Integrin alpha-V is an important driver in pancreatic adenocarcinoma progression.
Animals
Carcinoma, Pancreatic Ductal
/ genetics
Cell Line, Tumor
Cell Movement
Cell Proliferation
Disease Progression
Epithelial-Mesenchymal Transition
Gene Knockdown Techniques
Humans
Integrins
/ genetics
Lung Neoplasms
/ genetics
Mice
Neoplasm Transplantation
Pancreatic Neoplasms
/ genetics
Survival Analysis
Tissue Array Analysis
Up-Regulation
EMT
Integrin alpha-V
Metastatic cascade
Pancreatic cancer
TGF-beta signaling
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
26 Jun 2021
26 Jun 2021
Historique:
received:
01
12
2020
accepted:
13
04
2021
entrez:
27
6
2021
pubmed:
28
6
2021
medline:
15
12
2021
Statut:
epublish
Résumé
Mesothelial E- and P-selectins substantially mediate the intraperitoneal spread of Pancreatic ductal adenocarcinoma (PDA) cells in xenograft models. In the absence of selectins in the host, the integrin subunit alpha-V (ITGAV, CD51) was upregulated in the remaining metastatic deposits. Here we present the first experimental study to investigate if ITGAV plays a functional role in PDA tumor growth and progression with a particular focus on intraperitoneal carcinomatosis. Knockdown of ITGAV was generated using an RNA interference-mediated approach in two PDA cell lines. Tumor growth, intraperitoneal and distant metastasis were analyzed in a xenograft model. Cell lines were characterized in vitro. Gene expression of the xenograft tumors was analyzed. Patient samples were histologically classified and associations to survival were evaluated. The knockdown of ITGAV in PDA cells strongly reduces primary tumor growth, peritoneal carcinomatosis and spontaneous pulmonary metastasis. ITGAV activates latent TGF-β and thereby drives epithelial-mesenchymal transition. Combined depletion of ITGAV on the tumor cells and E- and P-selectins in the tumor-host synergistically almost abolishes intraperitoneal spread. Accordingly, high expression of ITGAV in PDA cells was associated with reduced survival in patients. Combined depletion of ITGAV in PDA cells and E- and P-selectins in host mice massively suppresses intraperitoneal carcinomatosis of PDA cells xenografted into immunodeficient mice, confirming the hypothesis of a partly redundant adhesion cascade of metastasizing cancer cells. Our data strongly encourage developing novel therapeutic approaches for the combined targeting of E- and P-selectins and ITGAV in PDA.
Sections du résumé
BACKGROUND
BACKGROUND
Mesothelial E- and P-selectins substantially mediate the intraperitoneal spread of Pancreatic ductal adenocarcinoma (PDA) cells in xenograft models. In the absence of selectins in the host, the integrin subunit alpha-V (ITGAV, CD51) was upregulated in the remaining metastatic deposits. Here we present the first experimental study to investigate if ITGAV plays a functional role in PDA tumor growth and progression with a particular focus on intraperitoneal carcinomatosis.
METHODS
METHODS
Knockdown of ITGAV was generated using an RNA interference-mediated approach in two PDA cell lines. Tumor growth, intraperitoneal and distant metastasis were analyzed in a xenograft model. Cell lines were characterized in vitro. Gene expression of the xenograft tumors was analyzed. Patient samples were histologically classified and associations to survival were evaluated.
RESULTS
RESULTS
The knockdown of ITGAV in PDA cells strongly reduces primary tumor growth, peritoneal carcinomatosis and spontaneous pulmonary metastasis. ITGAV activates latent TGF-β and thereby drives epithelial-mesenchymal transition. Combined depletion of ITGAV on the tumor cells and E- and P-selectins in the tumor-host synergistically almost abolishes intraperitoneal spread. Accordingly, high expression of ITGAV in PDA cells was associated with reduced survival in patients.
CONCLUSION
CONCLUSIONS
Combined depletion of ITGAV in PDA cells and E- and P-selectins in host mice massively suppresses intraperitoneal carcinomatosis of PDA cells xenografted into immunodeficient mice, confirming the hypothesis of a partly redundant adhesion cascade of metastasizing cancer cells. Our data strongly encourage developing novel therapeutic approaches for the combined targeting of E- and P-selectins and ITGAV in PDA.
