Ewald
- Laboratory of Extracellular Matrix Regeneration, Institute of Translational Medicine, Department of Health Sciences and Technology, ETH Zürich, Zürich, Schwerzenbach CH-8603, Switzerland
| | - Alexander Nyström
- Department of Dermatology, Medical Faculty, Medical Center - University of Freiburg, Freiburg DE-79104, Germany
- Freiburg Institute for Advanced Studies (FRIAS), Albertstraße 19, Freiburg im Breisgau DE-79104, Germany
| |
Collapse
|
|
6
|
Sialyl Lewis X/A and Cytokeratin Crosstalk in Triple Negative Breast Cancer. Cancers (Basel) 2023; 15:cancers15030731. [PMID: 36765690 PMCID: PMC9913872 DOI: 10.3390/cancers15030731] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/31/2022] [Accepted: 01/23/2023] [Indexed: 01/27/2023] Open
Abstract
Triple-negative breast cancer (TNBC) encompasses multiple entities and is generally highly aggressive and metastatic. We aimed to determine the clinical and biological relevance of Sialyl-Lewis X and A (sLeX/A)-a fucosylated glycan involved in metastasis-in TNBC. Here, we studied tissues from 50 TNBC patients, transcripts from a TNBC dataset from The Cancer Genome Atlas (TCGA) database, and a primary breast cancer cell line. All 50 TNBC tissue samples analysed expressed sLeX/A. Patients with high expression of sLeX/A had 3 years less disease-free survival than patients with lower expression. In tissue, sLeX/A negatively correlated with cytokeratins 5/6 (CK5/6, which was corroborated by the inverse correlation between fucosyltransferases and CK5/6 genes. Our observations were confirmed in vitro when inhibition of sLeX/A remarkably increased expression of CK5/6, followed by a decreased proliferation and invasion capacity. Among the reported glycoproteins bearing sLeX/A and based on the STRING tool, α6 integrin showed the highest interaction score with CK5/6. This is the first report on the sLeX/A expression in TNBC, highlighting its association with lower disease-free survival and its inverse crosstalk with CK5/6 with α6 integrin as a mediator. All in all, sLeX/A is critical for TNBC malignancy and a potential prognosis biomarker and therapeutic target.
Collapse
|
|
7
|
Fischer NG, Aparicio C. Junctional epithelium and hemidesmosomes: Tape and rivets for solving the "percutaneous device dilemma" in dental and other permanent implants. Bioact Mater 2022; 18:178-198. [PMID: 35387164 PMCID: PMC8961425 DOI: 10.1016/j.bioactmat.2022.03.019] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 02/14/2022] [Accepted: 03/12/2022] [Indexed: 02/06/2023] Open
Abstract
The percutaneous device dilemma describes etiological factors, centered around the disrupted epithelial tissue surrounding non-remodelable devices, that contribute to rampant percutaneous device infection. Natural percutaneous organs, in particular their extracellular matrix mediating the "device"/epithelium interface, serve as exquisite examples to inspire longer lasting long-term percutaneous device design. For example, the tooth's imperviousness to infection is mediated by the epithelium directly surrounding it, the junctional epithelium (JE). The hallmark feature of JE is formation of hemidesmosomes, cell/matrix adhesive structures that attach surrounding oral gingiva to the tooth's enamel through a basement membrane. Here, the authors survey the multifaceted functions of the JE, emphasizing the role of the matrix, with a particular focus on hemidesmosomes and their five main components. The authors highlight the known (and unknown) effects dental implant - as a model percutaneous device - placement has on JE regeneration and synthesize this information for application to other percutaneous devices. The authors conclude with a summary of bioengineering strategies aimed at solving the percutaneous device dilemma and invigorating greater collaboration between clinicians, bioengineers, and matrix biologists.
Collapse
Affiliation(s)
- Nicholas G. Fischer
- MDRCBB-Minnesota Dental Research Center for Biomaterials and Biomechanics, University of Minnesota, 16-212 Moos Tower, 515 Delaware St. SE, Minneapolis, MN, 55455, USA
| | - Conrado Aparicio
- MDRCBB-Minnesota Dental Research Center for Biomaterials and Biomechanics, University of Minnesota, 16-212 Moos Tower, 515 Delaware St. SE, Minneapolis, MN, 55455, USA
- Division of Basic Research, Faculty of Odontology, UIC Barcelona – Universitat Internacional de Catalunya, C/. Josep Trueta s/n, 08195, Sant Cugat del Valles, Barcelona, Spain
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), C/. Baldiri Reixac 10-12, 08028, Barcelona, Spain
| |
Collapse
|
|
8
|
COL17A1 facilitates tumor growth and predicts poor prognosis in pancreatic cancer. Biochem Biophys Res Commun 2022; 632:1-9. [DOI: 10.1016/j.bbrc.2022.09.049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 08/29/2022] [Accepted: 09/12/2022] [Indexed: 12/09/2022]
|
|
9
|
Jurj A, Ionescu C, Berindan-Neagoe I, Braicu C. The extracellular matrix alteration, implication in modulation of drug resistance mechanism: friends or foes? J Exp Clin Cancer Res 2022; 41:276. [PMID: 36114508 PMCID: PMC9479349 DOI: 10.1186/s13046-022-02484-1] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 09/01/2022] [Indexed: 11/10/2022] Open
Abstract
The extracellular matrix (ECM) is an important component of the tumor microenvironment (TME), having several important roles related to the hallmarks of cancer. In cancer, multiple components of the ECM have been shown to be altered. Although most of these alterations are represented by the increased or decreased quantity of the ECM components, changes regarding the functional alteration of a particular ECM component or of the ECM as a whole have been described. These alterations can be induced by the cancer cells directly or by the TME cells, with cancer-associated fibroblasts being of particular interest in this regard. Because the ECM has this wide array of functions in the tumor, preclinical and clinical studies have assessed the possibility of targeting the ECM, with some of them showing encouraging results. In the present review, we will highlight the most relevant ECM components presenting a comprehensive description of their physical, cellular and molecular properties which can alter the therapy response of the tumor cells. Lastly, some evidences regarding important biological processes were discussed, offering a more detailed understanding of how to modulate altered signalling pathways and to counteract drug resistance mechanisms in tumor cells.
Collapse
Affiliation(s)
- Ancuta Jurj
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, 400337, Cluj-Napoca, Romania
| | - Calin Ionescu
- 7Th Surgical Department, Iuliu Hațieganu University of Medicine and Pharmacy, 8 Victor Babes Street, 400012, Cluj-Napoca, Romania
- Surgical Department, Municipal Hospital, 400139, Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, 400337, Cluj-Napoca, Romania.
| | - Cornelia Braicu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, 400337, Cluj-Napoca, Romania.
- Research Center for Oncopathology and Translational Medicine (CCOMT), George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, 540139, Targu Mures, Romania.
| |
Collapse
|
|
10
|
FOTI C, GUARNERI F, DE PREZZO SA, CASSANO N, VENA GA, MERCURIO CS, D’ARIA G, ROMITA P. A case of bullous pemphigoid associated with metastatic bilio-pancreatic cancer. Ital J Dermatol Venerol 2022; 157:382-383. [DOI: 10.23736/s2784-8671.21.07159-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
|
|
11
|
Humphries JD, Zha J, Burns J, Askari JA, Below CR, Chastney MR, Jones MC, Mironov A, Knight D, O'Reilly DA, Dunne MJ, Garrod DR, Jorgensen C, Humphries MJ. Pancreatic ductal adenocarcinoma cells employ integrin α6β4 to form hemidesmosomes and regulate cell proliferation. Matrix Biol 2022; 110:16-39. [PMID: 35405272 DOI: 10.1016/j.matbio.2022.03.010] [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: 08/16/2021] [Revised: 03/15/2022] [Accepted: 03/31/2022] [Indexed: 12/24/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis due to its aggressive progression, late detection and lack of druggable driver mutations, which often combine to result in unsuitability for surgical intervention. Together with activating mutations of the small GTPase KRas, which are found in over 90% of PDAC tumours, a contributory factor for PDAC tumour progression is formation of a rigid extracellular matrix (ECM) and associated desmoplasia. This response leads to aberrant integrin signalling, and accelerated proliferation and invasion. To identify the integrin adhesion systems that operate in PDAC, we analysed a range of pancreatic ductal epithelial cell models using 2D, 3D and organoid culture systems. Proteomic analysis of isolated integrin receptor complexes from human pancreatic ductal epithelial (HPDE) cells predominantly identified integrin α6β4 and hemidesmosome components, rather than classical focal adhesion components. Electron microscopy, together with immunofluorescence, confirmed the formation of hemidesmosomes by HPDE cells, both in 2D and 3D culture systems. Similar results were obtained for the human PDAC cell line, SUIT-2. Analysis of HPDE cell secreted proteins and cell-derived matrices (CDM) demonstrated that HPDE cells secrete a range of laminin subunits and form a hemidesmosome-specific, laminin 332-enriched ECM. Expression of mutant KRas (G12V) did not affect hemidesmosome composition or formation by HPDE cells. Cell-ECM contacts formed by mouse and human PDAC organoids were also assessed by electron microscopy. Organoids generated from both the PDAC KPC mouse model and human patient-derived PDAC tissue displayed features of acinar-ductal cell polarity, and hemidesmosomes were visible proximal to prominent basement membranes. Furthermore, electron microscopy identified hemidesmosomes in normal human pancreas. Depletion of integrin β4 reduced cell proliferation in both SUIT-2 and HPDE cells, reduced the number of SUIT-2 cells in S-phase, and induced G1 cell cycle arrest, suggesting a requirement for α6β4-mediated adhesion for cell cycle progression and growth. Taken together, these data suggest that laminin-binding adhesion mechanisms in general, and hemidesmosome-mediated adhesion in particular, may be under-appreciated in the context of PDAC. Proteomic data are available via ProteomeXchange with the identifiers PXD027803, PXD027823 and PXD027827.
