Knockdown of the β(1) Integrin Subunit Reduces Primary Tumor Growth and Inhibits Pancreatic Cancer Metastasis

Overview

Journal Int J Cancer

Specialty Oncology

Date 2011 Apr 15

PMID 21491421

Citations 70

Authors

John J Grzesiak

Hop S Tran Cao

Douglas W Burton

Sharmeela Kaushal

Fabian Vargas

Paul Clopton

Cynthia S Snyder

Leonard J Deftos

Robert M Hoffman

Michael Bouvet

Affiliations

Soon will be listed here.

Abstract

To address the role of β(1) integrins in pancreatic cancer progression, we stably knocked down β(1) integrin subunit expression in human FG-RFP pancreatic cancer cells using lentiviral-based RNA interference. We then examined the effects of β(1) integrin subunit knockdown on pancreatic cancer cell adhesion, migration and proliferation on tumor microenvironment-specific extracellular matrix proteins in vitro and on tumor progression in vivo using a clinically relevant fluorescent orthotopic mouse model of pancreatic cancer. Knockdown of the β(1) integrin subunit inhibited cell adhesion, migration and proliferation on types I and IV collagen, fibronectin and laminin in vitro. In vivo, knockdown of the β(1) integrin subunit reduced primary tumor growth by 50% and completely inhibited spontaneously occurring metastasis. These observations indicate a critical role for the β(1) integrin subunit in pancreatic cancer progression and metastasis in particular. Our results suggest the β(1) integrin subunit as a therapeutic target for the treatment of pancreatic cancer, especially in the adjuvant setting to prevent metastasis of this highly aggressive cancer.

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References

Hemler M . VLA proteins in the integrin family: structures, functions, and their role on leukocytes. Annu Rev Immunol. 1990; 8:365-400. DOI: 10.1146/annurev.iy.08.040190.002053. View

Ruoslahti E . Integrins. J Clin Invest. 1991; 87(1):1-5. PMC: 294975. DOI: 10.1172/JCI114957. View

White D, Puranen S, Johnson M, Heino J . The collagen receptor subfamily of the integrins. Int J Biochem Cell Biol. 2004; 36(8):1405-10. DOI: 10.1016/j.biocel.2003.08.016. View

Menke A, Philippi C, Vogelmann R, Seidel B, Lutz M, Adler G . Down-regulation of E-cadherin gene expression by collagen type I and type III in pancreatic cancer cell lines. Cancer Res. 2001; 61(8):3508-17. View

Grzesiak J, Smith K, Burton D, Deftos L, Bouvet M . GSK3 and PKB/Akt are associated with integrin-mediated regulation of PTHrP, IL-6 and IL-8 expression in FG pancreatic cancer cells. Int J Cancer. 2004; 114(4):522-30. DOI: 10.1002/ijc.20748. View

Shintani Y, Hollingsworth M, Wheelock M, Johnson K . Collagen I promotes metastasis in pancreatic cancer by activating c-Jun NH(2)-terminal kinase 1 and up-regulating N-cadherin expression. Cancer Res. 2006; 66(24):11745-53. DOI: 10.1158/0008-5472.CAN-06-2322. View

Grzesiak J, Clopton P, Chalberg C, Smith K, Burton D, Silletti S . The extracellular matrix differentially regulates the expression of PTHrP and the PTH/PTHrP receptor in FG pancreatic cancer cells. Pancreas. 2004; 29(2):85-92. DOI: 10.1097/00006676-200408000-00001. View

Defilles C, Lissitzky J, Montero M, Andre F, Prevot C, Delamarre E . alphavbeta5/beta6 integrin suppression leads to a stimulation of alpha2beta1 dependent cell migration resistant to PI3K/Akt inhibition. Exp Cell Res. 2009; 315(11):1840-9. DOI: 10.1016/j.yexcr.2009.03.014. View

Fu X, Guadagni F, Hoffman R . A metastatic nude-mouse model of human pancreatic cancer constructed orthotopically with histologically intact patient specimens. Proc Natl Acad Sci U S A. 1992; 89(12):5645-9. PMC: 49349. DOI: 10.1073/pnas.89.12.5645. View

10.

Katz M, Takimoto S, Spivack D, Moossa A, Hoffman R, Bouvet M . An imageable highly metastatic orthotopic red fluorescent protein model of pancreatic cancer. Clin Exp Metastasis. 2004; 21(1):7-12. DOI: 10.1023/b:clin.0000017160.93812.3b. View

11.

Frisch S, Ruoslahti E . Integrins and anoikis. Curr Opin Cell Biol. 1997; 9(5):701-6. DOI: 10.1016/s0955-0674(97)80124-x. View

12.

Aplin J, Spanswick C, Behzad F, Kimber S, Vicovac L . Integrins beta 5, beta 3 and alpha v are apically distributed in endometrial epithelium. Mol Hum Reprod. 1996; 2(7):527-34. DOI: 10.1093/molehr/2.7.527. View

13.

Hoffman R . The multiple uses of fluorescent proteins to visualize cancer in vivo. Nat Rev Cancer. 2005; 5(10):796-806. DOI: 10.1038/nrc1717. View

14.

Yang M, Baranov E, Jiang P, Sun F, Li X, Li L . Whole-body optical imaging of green fluorescent protein-expressing tumors and metastases. Proc Natl Acad Sci U S A. 2000; 97(3):1206-11. PMC: 15570. DOI: 10.1073/pnas.97.3.1206. View

15.

Sonnenberg A, Modderman P, Hogervorst F . Laminin receptor on platelets is the integrin VLA-6. Nature. 1988; 336(6198):487-9. DOI: 10.1038/336487a0. View

16.

Imamichi Y, Konig A, Gress T, Menke A . Collagen type I-induced Smad-interacting protein 1 expression downregulates E-cadherin in pancreatic cancer. Oncogene. 2006; 26(16):2381-5. DOI: 10.1038/sj.onc.1210012. View

17.

Bardeesy N, DePinho R . Pancreatic cancer biology and genetics. Nat Rev Cancer. 2002; 2(12):897-909. DOI: 10.1038/nrc949. View

18.

Katz M, Takimoto S, Spivack D, Moossa A, Hoffman R, Bouvet M . A novel red fluorescent protein orthotopic pancreatic cancer model for the preclinical evaluation of chemotherapeutics. J Surg Res. 2003; 113(1):151-60. DOI: 10.1016/s0022-4804(03)00234-8. View

19.

Grzesiak J, Bouvet M . Determination of the ligand-binding specificities of the alpha2beta1 and alpha1beta1 integrins in a novel 3-dimensional in vitro model of pancreatic cancer. Pancreas. 2007; 34(2):220-8. DOI: 10.1097/01.mpa.0000250129.64650.f6. View

20.

Vogelmann R, Kreuser E, Adler G, Lutz M . Integrin alpha6beta1 role in metastatic behavior of human pancreatic carcinoma cells. Int J Cancer. 1999; 80(5):791-5. DOI: 10.1002/(sici)1097-0215(19990301)80:5<791::aid-ijc25>3.0.co;2-4. View