Identifiants
pubmed: 34174926
doi: 10.1186/s13046-021-01946-2
pii: 10.1186/s13046-021-01946-2
pmc: PMC8235815
doi:
Substances chimiques
ITGA5 protein, human
0
Integrins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
214Subventions
Organisme : Hamburger Gesellschaft zur Förderung der Krebsbekämpfung
ID : Project no. 192
Organisme : Deutsche Forschungsgemeinschaft
ID : WI 5115/2-1
Organisme : Deutsche Forschungsgemeinschaft
ID : AI 24/21-1
Références
Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin D, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144(8):1941–53. https://doi.org/10.1002/ijc.31937 .
doi: 10.1002/ijc.31937
pubmed: 30350310
pmcid: 30350310
Tanaka M, Mihaljevic AL, Probst P, Heckler M, Klaiber U, Heger U, et al. Meta-analysis of recurrence pattern after resection for pancreatic cancer. BJS. 2019;106(12):1590–601. https://doi.org/10.1002/bjs.11295 .
doi: 10.1002/bjs.11295
Gebauer F, Wicklein D, Stübke K, Nehmann N, Schmidt A, Salamon J, et al. Selectin binding is essential for peritoneal carcinomatosis in a xenograft model of human pancreatic adenocarcinoma in pfp−−/rag2-- mice. Gut. 2013;62(5):741–50. https://doi.org/10.1136/gutjnl-2011-300629 .
doi: 10.1136/gutjnl-2011-300629
pubmed: 22490524
Ciardiello C, Leone A, Lanuti P, Roca MS, Moccia T, Minciacchi VR, et al. Large oncosomes overexpressing integrin alpha-V promote prostate cancer adhesion and invasion via AKT activation. J Exp Clin Cancer Res Cr. 2019;38(1):317. https://doi.org/10.1186/s13046-019-1317-6 .
doi: 10.1186/s13046-019-1317-6
pubmed: 31319863
Milone MR, Pucci B, Bifulco K, Iannelli F, Lombardi R, Ciardiello C, et al. Proteomic analysis of zoledronic-acid resistant prostate cancer cells unveils novel pathways characterizing an invasive phenotype. Oncotarget. 2014;6:5324–41.
doi: 10.18632/oncotarget.2694
Wang Q, Yu C. Identification of biomarkers associated with extracellular vesicles based on an integrative pan-cancer bioinformatics analysis. Med Oncol. 2020;37(9):79. https://doi.org/10.1007/s12032-020-01404-7 .
doi: 10.1007/s12032-020-01404-7
pubmed: 32749536
Reader CS, Vallath S, Steele CW, Haider S, Brentnall A, Desai A, et al. The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy. J Pathol. 2019;249(3):332–42. https://doi.org/10.1002/path.5320 .
doi: 10.1002/path.5320
pubmed: 31259422
pmcid: 6852434
Moore KM, Desai A, de Delgado B, Trabulo SMD, Reader C, Brown NF, et al. Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus. Theranostics. 2020;10:2930–42.
doi: 10.7150/thno.38702
Kalinina T, Güngör C, Thieltges S, Möller-Krull M, Penas EMM, Wicklein D, et al. Establishment and characterization of a new human pancreatic adenocarcinoma cell line with high metastatic potential to the lung. BMC Cancer. 2010;10(1):295. https://doi.org/10.1186/1471-2407-10-295 .
doi: 10.1186/1471-2407-10-295
pubmed: 20553613
pmcid: 2927995
Tan MH, Nowak NJ, Loor R, Ochi H, Sandberg AA, Lopez C, et al. Characterization of a new primary human pancreatic tumor line. Cancer Investig. 1986;4(1):15–23. https://doi.org/10.3109/07357908609039823 .
doi: 10.3109/07357908609039823
Weber K, Mock U, Petrowitz B, Bartsch U, Fehse B. Lentiviral gene ontology (LeGO) vectors equipped with novel drug-selectable fluorescent proteins: new building blocks for cell marking and multi-gene analysis. Gene Ther. 2009;17:511–20.
doi: 10.1038/gt.2009.149
Wicklein D. RNAi technology to block the expression of molecules relevant to metastasis: the cell adhesion molecule CEACAM1 as an instructive example. Methods Mol Biol Clifton N J. 2012;878:241–50. https://doi.org/10.1007/978-1-61779-854-2_16 .
doi: 10.1007/978-1-61779-854-2_16
Sugarbaker PH. Surgical responsibilities in the management of peritoneal carcinomatosis. J Surg Oncol. 2010;101:713–24.
doi: 10.1002/jso.21484
Workman P, Aboagye EO, Balkwill F, Balmain A, Bruder G, Chaplin DJ, et al. Guidelines for the welfare and use of animals in cancer research. Brit J Cancer. 2010;102(11):1555–77. https://doi.org/10.1038/sj.bjc.6605642 .