Collapse
Affiliation(s)
- Jonathan D Humphries
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK
| | - Junzhe Zha
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK
| | - Jessica Burns
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK
| | - Janet A Askari
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK
| | - Christopher R Below
- Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Cheshire SK10 4TG, UK
| | - Megan R Chastney
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK
| | - Matthew C Jones
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK
| | - Aleksandr Mironov
- Electron Microscopy Core Facility (RRID: SCR_021147), Faculty of Biology, Medicine & Health, University of Manchester, Manchester M13 9PT, UK
| | - David Knight
- Biological Mass Spectrometry Core Facility (RRID: SCR_020987), Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, UK
| | - Derek A O'Reilly
- Department of Hepatobiliary and Pancreatic Surgery, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK; Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, UK
| | - Mark J Dunne
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, UK
| | - David R Garrod
- Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, UK
| | - Claus Jorgensen
- Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Cheshire SK10 4TG, UK
| | - Martin J Humphries
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
| |
Collapse
|
|
12
|
Fischer NG, Kobe AC, Dai J, He J, Wang H, Pizarek JA, De Jong DA, Ye Z, Huang S, Aparicio C. Tapping basement membrane motifs: Oral junctional epithelium for surface-mediated soft tissue attachment to prevent failure of percutaneous devices. Acta Biomater 2022; 141:70-88. [PMID: 34971784 PMCID: PMC8898307 DOI: 10.1016/j.actbio.2021.12.030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 12/21/2021] [Accepted: 12/23/2021] [Indexed: 01/08/2023]
Abstract
Teeth, long-lasting percutaneous organs, feature soft tissue attachment through adhesive structures, hemidesmosomes, in the junctional epithelium basement membrane adjacent to teeth. This soft tissue attachment prevents bacterial infection of the tooth despite the rich - and harsh - microbial composition of the oral cavity. Conversely, millions of percutaneous devices (catheters, dental, and orthopedic implants) fail from infection yearly. Standard of care antibiotic usage fuels antimicrobial resistance and is frequently ineffective. Infection prevention strategies, like for dental implants, have failed in generating durable soft tissue adhesion - like that seen with the tooth - to prevent bacterial colonization at the tissue-device interface. Here, inspired by the impervious natural attachment of the junctional epithelium to teeth, we synthesized four cell adhesion peptide (CAPs) nanocoatings, derived from basement membranes, to promote percutaneous device soft tissue attachment. The two leading nanocoatings upregulated integrin-mediated hemidesmosomes, selectively increased keratinocyte proliferation compared to fibroblasts, which cannot form hemidesmosomes, and expression of junctional epithelium adhesive markers. CAP nanocoatings displayed marked durability under simulated clinical conditions and the top performer CAP nanocoating was validated in a percutaneous implant murine model. Basement membrane CAP nanocoatings, inspired by the tooth and junctional epithelium, may provide an alternative anti-infective strategy for percutaneous devices to mitigate the worldwide threat of antimicrobial resistance. STATEMENT OF SIGNIFICANCE: Prevention and management of medical device infection is a significant healthcare challenge. Overzealous antibiotic use has motivated alternative material innovations to prevent infection. Here, we report implant cell adhesion peptide nanocoatings that mimic a long-lasting, natural "medical device," the tooth, through formation of cell adhesive structures called hemidesmosomes. Such nanocoatings sidestep the use of antimicrobial or antibiotic elements to form a soft-tissue seal around implants. The top performing nanocoatings prompted expression of hemidesmosomes and defensive factors to mimic the tooth and was validated in an animal model. Application of cell adhesion peptide nanocoatings may provide an alternative to preventing, rather that necessarily treating, medical device infection across a range of device indications, like dental implants.
Collapse
Affiliation(s)
- Nicholas G Fischer
- MDRCBB-Minnesota Dental Research Center for Biomaterials and Biomechanics, University of Minnesota, 16-212 Moos Tower, 515 Delaware St. SE, Minneapolis, Minnesota 55455, United States
| | - Alexandra C Kobe
- MDRCBB-Minnesota Dental Research Center for Biomaterials and Biomechanics, University of Minnesota, 16-212 Moos Tower, 515 Delaware St. SE, Minneapolis, Minnesota 55455, United States
| | - Jinhong Dai
- Institute of Stomatology, School and Hospital of Stomatology, Department of Prosthodontics, Wenzhou Medical University, 373 Xueyuan Xi Road, Wenzhou, Zhejiang 325027, China
| | - Jiahe He
- MDRCBB-Minnesota Dental Research Center for Biomaterials and Biomechanics, University of Minnesota, 16-212 Moos Tower, 515 Delaware St. SE, Minneapolis, Minnesota 55455, United States
| | - Hongning Wang
- Institute of Stomatology, School and Hospital of Stomatology, Department of Prosthodontics, Wenzhou Medical University, 373 Xueyuan Xi Road, Wenzhou, Zhejiang 325027, China
| | - John A Pizarek
- MDRCBB-Minnesota Dental Research Center for Biomaterials and Biomechanics, University of Minnesota, 16-212 Moos Tower, 515 Delaware St. SE, Minneapolis, Minnesota 55455, United States; United States Navy Dental Corps, Naval Medical Leader and Professional Development Command, 8955 Wood Road Bethesda, MD 20889, United States
| | - David A De Jong
- MDRCBB-Minnesota Dental Research Center for Biomaterials and Biomechanics, University of Minnesota, 16-212 Moos Tower, 515 Delaware St. SE, Minneapolis, Minnesota 55455, United States
| | - Zhou Ye
- MDRCBB-Minnesota Dental Research Center for Biomaterials and Biomechanics, University of Minnesota, 16-212 Moos Tower, 515 Delaware St. SE, Minneapolis, Minnesota 55455, United States
| | - Shengbin Huang
- Institute of Stomatology, School and Hospital of Stomatology, Department of Prosthodontics, Wenzhou Medical University, 373 Xueyuan Xi Road, Wenzhou, Zhejiang 325027, China
| | - Conrado Aparicio
- MDRCBB-Minnesota Dental Research Center for Biomaterials and Biomechanics, University of Minnesota, 16-212 Moos Tower, 515 Delaware St. SE, Minneapolis, Minnesota 55455, United States.
| |
Collapse
|
|
13
|
Tuusa J, Kokkonen N, Tasanen K. BP180/Collagen XVII: A Molecular View. Int J Mol Sci 2021; 22:12233. [PMID: 34830116 PMCID: PMC8623354 DOI: 10.3390/ijms222212233] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 12/12/2022] Open
Abstract
BP180 is a type II collagenous transmembrane protein and is best known as the major autoantigen in the blistering skin disease bullous pemphigoid (BP). The BP180 trimer is a central component in type I hemidesmosomes (HD), which cause the adhesion between epidermal keratinocytes and the basal lamina, but BP180 is also expressed in several non-HD locations, where its functions are poorly characterized. The immunological roles of intact and proteolytically processed BP180, relevant in BP, have been subject to intensive research, but novel functions in cell proliferation, differentiation, and aging have also recently been described. To better understand the multiple physiological functions of BP180, the focus should return to the protein itself. Here, we comprehensively review the properties of the BP180 molecule, present new data on the biochemical features of its intracellular domain, and discuss their significance with regard to BP180 folding and protein-protein interactions.
Collapse
Affiliation(s)
| | | | - Kaisa Tasanen
- PEDEGO Research Unit, Department of Dermatology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 8000, FI-90014 Oulu, Finland; (J.T.); (N.K.)
| |
Collapse
|
|
14
|
Nanba D, Toki F, Asakawa K, Matsumura H, Shiraishi K, Sayama K, Matsuzaki K, Toki H, Nishimura EK. EGFR-mediated epidermal stem cell motility drives skin regeneration through COL17A1 proteolysis. J Cell Biol 2021; 220:e202012073. [PMID: 34550317 PMCID: PMC8563287 DOI: 10.1083/jcb.202012073] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 06/25/2021] [Accepted: 08/12/2021] [Indexed: 01/09/2023] Open
Abstract
Skin regenerative capacity declines with age, but the underlying mechanisms are largely unknown. Here we demonstrate a functional link between epidermal growth factor receptor (EGFR) signaling and type XVII collagen (COL17A1) proteolysis on age-associated alteration of keratinocyte stem cell dynamics in skin regeneration. Live-imaging and computer simulation experiments predicted that human keratinocyte stem cell motility is coupled with self-renewal and epidermal regeneration. Receptor tyrosine kinase array identified the age-associated decline of EGFR signaling in mouse skin wound healing. Culture experiments proved that EGFR activation drives human keratinocyte stem cell motility with increase of COL17A1 by inhibiting its proteolysis through the secretion of tissue inhibitor of metalloproteinases 1 (TIMP1). Intriguingly, COL17A1 directly regulated keratinocyte stem cell motility and collective cell migration by coordinating actin and keratin filament networks. We conclude that EGFR-COL17A1 axis-mediated keratinocyte stem cell motility drives epidermal regeneration, which provides a novel therapeutic approach for age-associated impaired skin regeneration.
