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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2021 | Research

Integrin alpha-V is an important driver in pancreatic adenocarcinoma progression

Authors: Marius Kemper, Alina Schiecke, Hanna Maar, Sergey Nikulin, Andrey Poloznikov, Vladimir Galatenko, Michael Tachezy, Florian Gebauer, Tobias Lange, Kristoffer Riecken, Alexander Tonevitsky, Achim Aigner, Jakob Izbicki, Udo Schumacher, Daniel Wicklein

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

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

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

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

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.

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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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

10.

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.CrossRef

11.

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.CrossRefPubMed

12.

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.CrossRef

13.

Sugarbaker PH. Surgical responsibilities in the management of peritoneal carcinomatosis. J Surg Oncol. 2010;101:713–24.CrossRefPubMed

14.

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.CrossRefPubMedPubMedCentral

15.

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.CrossRefPubMed

16.

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.CrossRefPubMed

17.

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.

18.

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.CrossRefPubMed

19.

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.

20.

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.CrossRefPubMedPubMedCentral

21.

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

22.

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.CrossRefPubMedPubMedCentral

23.

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.CrossRefPubMed

24.

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.CrossRefPubMed

25.

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.PubMedPubMedCentral

26.

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.CrossRefPubMedPubMedCentral

27.

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.CrossRefPubMedPubMedCentral

28.

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.CrossRefPubMed

29.

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.CrossRefPubMed

30.

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.CrossRefPubMedPubMedCentral

31.

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.CrossRefPubMed

32.

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.CrossRefPubMed

33.

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.CrossRefPubMedPubMedCentral

34.

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.CrossRefPubMedPubMedCentral

35.

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.CrossRef

36.

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.CrossRefPubMed

37.

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.CrossRefPubMed

38.

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.CrossRefPubMedPubMedCentral

39.

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.CrossRefPubMedPubMedCentral

40.

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.CrossRefPubMed

41.

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.CrossRefPubMedPubMedCentral

42.

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.CrossRefPubMed

43.

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.CrossRefPubMed

44.

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.CrossRefPubMedPubMedCentral

Title: Integrin alpha-V is an important driver in pancreatic adenocarcinoma progression
Authors: Marius Kemper
Alina Schiecke
Hanna Maar
Sergey Nikulin
Andrey Poloznikov
Vladimir Galatenko
Michael Tachezy
Florian Gebauer
Tobias Lange
Kristoffer Riecken
Alexander Tonevitsky
Achim Aigner
Jakob Izbicki
Udo Schumacher
Daniel Wicklein
Publication date: 01-12-2021
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-01946-2

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Abstract

Background

Methods

Results

Conclusion

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