doi: 10.1038/sj.bjc.6605642
pubmed: 20502460
pmcid: 2883160
Nehmann N, Wicklein D, Schumacher U, Müller R. Comparison of two techniques for the screening of human tumor cells in mouse blood: quantitative real-time polymerase chain reaction (qRT-PCR) versus laser scanning cytometry (LSC). Acta Histochem. 2010;112(5):489–96. https://doi.org/10.1016/j.acthis.2009.05.004 .
doi: 10.1016/j.acthis.2009.05.004
pubmed: 19732944
Lange T, Ullrich S, Müller I, Nentwich MF, Stübke K, Feldhaus S, et al. Human prostate cancer in a clinically relevant Xenograft mouse model: identification of β(1,6)-branched oligosaccharides as a marker of tumor progression. Clin Cancer Res. 2012;18(5):1364–73. https://doi.org/10.1158/1078-0432.CCR-11-2900 .
doi: 10.1158/1078-0432.CCR-11-2900
pubmed: 22261809
Bamberger A, Methner C, Lisboa B, Städtler C, Schulte H, Löning T, et al. Expression pattern of the AP-1 family in breast cancer: association of fosB expression with a well-differentiated, receptor-positive tumor phenotype. Int J Cancer. 1999;84(5):533–8. https://doi.org/10.1002/(SICI)1097-0215(19991022)84:5<533::AID-IJC16>3.0.CO;2-J .
Dancau A-M, Simon R, Mirlacher M, Sauter G. Methods in molecular biology. Methods Mol Biol. 2016;1381:53–65. https://doi.org/10.1007/978-1-4939-3204-7_3 .
doi: 10.1007/978-1-4939-3204-7_3
pubmed: 26667454
Khan Z, Marshall JF. The role of integrins in TGFβ activation in the tumour stroma. Cell Tissue Res. 2016;365(3): 657–73. https://doi.org/10.1007/s00441-016-2474-y .
Waddell N, Pajic M, Patch A-M, Chang DK, Kassahn KS, Bailey P, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495–501. https://doi.org/10.1038/nature14169 .
doi: 10.1038/nature14169
pubmed: 25719666
pmcid: 4523082
Birbeck M, Wheatley D. An electron microscopic study of the invasion of ascites tumor cells into the abdominal wall. Cancer Res. 1965;25:490–7.
pubmed: 14297487
Annes JP, Chen Y, Munger JS, Rifkin DB. Integrin alphaVbeta6-mediated activation of latent TGF-beta requires the latent TGF-beta binding protein-1. J Cell Biol. 2004;165(5):723–34. https://doi.org/10.1083/jcb.200312172 .
doi: 10.1083/jcb.200312172
pubmed: 15184403
pmcid: 2172370
Costanza B, Rademaker G, Tiamiou A, Tullio PD, Leenders J, Blomme A, et al. Transforming growth factor beta-induced, an extracellular matrix interacting protein, enhances glycolysis and promotes pancreatic cancer cell migration. Int J Cancer. 2019;145(6):1570–84. https://doi.org/10.1002/ijc.32247 .
doi: 10.1002/ijc.32247
pubmed: 30834519
Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117(7):927–39. https://doi.org/10.1016/j.cell.2004.06.006 .
doi: 10.1016/j.cell.2004.06.006
pubmed: 15210113
Li X-P, Zhang X-W, Zheng L-Z, Guo W-J. Expression of CD44 in pancreatic cancer and its significance. Int J Clin Exp Pathol. 2015;8:6724–31.
pubmed: 26261555
pmcid: 4525889
Stickel N, Hanke K, Marschner D, Prinz G, Köhler M, Melchinger W, et al. MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation. Leukemia. 2017;31(12):2732–41. https://doi.org/10.1038/leu.2017.137 .
doi: 10.1038/leu.2017.137
pubmed: 28484267
pmcid: 6231537
Sökeland G, Schumacher U. The functional role of integrins during intra- and extravasation within the metastatic cascade. Mol Cancer. 2019;18(1):12. https://doi.org/10.1186/s12943-018-0937-3 .
doi: 10.1186/s12943-018-0937-3
pubmed: 30657059
pmcid: 6337777
Schwankhaus N, Gathmann C, Wicklein D, Riecken K, Schumacher U, Valentiner U. Cell adhesion molecules in metastatic neuroblastoma models. Clin Exp Metastasis. 2014;31(4):483–96. https://doi.org/10.1007/s10585-014-9643-8 .