Collapse
Affiliation(s)
- Daisuke Nanba
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Fujio Toki
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kyosuke Asakawa
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroyuki Matsumura
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ken Shiraishi
- Department of Dermatology, Ehime University School of Medicine, Toon, Japan
| | - Koji Sayama
- Department of Dermatology, Ehime University School of Medicine, Toon, Japan
| | - Kyoichi Matsuzaki
- Department of Plastic and Reconstructive Surgery, International University of Health and Welfare, School of Medicine, Narita, Japan
| | - Hiroshi Toki
- Research Center for Nuclear Physics, Osaka University, Osaka, Japan
- Health Care Division, Health and Counseling Center, Osaka University, Osaka, Japan
| | - Emi K. Nishimura
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
- Division of Aging and Regeneration, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
15
|
Wu Y, Zhou Q, Guo F, Chen M, Tao X, Dong D. S100 Proteins in Pancreatic Cancer: Current Knowledge and Future Perspectives. Front Oncol 2021; 11:711180. [PMID: 34527585 PMCID: PMC8435722 DOI: 10.3389/fonc.2021.711180] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/12/2021] [Indexed: 12/25/2022] Open
Abstract
Pancreatic cancer (PC) is a highly malignant tumor occurring in the digestive system. Currently, there is a lack of specific and effective interventions for PC; thus, further exploration regarding the pathogenesis of this malignancy is warranted. The S100 protein family, a collection of calcium-binding proteins expressed only in vertebrates, comprises 25 members with high sequence and structural similarity. Dysregulated expression of S100 proteins is a biomarker of cancer progression and prognosis. Functionally, these proteins are associated with the regulation of multiple cellular processes, including proliferation, apoptosis, growth, differentiation, enzyme activation, migration/invasion, Ca2+ homeostasis, and energy metabolism. This review highlights the significance of the S100 family in the diagnosis and prognosis of PC and its vital functions in tumor cell metastasis, invasion and proliferation. A further understanding of S100 proteins will provide potential therapeutic targets for preventing or treating PC.
Collapse
Affiliation(s)
- Yu Wu
- Department of Clinical Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China.,College of Pharmacy, Dalian Medical University, Dalian, China
| | - Qi Zhou
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Fangyue Guo
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Mingming Chen
- Department of Clinical Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China.,College of Pharmacy, Dalian Medical University, Dalian, China
| | - Xufeng Tao
- School of Chemical Engineering, Dalian University of Technology, Dalian, China
| | - Deshi Dong
- Department of Clinical Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| |
Collapse
|
|
16
|
High Expression of COL17A1 Predicts Poor Prognosis and Promotes the Tumor Progression via NF- κB Pathway in Pancreatic Adenocarcinoma. JOURNAL OF ONCOLOGY 2020; 2020:8868245. [PMID: 33381179 PMCID: PMC7758145 DOI: 10.1155/2020/8868245] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 11/23/2020] [Accepted: 12/05/2020] [Indexed: 11/17/2022]
Abstract
COL17A1 (collagen type XVII alpha 1 chain) is known to be upregulated and has a prognostic role in many malignancies, as well as contributing to cell proliferation, apoptosis, and invasion. However, little knowledge is available on the expression and prognostic value of COL17A1 in pancreatic adenocarcinoma (PDAC). In our study, we searched the public database and found that mRNA and protein levels of COL17A1 are commonly upregulated in PDAC tissues. The immunohistochemical analysis conducted by us revealed enhanced expression of COL17A1 protein in 169 PDAC samples compared with that in 67 adjacent normal tissues. We also observed a significantly positive correlation between COL17A1 expression and lymph node metastasis (p < 0.0001), TNM clinical stage (p < 0.0001), and pathology differentiation (p < 0.01). The KM-plot results indicated that PDAC patients with a high COL17A1 expression have a poorer overall survival (p < 0.001) than those with a low COL17A1 expression. The result of the Cox regression analysis of multivariate data suggested COL17A1 is an independent prognostic indicator of PDAC patients' overall survival. CCK-8, wound healing, and transwell assays suggested that COL17A1 knockdown markedly inhibited tumor proliferation and invasion in PDAC cells, and cells with COL17A1 overexpression had a prominently higher proliferative and invasive capacity. Knockdown of COL17A1 significantly upregulated the apoptosis rate. We deduce that upregulated COL17A1 activated the NF-κB pathway in PDAC cells. In summary, our studies showed the prognostic value of COL17A1 in PDAC and that COL17A1 may act as a molecular therapeutic target for PDAC treatment.
Collapse
|
|
17
|
Jones VA, Patel PM, Gibson FT, Cordova A, Amber KT. The Role of Collagen XVII in Cancer: Squamous Cell Carcinoma and Beyond. Front Oncol 2020; 10:352. [PMID: 32266137 PMCID: PMC7096347 DOI: 10.3389/fonc.2020.00352] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 02/28/2020] [Indexed: 12/12/2022] Open
Abstract
Alterations in the extracellular matrix (ECM) likely facilitate the first steps of cancer cell metastasis and supports tumor progression. Recent data has demonstrated that alterations in collagen XVII (BP180), a transmembrane protein and structural component of the ECM, can have profound effects on cancer invasiveness. Collagen XVII is a homotrimer of three α1 (XVII) chains. Its intracellular domain contains binding sites for plectin, integrin β4, and BP230, while the extracellular domain facilitates interactions between the cell and the ECM. Collagen XVII and its shed ectodomain have been implicated in cell motility and adhesion and are believed to promote tumor development and invasion. A strong association of collagen XVII ectodomain shedding and tumor invasiveness occurs in squamous cell carcinoma (SCC). Aberrant expression of collagen XVII has been reported in many epithelial cancers, ranging from squamous cell carcinoma to colon, pancreatic, mammary, and ovarian carcinoma. Thus, in this review, we focus on collagen XVII's role in neoplasia and tumorigenesis. Lastly, we discuss the importance of targeting collagen XVII and its ectodomain shedding as a novel strategy to curb tumor growth and reduce metastatic potential.
Collapse
Affiliation(s)
- Virginia A Jones
- Skin Immunology Laboratory, Department of Dermatology, University of Illinois at Chicago, Chicago, IL, United States
| | - Payal M Patel
- Skin Immunology Laboratory, Department of Dermatology, University of Illinois at Chicago, Chicago, IL, United States
| | - Frederick T Gibson
- Skin Immunology Laboratory, Department of Dermatology, University of Illinois at Chicago, Chicago, IL, United States
| | - Adriana Cordova
- Skin Immunology Laboratory, Department of Dermatology, University of Illinois at Chicago, Chicago, IL, United States
| | - Kyle T Amber
- Skin Immunology Laboratory, Department of Dermatology, University of Illinois at Chicago, Chicago, IL, United States
| |
Collapse
|
|
18
|
Modifying the Tumour Microenvironment: Challenges and Future Perspectives for Anticancer Plasma Treatments. Cancers (Basel) 2019; 11:cancers11121920. [PMID: 31810265 PMCID: PMC6966454 DOI: 10.3390/cancers11121920] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 11/24/2019] [Accepted: 11/25/2019] [Indexed: 02/07/2023] Open
Abstract
Tumours are complex systems formed by cellular (malignant, immune, and endothelial cells, fibroblasts) and acellular components (extracellular matrix (ECM) constituents and secreted factors). A close interplay between these factors, collectively called the tumour microenvironment, is required to respond appropriately to external cues and to determine the treatment outcome. Cold plasma (here referred as ‘plasma’) is an emerging anticancer technology that generates a unique cocktail of reactive oxygen and nitrogen species to eliminate cancerous cells via multiple mechanisms of action. While plasma is currently regarded as a local therapy, it can also modulate the mechanisms of cell-to-cell and cell-to-ECM communication, which could facilitate the propagation of its effect in tissue and distant sites. However, it is still largely unknown how the physical interactions occurring between cells and/or the ECM in the tumour microenvironment affect the plasma therapy outcome. In this review, we discuss the effect of plasma on cell-to-cell and cell-to-ECM communication in the context of the tumour microenvironment and suggest new avenues of research to advance our knowledge in the field. Furthermore, we revise the relevant state-of-the-art in three-dimensional in vitro models that could be used to analyse cell-to-cell and cell-to-ECM communication and further strengthen our understanding of the effect of plasma in solid tumours.
Collapse
|
|
19
|
Cruz da Silva E, Dontenwill M, Choulier L, Lehmann M. Role of Integrins in Resistance to Therapies Targeting Growth Factor Receptors in Cancer. Cancers (Basel) 2019; 11:cancers11050692. [PMID: 31109009 PMCID: PMC6562376 DOI: 10.3390/cancers11050692] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/13/2019] [Accepted: 05/14/2019] [Indexed: 02/07/2023] Open
Abstract
Integrins contribute to cancer progression and aggressiveness by activating intracellular signal transduction pathways and transducing mechanical tension forces. Remarkably, these adhesion receptors share common signaling networks with receptor tyrosine kinases (RTKs) and support their oncogenic activity, thereby promoting cancer cell proliferation, survival and invasion. During the last decade, preclinical studies have revealed that integrins play an important role in resistance to therapies targeting RTKs and their downstream pathways. A remarkable feature of integrins is their wide-ranging interconnection with RTKs, which helps cancer cells to adapt and better survive therapeutic treatments. In this context, we should consider not only the integrins expressed in cancer cells but also those expressed in stromal cells, since these can mechanically increase the rigidity of the tumor microenvironment and confer resistance to treatment. This review presents some of these mechanisms and outlines new treatment options for improving the efficacy of therapies targeting RTK signaling.
Collapse
Affiliation(s)
- Elisabete Cruz da Silva
- UMR 7021 CNRS, Laboratoire de Bioimagerie et Pathologies, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, 67401 Illkirch, France.
| | - Monique Dontenwill
- UMR 7021 CNRS, Laboratoire de Bioimagerie et Pathologies, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, 67401 Illkirch, France.
| | - Laurence Choulier
- UMR 7021 CNRS, Laboratoire de Bioimagerie et Pathologies, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, 67401 Illkirch, France.
| | - Maxime Lehmann
- UMR 7021 CNRS, Laboratoire de Bioimagerie et Pathologies, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, 67401 Illkirch, France.
| |
Collapse
|
|
20
|
Mu W, Wang Z, Zöller M. Ping-Pong-Tumor and Host in Pancreatic Cancer Progression. Front Oncol 2019; 9:1359. [PMID: 31921628 PMCID: PMC6927459 DOI: 10.3389/fonc.2019.01359] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 11/18/2019] [Indexed: 12/12/2022] Open
Abstract
Metastasis is the main cause of high pancreatic cancer (PaCa) mortality and trials dampening PaCa mortality rates are not satisfying. Tumor progression is driven by the crosstalk between tumor cells, predominantly cancer-initiating cells (CIC), and surrounding cells and tissues as well as distant organs, where tumor-derived extracellular vesicles (TEX) are of major importance. A strong stroma reaction, recruitment of immunosuppressive leukocytes, perineural invasion, and early spread toward the peritoneal cavity, liver, and lung are shared with several epithelial cell-derived cancer, but are most prominent in PaCa. Here, we report on the state of knowledge on the PaCIC markers Tspan8, alpha6beta4, CD44v6, CXCR4, LRP5/6, LRG5, claudin7, EpCAM, and CD133, which all, but at different steps, are engaged in the metastatic cascade, frequently via PaCIC-TEX. This includes the contribution of PaCIC markers to TEX biogenesis, targeting, and uptake. We then discuss PaCa-selective features, where feedback loops between stromal elements and tumor cells, including distorted transcription, signal transduction, and metabolic shifts, establish vicious circles. For the latter particularly pancreatic stellate cells (PSC) are responsible, furnishing PaCa to cope with poor angiogenesis-promoted hypoxia by metabolic shifts and direct nutrient transfer via vesicles. Furthermore, nerves including Schwann cells deliver a large range of tumor cell attracting factors and Schwann cells additionally support PaCa cell survival by signaling receptor binding. PSC, tumor-associated macrophages, and components of the dysplastic stroma contribute to perineural invasion with signaling pathway activation including the cholinergic system. Last, PaCa aggressiveness is strongly assisted by the immune system. Although rich in immune cells, only immunosuppressive cells and factors are recovered in proximity to tumor cells and hamper effector immune cells entering the tumor stroma. Besides a paucity of immunostimulatory factors and receptors, immunosuppressive cytokines, myeloid-derived suppressor cells, regulatory T-cells, and M2 macrophages as well as PSC actively inhibit effector cell activation. This accounts for NK cells of the non-adaptive and cytotoxic T-cells of the adaptive immune system. We anticipate further deciphering the molecular background of these recently unraveled intermingled phenomena may turn most lethal PaCa into a curatively treatable disease.
Collapse
Affiliation(s)
- Wei Mu
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Wei Mu
| | - Zhe Wang
- Department of Oncology, The First Affiliated Hospital of Guangdong, Pharmaceutical University, Guangzhou, China
| | - Margot Zöller
- Department of Oncology, The First Affiliated Hospital of Guangdong, Pharmaceutical University, Guangzhou, China
| |
Collapse
|
|
21
|
Günther T, Tulipano G, Dournaud P, Bousquet C, Csaba Z, Kreienkamp HJ, Lupp A, Korbonits M, Castaño JP, Wester HJ, Culler M, Melmed S, Schulz S. International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature. Pharmacol Rev 2018; 70:763-835. [PMID: 30232095 PMCID: PMC6148080 DOI: 10.1124/pr.117.015388] [Citation(s) in RCA: 164] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein-coupled receptors (GPCRs) called somatostatin receptor (SST)1-5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature.
Collapse
Affiliation(s)
- Thomas Günther
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Giovanni Tulipano
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Pascal Dournaud
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Corinne Bousquet
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Zsolt Csaba
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Hans-Jürgen Kreienkamp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Amelie Lupp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Márta Korbonits
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Justo P Castaño
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Hans-Jürgen Wester
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Michael Culler
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Shlomo Melmed
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Stefan Schulz
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| |
Collapse
|
|
22
|
Yu A, Wang Y, Bian Y, Chen L, Guo J, Shen W, Chen D, Liu S, Sun X. IL-1β promotes the nuclear translocaiton of S100A4 protein in gastric cancer cells MGC803 and the cell's stem-like properties through PI3K pathway. J Cell Biochem 2018; 119:8163-8173. [PMID: 29932233 DOI: 10.1002/jcb.26813] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 02/23/2018] [Indexed: 12/16/2022]
Abstract
It has been shown that nuclear expression of S100A4 is significantly correlated with increased metastasis and reduced survival in patients with gastric cancer and many other cancers. However, the factors which could influence the nuclear contents of S100A4 in cancer cells are not clear. It has also been reported that Interleukin-1β (IL-1β) promotes the nuclear translocation of S100A4 in chondrocytes. Previous studies have shown that IL-1β promotes the stemness of colon cancer cells, and S100A4 is also involved in maintaining cancer-initiating cells in head and neck cancers. We speculate that IL-1β might promote the nuclear translocation of S100A4 protein in MGC803 gastric cancer cells and therefore enhance their stem-like properties. The results from Western-blot and qRT-PCR analysis showed that IL-1β increased the nuclear and total cellular content of S100A4 protein and S100A4 mRNA level in MGC803 cells. LY294002, a pharmacological inhibitor of Phosphoinositide 3-kinase (PI3K) reversed the above effects. Functional studies indicated that IL-1β promoted the colony-forming and spheroid-forming capabilities of the cells and the expression of SOX2 and NANOG gene. PI3K or S100A4 inhibition reversed the IL-1β-mediated increase in colony and spheroid-forming capabilities of the cells. LY294002 also reversed the elevated SOX2 and NANOG expression induced by IL-1β. Our study demonstrated that IL-1β promote the nuclear translocation of S100A4 protein in gastric cancer cells MGC803, which are PI3K dependent, suggesting the existence of IL-1β-PI3K-S100A4 pathway for the first time. The study also showed that IL-1β promoted stem-like properties of the cells through the new pathway.
Collapse
Affiliation(s)
- Aiwen Yu
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China.,Department of Rehabilitation, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yu Wang
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China
| | - Yue Bian
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China
| | - Lisha Chen
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China
| | - Junfu Guo
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China
| | - Wei Shen
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China
| | - Danqi Chen
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China
| | - Shanshan Liu
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China
| | - Xiuju Sun
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China
| |
Collapse
|
|
23
|
Fu R, Zhu Y, Jiang X, Li Y, Zhu M, Dong M, Huang Z, Wang C, Labouesse M, Zhang H. CCAR-1 affects hemidesmosome biogenesis by regulating unc-52/perlecan alternative splicing in the C. elegans epidermis. J Cell Sci 2018; 131:jcs.214379. [PMID: 29748380 DOI: 10.1242/jcs.214379] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 05/02/2018] [Indexed: 12/31/2022] Open
Abstract
Hemidesmosomes are epithelial-specific attachment structures that maintain tissue integrity and resist tension. Despite their importance, how hemidesmosomes are regulated at the post-transcriptional level is poorly understood. Caenorhabditiselegans hemidesmosomes (CeHDs) have a similar structure and composition to their mammalian counterparts, making C. elegans an ideal model for studying hemidesmosomes. Here, we focus on the transcription regulator CCAR-1, identified in a previous genetic screen searching for enhancers of mutations in the conserved hemidesmosome component VAB-10A (known as plectin in mammals). Loss of CCAR-1 function in a vab-10(e698) background results in CeHD disruption and muscle detachment from the epidermis. CCAR-1 regulates CeHD biogenesis, not by controlling the transcription of CeHD-related genes, but by affecting the alternative splicing of unc-52 (known as perlecan or HSPG2 in mammals), the predicted basement extracellular matrix (ECM) ligand of CeHDs. CCAR-1 physically interacts with HRP-2 (hnRNPR in mammals), a splicing factor known to mediate unc-52 alternative splicing to control the proportions of different UNC-52 isoforms and stabilize CeHDs. Our discovery underlines the importance of post-transcriptional regulation in hemidesmosome reorganization. It also uncovers previously unappreciated roles of CCAR-1 in alternative splicing and hemidesmosome biogenesis, shedding new light on the mechanisms through which mammalian CCAR1 functions in tumorigenesis.