doi: 10.1007/s10585-014-9643-8
pubmed: 24549749
Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, Pellicoro A, et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med. 2013;19:1617–24.
doi: 10.1038/nm.3282
Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45(W1):W98–102. https://doi.org/10.1093/nar/gkx247 .
doi: 10.1093/nar/gkx247
pubmed: 5570223
pmcid: 5570223
Uhlen M, Zhang C, Lee S, Sjöstedt E, Fagerberg L, Bidkhori G, et al. A pathology atlas of the human cancer transcriptome. Science. 2017;357:eaan2507.
doi: 10.1126/science.aan2507
Park H, Bang J, Nam A, Park J, Jin M, Bang Y, et al. The prognostic role of soluble TGF-beta and its dynamics in unresectable pancreatic cancer treated with chemotherapy. Cancer Med. 2020;9(1):43–51. https://doi.org/10.1002/cam4.2677 .
doi: 10.1002/cam4.2677
pubmed: 31701645
Zhao M, Mishra L, Deng C-X. The role of TGF-β/SMAD4 signaling in cancer. Int J Biol Sci. 2018;14(2):111–23. https://doi.org/10.7150/ijbs.23230 .
doi: 10.7150/ijbs.23230
pubmed: 29483830
pmcid: 5821033
Hezel AF, Deshpande V, Zimmerman SM, Contino G, Alagesan B, O'Dell MR, et al. TGF-β and αvβ6 integrin act in a common pathway to suppress pancreatic cancer progression. Cancer Res. 2012;72(18):4840–5. https://doi.org/10.1158/0008-5472.CAN-12-0634 .
doi: 10.1158/0008-5472.CAN-12-0634
pubmed: 22787119
pmcid: 3764481
Bates RC, Bellovin DI, Brown C, Maynard E, Wu B, Kawakatsu H, et al. Transcriptional activation of integrin β6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J Clin Ivest. 2005;115(2):339–47. https://doi.org/10.1172/JCI200523183 .
doi: 10.1172/JCI200523183
Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 2009;19(2):156–72. https://doi.org/10.1038/cr.2009.5 .
doi: 10.1038/cr.2009.5
pubmed: 19153598
Aarsen LAKV, Leone DR, Ho S, Dolinski BM, McCoon PE, LePage DJ, et al. Antibody-mediated blockade of integrin alpha v beta 6 inhibits tumor progression in vivo by a transforming growth factor-beta-regulated mechanism. Cancer Res. 2008;68(2):561–70. https://doi.org/10.1158/0008-5472.CAN-07-2307 .
doi: 10.1158/0008-5472.CAN-07-2307
pubmed: 18199553
Wipff P-J, Rifkin DB, Meister J-J, Hinz B. Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol. 2007;179(6):1311–23. https://doi.org/10.1083/jcb.200704042 .
doi: 10.1083/jcb.200704042
pubmed: 18086923
pmcid: 2140013
Biffi G, Oni T, Spielman B, Hao Y, Elyada E, Park Y, et al. IL1-induced JAK/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 2018;9:282–301.
doi: 10.1158/2159-8290.CD-18-0710
Miles FL, Sikes RA. Insidious changes in stromal matrix fuel cancer progression. Mol Cancer Res Mcr. 2014;12(3):297–312. https://doi.org/10.1158/1541-7786.MCR-13-0535 .
doi: 10.1158/1541-7786.MCR-13-0535
pubmed: 24452359
Attieh Y, Clark AG, Grass C, Richon S, Pocard M, Mariani P, et al. Cancer-associated fibroblasts lead tumor invasion through integrin-β3–dependent fibronectin assembly. J Cell Biol. 2017;216(11):3509–20. https://doi.org/10.1083/jcb.201702033 .
doi: 10.1083/jcb.201702033
pubmed: 28931556
pmcid: 5674886
Hinz B. It has to be the αv: myofibroblast integrins activate latent TGF-β1. Nat Med. 2013;19(12):1567–8. https://doi.org/10.1038/nm.3421 .
doi: 10.1038/nm.3421
pubmed: 24309651
Aroldi F, Zaniboni A. Immunotherapy for pancreatic cancer: present and future. Immunotherapy. 2017;9(7):607–16. https://doi.org/10.2217/imt-2016-0142 .
doi: 10.2217/imt-2016-0142
pubmed: 28595517
Haabeth O, Tveita A, Fauskanger M, Schjesvold F, Lorvik K, Hofgaard P, et al. How do CD4+ T cells detect and eliminate tumor cells that either lack or express MHC class II molecules? Front Immunol. 2014;5:174.
doi: 10.3389/fimmu.2014.00174