Collapse
Affiliation(s)
- Rong Fu
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Yi Zhu
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Xiaowan Jiang
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Yuanbao Li
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Ming Zhu
- National Institute of Biological Sciences, Beijing 102206, China
| | - Mengqiu Dong
- National Institute of Biological Sciences, Beijing 102206, China
| | - Zhaohui Huang
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Chunxia Wang
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Michel Labouesse
- Institut de Biologie Paris Seine, Université Pierre et Marie Curie, Paris 75005, France
| | - Huimin Zhang
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| |
Collapse
|
|
24
|
Sandow C, Fugler LA, Leise B, Riggs L, Monroe WT, Totaro N, Belknap J, Eades S. Ex vivo effects of insulin on the structural integrity of equine digital lamellae. Equine Vet J 2018; 51:131-135. [PMID: 29758109 DOI: 10.1111/evj.12964] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 05/05/2018] [Indexed: 12/27/2022]
Abstract
BACKGROUND Laminitis has a considerable impact on the equine industry. Endocrinopathic laminitis is the most common form and affected horses often have hyperinsulinaemia due to an underlying metabolic disorder. OBJECTIVES The aim of this study was to determine if insulin weakens the structural integrity of digital lamellae and to develop an ex vivo model for the study of hyperinsulinaemia-induced lamellar failure. STUDY DESIGN Ex vivo experiment. METHODS Biomechanical testing was used to assess the structural integrity of lamellar explants exposed to either medium alone (control) or medium supplemented with insulin. Lamellar explants comprised of hoof wall, lamellar tissue and distal phalanx were harvested from four adult horses with no evidence of inflammatory disease or pre-existing disease of the digit. Following an equilibration period, explants were incubated in medium or medium supplemented with insulin (2.5 μg/ml) for 8 h prior to biomechanical testing to obtain load (N), stress (MPa), elongation to failure (mm), and Young's modulus (MPa) for each explant. Significant differences were assessed using a mixed linear model with horses as a random factor and control or insulin-treated group as a fixed factor. RESULTS Lamellar explants incubated in medium supplemented with insulin failed at significantly lower load (P = 0.0001) and lower stress (P = 0.001) and had greater elongation to failure (P = 0.02). MAIN LIMITATIONS In addition to the ex vivo nature of the study, location-dependent variability in explant structural integrity and variable diffusion of nutrients due to explant size may have been limitations. However, the study design attempted to account for these limitations through random assignment of explants to treatment groups independent of location and by evaluating stress to failure. CONCLUSIONS Insulin weakens the structural integrity of equine lamellar explants and an ex vivo model for evaluation of hyperinsulinaemia-induced lamellar failure was established. The summary is available in Spanish - see Supporting Information.
Collapse
Affiliation(s)
- C Sandow
- Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
| | - L A Fugler
- Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
| | - B Leise
- Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
| | - L Riggs
- Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
| | - W T Monroe
- Department of Biological and Agricultural Engineering, Louisiana State University, Baton Rouge, Louisiana, USA
| | - N Totaro
- Department of Biological and Agricultural Engineering, Louisiana State University, Baton Rouge, Louisiana, USA
| | - J Belknap
- Veterinary Clinical Sciences, The Ohio State University College of Veterinary Medicine, Columbus, Ohio, USA
| | - S Eades
- Department of Large Animal Clinical Sciences, Texas A&M University, College of Veterinary Medicine and Biomedical Sciences, College Station, Texas, USA
| |
Collapse
|
|
25
|
Galiger C, Löffek S, Stemmler MP, Kroeger JK, Mittapalli VR, Fauth L, Esser PR, Kern JS, Meiss F, Laßmann S, Bruckner-Tuderman L, Franzke CW. Targeting of Cell Surface Proteolysis of Collagen XVII Impedes Squamous Cell Carcinoma Progression. Mol Ther 2018; 26:17-30. [PMID: 29055623 PMCID: PMC5763164 DOI: 10.1016/j.ymthe.2017.09.022] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 09/21/2017] [Accepted: 09/21/2017] [Indexed: 02/07/2023] Open
Abstract
Squamous cell carcinoma (SCC) is one of the most common skin cancers and causes significant morbidity. Although the expression of the epithelial adhesion molecule collagen XVII (ColXVII) has been linked to SCC invasion, only little is known about its mechanistic contribution. Here, we demonstrate that ColXVII expression is essential for SCC cell proliferation and motility. Moreover, it revealed that particularly the post-translational modification of ColXVII by ectodomain shedding is the major driver of SCC progression, because ectodomain-selective immunostaining was mainly localized at the invasive front of human cutaneous SCCs, and exclusive expression of a non-sheddable ColXVII mutant in SCC-25 cells inhibits their matrix-independent growth and invasiveness. This cell surface proteolysis, which is strongly elevated during SCC invasion and metastasis, releases soluble ectodomains and membrane-anchored endodomains. Both released ColXVII domains play distinct roles in tumor progression: the endodomain induces proliferation and survival, whereas the ectodomain accelerates invasiveness. Furthermore, specific blockage of shedding by monoclonal ColXVII antibodies repressed matrix-independent growth and invasion of SCC cells in organotypic co-cultures. Thus, selective inhibition of ColXVII shedding may offer a promising therapeutic strategy to prevent SCC progression.
Collapse
Affiliation(s)
- Célimène Galiger
- Department of Dermatology, Medical Center and Faculty of Medicine-University of Freiburg, 79104 Freiburg, Germany
| | - Stefanie Löffek
- Department of Dermatology, Medical Center and Faculty of Medicine-University of Freiburg, 79104 Freiburg, Germany
| | - Marc P Stemmler
- Department of Experimental Medicine I, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Jasmin K Kroeger
- Department of Dermatology, Medical Center and Faculty of Medicine-University of Freiburg, 79104 Freiburg, Germany
| | - Venugopal R Mittapalli
- Department of Dermatology, Medical Center and Faculty of Medicine-University of Freiburg, 79104 Freiburg, Germany
| | - Lisa Fauth
- Institute for Surgical Pathology, Medical Center and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Philipp R Esser
- Department of Dermatology, Medical Center and Faculty of Medicine-University of Freiburg, 79104 Freiburg, Germany
| | - Johannes S Kern
- Department of Dermatology, Medical Center and Faculty of Medicine-University of Freiburg, 79104 Freiburg, Germany
| | - Frank Meiss
- Department of Dermatology, Medical Center and Faculty of Medicine-University of Freiburg, 79104 Freiburg, Germany
| | - Silke Laßmann
- Institute for Surgical Pathology, Medical Center and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; Centre for Biological Signalling Studies BIOSS, ALU Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Leena Bruckner-Tuderman
- Department of Dermatology, Medical Center and Faculty of Medicine-University of Freiburg, 79104 Freiburg, Germany; Centre for Biological Signalling Studies BIOSS, ALU Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Claus-Werner Franzke
- Department of Dermatology, Medical Center and Faculty of Medicine-University of Freiburg, 79104 Freiburg, Germany.
| |
Collapse
|
|
26
|
TWEAK/Fn14 Activation Contributes to the Pathogenesis of Bullous Pemphigoid. J Invest Dermatol 2017; 137:1512-1522. [DOI: 10.1016/j.jid.2017.03.019] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 03/06/2017] [Accepted: 03/07/2017] [Indexed: 01/05/2023]
|
|
27
|
Yodsurang V, Tanikawa C, Miyamoto T, Lo PHY, Hirata M, Matsuda K. Identification of a novel p53 target, COL17A1, that inhibits breast cancer cell migration and invasion. Oncotarget 2017; 8:55790-55803. [PMID: 28915553 PMCID: PMC5593524 DOI: 10.18632/oncotarget.18433] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 05/29/2017] [Indexed: 12/23/2022] Open
Abstract
p53 mutation is a marker of poor prognosis in breast cancers. To identify downstream targets of p53, we screened two transcriptome datasets, including cDNA microarrays of MCF10A breast epithelial cells with wild-type p53 or p53-null background, and RNA sequence analysis of breast invasive carcinoma. Here, we unveil ten novel p53 target candidates that are up-regulated after the induction of p53 in wild-type cells. Their expressions are also high in breast invasive carcinoma tissues with wild-type p53. The GO analysis identified epidermis development and ectoderm development, which COL17A1 participates, as significantly up-regulated by wild-type p53. The COL17A1 expressions increased in a p53-dependent manner in human breast cells and mouse mammary tissues. Reporter assay and ChIP assay identified intronic p53-binding sequences in the COL17A1 gene. The MDA-MB-231 cells that genetically over-express COL17A1 gene product exhibited reduced migration and invasion in vitro. Similarly, COL17A1 expression was decreased in metastatic tumors compared to primary tumors and normal tissues, even from the same patients. Moreover, high COL17A1 expression was associated with longer survival of patients with invasive breast carcinoma. In conclusion, we revealed that COL17A1 is a novel p53 transcriptional target in breast tissues that inhibits cell migration and invasion and is associated with better prognosis.
Collapse
Affiliation(s)
- Varalee Yodsurang
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo, Japan
| | - Chizu Tanikawa
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Takafumi Miyamoto
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Paulisally Hau Yi Lo
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Makoto Hirata
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Koichi Matsuda
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo, Japan.,Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
28
|
Lane HE, Burns TA, Hegedus OC, Watts MR, Weber PS, Woltman KA, Geor RJ, McCutcheon LJ, Eades SC, Mathes LE, Belknap JK. Lamellar events related to insulin‐like growth factor‐1 receptor signalling in two models relevant to endocrinopathic laminitis. Equine Vet J 2017; 49:643-654. [DOI: 10.1111/evj.12663] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 01/04/2017] [Indexed: 12/20/2022]
Affiliation(s)
- H. E. Lane
- Department of Veterinary Clinical Sciences College of Veterinary Medicine Ohio State University Columbus Ohio USA
| | - T. A. Burns
- Department of Veterinary Clinical Sciences College of Veterinary Medicine Ohio State University Columbus Ohio USA
| | - O. C. Hegedus
- Department of Veterinary Clinical Sciences College of Veterinary Medicine Ohio State University Columbus Ohio USA
| | - M. R. Watts
- Department of Veterinary Clinical Sciences College of Veterinary Medicine Ohio State University Columbus Ohio USA
| | - P. S. Weber
- Department of Large Animal Clinical Sciences College of Veterinary Medicine Michigan State University East Lansing Michigan USA
| | - K. A. Woltman
- Department of Large Animal Clinical Sciences College of Veterinary Medicine Michigan State University East Lansing Michigan USA
| | - R. J. Geor
- Department of Large Animal Clinical Sciences College of Veterinary Medicine Michigan State University East Lansing Michigan USA
| | - L. J. McCutcheon
- Department of Large Animal Clinical Sciences College of Veterinary Medicine Michigan State University East Lansing Michigan USA
| | - S. C. Eades
- Department of Veterinary Clinical Sciences School of Veterinary Medicine Louisiana State University Baton Rouge Louisiana USA
| | - L. E. Mathes
- Department of Veterinary Clinical Sciences College of Veterinary Medicine Ohio State University Columbus Ohio USA
- Department of Veterinary Biosciences College of Veterinary Medicine Ohio State University Columbus Ohio USA
| | - J. K. Belknap
- Department of Veterinary Clinical Sciences College of Veterinary Medicine Ohio State University Columbus Ohio USA
| |
Collapse
|
|
29
|
Romeijn TR, Jonkman MF, Knoppers C, Pas HH, Diercks GFH. Complement in bullous pemphigoid: results from a large observational study. Br J Dermatol 2016; 176:517-519. [PMID: 27344014 DOI: 10.1111/bjd.14822] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- T R Romeijn
- Department of Pathology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands
| | - M F Jonkman
- Department of Dermatology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands
| | - C Knoppers
- Department of Dermatology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands
| | - H H Pas
- Department of Dermatology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands
| | - G F H Diercks
- Department of Pathology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.,Department of Dermatology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands
| |
Collapse
|
|
30
|
Heiler S, Wang Z, Zöller M. Pancreatic cancer stem cell markers and exosomes - the incentive push. World J Gastroenterol 2016; 22:5971-6007. [PMID: 27468191 PMCID: PMC4948278 DOI: 10.3748/wjg.v22.i26.5971] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Revised: 06/03/2016] [Accepted: 06/28/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PaCa) has the highest death rate and incidence is increasing. Poor prognosis is due to late diagnosis and early metastatic spread, which is ascribed to a minor population of so called cancer stem cells (CSC) within the mass of the primary tumor. CSC are defined by biological features, which they share with adult stem cells like longevity, rare cell division, the capacity for self renewal, differentiation, drug resistance and the requirement for a niche. CSC can also be identified by sets of markers, which for pancreatic CSC (Pa-CSC) include CD44v6, c-Met, Tspan8, alpha6beta4, CXCR4, CD133, EpCAM and claudin7. The functional relevance of CSC markers is still disputed. We hypothesize that Pa-CSC markers play a decisive role in tumor progression. This is fostered by the location in glycolipid-enriched membrane domains, which function as signaling platform and support connectivity of the individual Pa-CSC markers. Outside-in signaling supports apoptosis resistance, stem cell gene expression and tumor suppressor gene repression as well as miRNA transcription and silencing. Pa-CSC markers also contribute to motility and invasiveness. By ligand binding host cells are triggered towards creating a milieu supporting Pa-CSC maintenance. Furthermore, CSC markers contribute to the generation, loading and delivery of exosomes, whereby CSC gain the capacity for a cell-cell contact independent crosstalk with the host and neighboring non-CSC. This allows Pa-CSC exosomes (TEX) to reprogram neighboring non-CSC towards epithelial mesenchymal transition and to stimulate host cells towards preparing a niche for metastasizing tumor cells. Finally, TEX communicate with the matrix to support tumor cell motility, invasion and homing. We will discuss the possibility that CSC markers are the initial trigger for these processes and what is the special contribution of CSC-TEX.
Collapse
|
|
31
|
Moatassim-Billah S, Duluc C, Samain R, Jean C, Perraud A, Decaup E, Cassant-Sourdy S, Bakri Y, Selves J, Schmid H, Martineau Y, Mathonnet M, Pyronnet S, Bousquet C. Anti-metastatic potential of somatostatin analog SOM230: Indirect pharmacological targeting of pancreatic cancer-associated fibroblasts. Oncotarget 2016; 7:41584-41598. [PMID: 27177087 PMCID: PMC5173080 DOI: 10.18632/oncotarget.9296] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 03/31/2016] [Indexed: 12/26/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) shows a rich stroma where cancer-associated fibroblasts (CAFs) represent the major cell type. CAFs are master secretors of proteins with pro-tumor features. CAF targeting remains a promising challenge for PDA, a devastating disease where treatments focusing on cancer cells have failed. We previously introduced a novel pharmacological CAF-targeting approach using the somatostatin analog SOM230 (pasireotide) that inhibits protein synthesis in CAFs, and subsequent chemoprotective features of CAF secretome. Using primary cultures of CAF isolated from human PDA resections, we here report that CAF secretome stimulates in vitro cancer cell survival, migration and invasive features, that are abolished when CAFs are treated with SOM230. Mechanistically, SOM230 inhibitory effect on CAFs depends on the somatostatin receptor subtype sst1 expressed in CAFs but not in non-activated pancreatic fibroblasts, and on protein synthesis shutdown through eiF4E-Binding Protein-1 (4E-BP1) expression decrease. We identify interleukin-6 as a SOM230-inhibited CAF-secreted effector, which stimulates cancer cell features through phosphoinositide 3-kinase activation. In vivo, mice orthotopically co-xenografted with the human pancreatic cancer MiaPaCa-2 cells and CAFs develop pancreatic tumors, on which SOM230 treatment does not inhibit growth but abrogates metastasis. Consistently, CAF secretome stimulates epithelial-to-mesenchymal transition in cancer cells, which is reversed upon CAF treatment with SOM230. Our results highlight a novel promising anti-metastatic potential for SOM230 indirectly targeting pancreatic cancer cell invasion through pharmacological inhibition of stromal CAFs.
Collapse
Affiliation(s)
- Siham Moatassim-Billah
- Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France
- Biochemistry-Immunology Laboratory, Faculty of Sciences Rabat, University Mohammed V - Agdal, Rabat, Morocco
| | - Camille Duluc
- Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France
| | - Rémi Samain
- Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France
| | - Christine Jean
- Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France
| | - Aurélie Perraud
- EA 3842 Laboratory, Medicine and Pharmacy Faculties, Limoges University, Limoges, France
| | - Emilie Decaup
- Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France
| | - Stéphanie Cassant-Sourdy
- Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France
| | - Youssef Bakri
- Biochemistry-Immunology Laboratory, Faculty of Sciences Rabat, University Mohammed V - Agdal, Rabat, Morocco
| | - Janick Selves
- Pathology Department, Institut Universitaire du Cancer de Toulouse, Toulouse, France
| | - Herbert Schmid
- Oncology Global Development, Novartis Pharmaceuticals, Basel, Switzerland
| | - Yvan Martineau
- Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France
| | - Muriel Mathonnet
- EA 3842 Laboratory, Medicine and Pharmacy Faculties, Limoges University, Limoges, France
| | - Stéphane Pyronnet
- Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France
| | - Corinne Bousquet
- Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France
| |
Collapse
|
|
32
|
Abstract
Bullous pemphigoid (BP) is an autoimmune subepidermal blistering skin disease mainly affecting older individuals. Pathogenic autoantibodies preferentially target the non-collagenous 16A domain of collagen XVII (also called BP antigen 2, BPAG2) present in hemidesmosomes. The pathogenic anti-BPAG2 antibodies cause the dermal-epidermal separation in neonatal and adult mice as well as in cryosections of human skin. These experimental BP models stress a pivotal role for neutrophils and the Fcγ receptor of immunoglobulins. Mice that have been genetically manipulated in the pathogenic domain of BPAG2 spontaneously develop subepidermal blistering with pruritus and eosinophilic infiltration. BPAG2 is physiologically and aberrantly expressed in neuronal tissue and internal malignancies, and the associations of BP with Parkinson's disease, stroke and internal malignancies invites new investigations into the immunological dysregulation behind the comorbidity.
Collapse
Affiliation(s)
- Masutaka Furue
- Department of Dermatology, Kyushu University, Fukuoka, Japan
| | - Takafumi Kadono
- Department of Dermatology, St Marianna University School of Medicine, Kawasaki, Japan
| |
Collapse
|
|
33
|
Duluc C, Moatassim-Billah S, Chalabi-Dchar M, Perraud A, Samain R, Breibach F, Gayral M, Cordelier P, Delisle MB, Bousquet-Dubouch MP, Tomasini R, Schmid H, Mathonnet M, Pyronnet S, Martineau Y, Bousquet C. Pharmacological targeting of the protein synthesis mTOR/4E-BP1 pathway in cancer-associated fibroblasts abrogates pancreatic tumour chemoresistance. EMBO Mol Med 2016; 7:735-53. [PMID: 25834145 PMCID: PMC4459815 DOI: 10.15252/emmm.201404346] [Citation(s) in RCA: 159] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is extremely stroma-rich. Cancer-associated fibroblasts (CAFs) secrete proteins that activate survival and promote chemoresistance of cancer cells. Our results demonstrate that CAF secretome-triggered chemoresistance is abolished upon inhibition of the protein synthesis mTOR/4E-BP1 regulatory pathway which we found highly activated in primary cultures of α-SMA-positive CAFs, isolated from human PDAC resections. CAFs selectively express the sst1 somatostatin receptor. The SOM230 analogue (Pasireotide) activates the sst1 receptor and inhibits the mTOR/4E-BP1 pathway and the resultant synthesis of secreted proteins including IL-6. Consequently, tumour growth and chemoresistance in nude mice xenografted with pancreatic cancer cells and CAFs, or with pieces of resected human PDACs, are reduced when chemotherapy (gemcitabine) is combined with SOM230 treatment. While gemcitabine alone has marginal effects, SOM230 is permissive to gemcitabine-induced cancer cell apoptosis and acts as an antifibrotic agent. We propose that selective inhibition of CAF protein synthesis with sst1-directed pharmacological compounds represents an anti-stromal-targeted therapy with promising chemosensitization potential.
Collapse
Affiliation(s)
- Camille Duluc
- INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France
| | - Siham Moatassim-Billah
- INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France Biochemistry-Immunology Laboratory, Faculty of Sciences Rabat, University Mohammed V - Agdal, Agdal, Morocco
| | - Mounira Chalabi-Dchar
- INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France
| | - Aurélie Perraud
- EA 3842 Laboratory, Medicine and Pharmacy Faculties, Limoges University, Limoges, France
| | - Rémi Samain
- INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France
| | | | - Marion Gayral
- INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France
| | - Pierre Cordelier
- INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France
| | | | - Marie-Pierre Bousquet-Dubouch
- CNRS UMR-5089, Institut de Pharmacologie et de Biologie structurale (IPBS), Université de Toulouse, Toulouse, France
| | - Richard Tomasini
- CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM105; CNRS, UMR7258, Marseille, France
| | | | - Muriel Mathonnet
- EA 3842 Laboratory, Medicine and Pharmacy Faculties, Limoges University, Limoges, France
| | - Stéphane Pyronnet
- INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France
| | - Yvan Martineau
- INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France
| | - Corinne Bousquet
- INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France
| |
Collapse
|
|
34
|
Matsumura H, Mohri Y, Binh NT, Morinaga H, Fukuda M, Ito M, Kurata S, Hoeijmakers J, Nishimura EK. Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis. Science 2016; 351:aad4395. [PMID: 26912707 DOI: 10.1126/science.aad4395] [Citation(s) in RCA: 264] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 12/17/2015] [Indexed: 12/12/2022]
Abstract
Hair thinning and loss are prominent aging phenotypes but have an unknown mechanism. We show that hair follicle stem cell (HFSC) aging causes the stepwise miniaturization of hair follicles and eventual hair loss in wild-type mice and in humans. In vivo fate analysis of HFSCs revealed that the DNA damage response in HFSCs causes proteolysis of type XVII collagen (COL17A1/BP180), a critical molecule for HFSC maintenance, to trigger HFSC aging, characterized by the loss of stemness signatures and by epidermal commitment. Aged HFSCs are cyclically eliminated from the skin through terminal epidermal differentiation, thereby causing hair follicle miniaturization. The aging process can be recapitulated by Col17a1 deficiency and prevented by the forced maintenance of COL17A1 in HFSCs, demonstrating that COL17A1 in HFSCs orchestrates the stem cell-centric aging program of the epithelial mini-organ.
Collapse
Affiliation(s)
- Hiroyuki Matsumura
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Yasuaki Mohri
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Nguyen Thanh Binh
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan. Department of Stem Cell Medicine, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan
| | - Hironobu Morinaga
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Makoto Fukuda
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Mayumi Ito
- Departments of Dermatology and Cell Biology, New York University School of Medicine, New York, NY, USA
| | - Sotaro Kurata
- Beppu Garden-Hill Clinic, Kurata Clinic, Beppu city, Oita 8740831, Japan
| | - Jan Hoeijmakers
- Department of Genetics, Cancer Genomics Center, Erasmus MC, Room Ee 722, Dr. Wytemaweg 80, 3015 CN Rotterdam, Netherlands
| | - Emi K Nishimura
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
| |
Collapse
|
|
35
|
Aung W, Tsuji AB, Sudo H, Sugyo A, Furukawa T, Ukai Y, Kurosawa Y, Saga T. Immunotargeting of Integrin α6β4 for Single-Photon Emission Computed Tomography and Near-Infrared Fluorescence Imaging in a Pancreatic Cancer Model. Mol Imaging 2016; 15:15/0/1536012115624917. [PMID: 27030400 PMCID: PMC5469600 DOI: 10.1177/1536012115624917] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 11/01/2015] [Indexed: 12/15/2022] Open
Abstract
To explore suitable imaging probes for early and specific detection of pancreatic cancer, we demonstrated that α6β4 integrin is a good target and employed single-photon emission computed tomography (SPECT) or near-infrared (NIR) imaging for immunotargeting. Expression levels of α6β4 were examined by Western blotting and flow cytometry in certain human pancreatic cancer cell lines. The human cell line BxPC-3 was used for α6β4-positive and a mouse cell line, A4, was used for negative counterpart. We labeled antibody against α6β4 with Indium-111 (111In) or indocyanine green (ICG). After injection of 111In-labeled probe to tumor-bearing mice, biodistribution, SPECT, autoradiography (ARG), and immunohistochemical (IHC) studies were conducted. After administration of ICG-labeled probe, in vivo and ex vivo NIR imaging and fluorescence microscopy of tumors were performed. BxPC-3 tumor showed a higher radioligand binding in SPECT and higher fluorescence intensity as well as a delay in the probe washout in NIR imaging when compared to A4 tumor. The biodistribution profile of 111In-labeled probe, ARG, and IHC confirmed the α6β4 specific binding of the probe. Here, we propose that α6β4 is a desirable target for the diagnosis of pancreatic cancer and that it could be detected by radionuclide imaging and NIR imaging using a radiolabeled or ICG-labeled α6β4 antibody.
Collapse
Affiliation(s)
- Winn Aung
- Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Atsushi B Tsuji
- Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Hitomi Sudo
- Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Aya Sugyo
- Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Takako Furukawa
- Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | | | - Yoshikazu Kurosawa
- Innovation Center for Advanced Medicine, Fujita Health University, Toyoake, Japan
| | - Tsuneo Saga
- Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| |
Collapse
|
|
36
|
Taffoni C, Pujol N. Mechanisms of innate immunity in C. elegans epidermis. Tissue Barriers 2015; 3:e1078432. [PMID: 26716073 PMCID: PMC4681281 DOI: 10.1080/21688370.2015.1078432] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 07/17/2015] [Accepted: 07/24/2015] [Indexed: 01/26/2023] Open
Abstract
The roundworm C. elegans has been successfully used for more than 50 y as a genetically tractable invertebrate model in diverse biological fields such as neurobiology, development and interactions. C. elegans feeds on bacteria and can be naturally infected by a wide range of microorganisms, including viruses, bacteria and fungi. Most of these pathogens infect C. elegans through its gut, but some have developed ways to infect the epidermis. In this review, we will mainly focus on epidermal innate immunity, in particular the signaling pathways and effectors activated upon wounding and fungal infection that serve to protect the host. We will discuss the parallels that exist between epidermal innate immune responses in nematodes and mammals.
Collapse
Affiliation(s)
- Clara Taffoni
- Center d'Immunologie de Marseille-Luminy; Aix Marseille Université UM2 ; Inserm; Marseille, France
| | - Nathalie Pujol
- Center d'Immunologie de Marseille-Luminy; Aix Marseille Université UM2 ; Inserm; Marseille, France
| |
Collapse
|
|
37
|
Chalabi-Dchar M, Cassant-Sourdy S, Duluc C, Fanjul M, Lulka H, Samain R, Roche C, Breibach F, Delisle MB, Poupot M, Dufresne M, Shimaoka T, Yonehara S, Mathonnet M, Pyronnet S, Bousquet C. Loss of Somatostatin Receptor Subtype 2 Promotes Growth of KRAS-Induced Pancreatic Tumors in Mice by Activating PI3K Signaling and Overexpression of CXCL16. Gastroenterology 2015; 148:1452-65. [PMID: 25683115 DOI: 10.1053/j.gastro.2015.02.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 02/04/2015] [Accepted: 02/06/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS The KRAS gene is mutated in most pancreatic ductal adenocarcinomas (PDAC). Expression of this KRAS oncoprotein in mice is sufficient to initiate carcinogenesis but not progression to cancer. Activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is required for KRAS for induction and maintenance of PDAC in mice. The somatostatin receptor subtype 2 (sst2) inhibits PI3K, but sst2 expression is lost during the development of human PDAC. We investigated the effects of sst2 loss during KRAS-induced PDAC development in mice. METHODS We analyzed tumor growth in mice that expressed the oncogenic form of KRAS (KRAS(G12D)) in pancreatic precursor cells, as well as sst2+/- and sst2-/-, and in crossed KRAS(G12D);sst2+/- and KRAS(G12D);sst2-/- mice. Pancreatic tissues and acini were collected and assessed by histologic, immunoblot, immunohistochemical, and reverse-transcription polymerase chain reaction analyses. We also compared protein levels in paraffin-embedded PDAC samples from patients vs heathy pancreatic tissues from individuals without pancreatic cancer. RESULTS In sst2+/- mice, PI3K was activated and signaled via AKT (PKB; protein kinase B); when these mice were crossed with KRAS(G12D) mice, premalignant lesions, tumors, and lymph node metastases developed more rapidly than in KRAS(G12D) mice. In crossed KRAS(G12D);sst2+/- mice, activation of PI3K signaling via AKT resulted in activation of nuclear factor-κB (NF-κB), which increased KRAS activity and its downstream pathways, promoting initiation and progression of neoplastic lesions. We found this activation loop to be mediated by PI3K-induced production of the chemokine CXCL16. Administration of a CXCL16-neutralizing antibody to KRAS(G12D) mice reduced activation of PI3K signaling to AKT and NF-κB, blocking carcinogenesis. Levels of CXCL16 and its receptor CXCR6 were significantly higher in PDAC tissues and surrounding acini than in healthy pancreatic tissues from mice or human beings. In addition, expression of sst2 was progressively lost, involving increased PI3K activity, in mouse lesions that expressed KRAS(G12D) and progressed to PDAC. CONCLUSIONS Based on analyses of mice, loss of sst2 from pancreatic tissues activates PI3K signaling via AKT, leading to activation of NF-κB, amplification of oncogenic KRAS signaling, increased expression of CXCL16, and pancreatic tumor formation. CXCL16 might be a therapeutic target for PDAC.
Collapse
Affiliation(s)
- Mounira Chalabi-Dchar
- INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France
| | - Stéphanie Cassant-Sourdy
- INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France
| | - Camille Duluc
- INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France
| | - Marjorie Fanjul
- INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France
| | - Hubert Lulka
- INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France
| | - Rémi Samain
- INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France
| | - Catherine Roche
- UMR7286 CNRS-Aix-Marseille University, Neurobiology and Neurophysiology Research Center of Marseille, and Laboratory of Molecular Biology, AP-HM Conception, Marseille, France
| | | | | | - Mary Poupot
- INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France
| | - Marlène Dufresne
- INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France
| | - Takeshi Shimaoka
- Department of Molecular Preventive Medicine, Graduate School of Medicine, Tokyo University, Tokyo, Japan
| | - Shin Yonehara
- Laboratory of Molecular and Cellular Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Muriel Mathonnet
- EA 3842 Laboratory, Medicine and Pharmacy Faculties, Limoges University, Limoges, France
| | - Stéphane Pyronnet
- INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France
| | - Corinne Bousquet
- INSERM UMR-1037, Toulouse University, Cancer Research Center of Toulouse, Equipe Labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer, Toulouse, France.
| |
Collapse
|
|
38
|
Osmani N, Labouesse M. Remodeling of keratin-coupled cell adhesion complexes. Curr Opin Cell Biol 2014; 32:30-8. [PMID: 25460779 DOI: 10.1016/j.ceb.2014.10.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 10/13/2014] [Accepted: 10/18/2014] [Indexed: 12/12/2022]
Abstract
Epithelial cells constitute the main barrier between the inside and outside of organs, acting as gatekeepers of their structure and integrity. Hemidesmosomes and desmosomes are respectively cell-matrix and cell-cell adhesions coupled to the intermediate filament cytoskeleton. These adhesions ensure mechanical integrity of the epithelial barrier. Although desmosomes and hemidesmosomes are essential in maintaining strong cell-cell and cell-matrix adhesions, there is an emerging view that they should be remodeled in order to maintain epithelial homeostasis. Here we review the adhesion properties of desmosomes and hemidesmosomes, as well as the mechanisms driving their remodeling. We also discuss recent data suggesting that keratin-coupled adhesion complexes can sense the biomechanical cellular environment and participate in the cellular response to such external cues.
Collapse
Affiliation(s)
- Naël Osmani
- IGBMC, Development and Stem Cells Program, 67400 Illkirch, France; CNRS (UMR 7104), 67400 Illkirch, France; INSERM (U964), 67400 Illkirch, France; Université de Strasbourg, 67400 Illkirch, France.
| | - Michel Labouesse
- IGBMC, Development and Stem Cells Program, 67400 Illkirch, France; CNRS (UMR 7104), 67400 Illkirch, France; INSERM (U964), 67400 Illkirch, France; Université de Strasbourg, 67400 Illkirch, France.
| |
Collapse
|
|
39
|
Pyronnet S, Guillermet-Guibert J, Bousquet C. Restoring hemidesmosomes to prevent cancer cell invasiveness. Oncotarget 2014; 4:1123-4. [PMID: 23985954 PMCID: PMC3787141 DOI: 10.18632/oncotarget.1196] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
|
|
40
|
Chalabi M, Duluc C, Caron P, Vezzosi D, Guillermet-Guibert J, Pyronnet S, Bousquet C. Somatostatin analogs: does pharmacology impact antitumor efficacy? Trends Endocrinol Metab 2014; 25:115-27. [PMID: 24405892 DOI: 10.1016/j.tem.2013.11.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Revised: 11/05/2013] [Accepted: 11/15/2013] [Indexed: 01/17/2023]
Abstract
Somatostatin is an endogenous inhibitor of secretion and cell proliferation. These features render somatostatin a logical candidate for the management of neuroendocrine tumors that express somatostatin receptors. Synthetic somatostatin analogs (SSAs) have longer half-lives than somatostatin, but have similar activities, and are used for the treatment of these types of disorders. Interest has focused on novel multireceptor analogs with broader affinity to several of the five somatostatin receptors, thereby presenting putatively higher antitumor activities. Recent evidence indicates that SSAs cannot be considered mimics of native somatostatin in regulating signaling pathways downstream of receptors. Here we review this knowledge, discuss the concept of biased agonism, and highlight what considerations need to be taken into account for the optimal clinical use of SSAs.
Collapse
Affiliation(s)
- Mounira Chalabi
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), 31432 Toulouse, France; Université Toulouse III Paul Sabatier, 31062 Toulouse, France
| | - Camille Duluc
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), 31432 Toulouse, France; Université Toulouse III Paul Sabatier, 31062 Toulouse, France
| | - Philippe Caron
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), 31432 Toulouse, France; Université Toulouse III Paul Sabatier, 31062 Toulouse, France; Service d'Endocrinologie et Maladies Métaboliques, Pôle Cardio-Vasculaire et Métabolique, Centre Hospitalier Universitaire (CHU) Larrey, 31059 Toulouse, France
| | - Delphine Vezzosi
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), 31432 Toulouse, France; Université Toulouse III Paul Sabatier, 31062 Toulouse, France; Service d'Endocrinologie et Maladies Métaboliques, Pôle Cardio-Vasculaire et Métabolique, Centre Hospitalier Universitaire (CHU) Larrey, 31059 Toulouse, France
| | - Julie Guillermet-Guibert
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), 31432 Toulouse, France; Université Toulouse III Paul Sabatier, 31062 Toulouse, France
| | - Stéphane Pyronnet
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), 31432 Toulouse, France; Université Toulouse III Paul Sabatier, 31062 Toulouse, France
| | - Corinne Bousquet
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), 31432 Toulouse, France; Université Toulouse III Paul Sabatier, 31062 Toulouse, France.
| |
Collapse
|