Abstract 547: A function-blocking monoclonal antibody directed against the collagen-binding α2 integrin subunit inhibits primary tumor growth and metastasis in a fluorescent orthotopic mouse model of pancreatic cancer
Authors: Grzesiak John J. , Tran Cao Hop S. , Kaushal Sharmeela , Hoffman Robert M. , Bouvet Michael 
Published: June 2012

Pancreatic cancer is characterized by a hallmark desmoplastic response that includes the highly up-regulated expression of type I collagen. Previous studies indicate that type I collagen promotes the malignant phenotype in pancreatic cancer in vitro and in vivo as evidenced by increased cell adhesion, migration, proliferation, tumorigenesis, and resistance to chemically-induced apoptosis. Tumor cells interact with type I collagen and other ECM proteins via integrins, a family of heterodimeric transmembrane receptor proteins comprised of various combinations of non-covalently linked α and β subunits. Our previous studies using both 2D and 3D in vitro assays (adhesion, migration, and proliferation) with function-blocking monoclonal antibodies directed against various integrin subunits, as well as affinity chromatography on type I collagen-sepharose followed by immunoprecipitation, demonstrate clearly that the α2β1 integrin specifically mediates pancreatic cancer cell interactions with type I collagen. In the present study, we examined the effect of function-blocking monoclonal antibodies directed against the α2 (P1E6) and α3 (P1B5) integrin subunits on tumor progression in vivo using a fluorescent orthotopic mouse model of pancreatic cancer. FG-RFP pancreatic cancer cells were orthotopically implanted in the pancreas of six-week old female nude mice. After two weeks, mice were randomized into three groups of five mice each, and treated for five weeks with weekly tail-vein injections of P1E6 or P1B5 (both IgG1) at 3 mg/kg, or vehicle-only (PBS). Six weeks after the start of treatment, mice were euthanized, necropsy was performed, including removal of the primary tumor, and the animals underwent intravital fluorescence imaging for identification of metastases. Our data indicate that the α2 antibody (P1E6) significantly reduced primary tumor weight by more than 60% compared to vehicle-only and α3 antibody (P1B5) controls (1.03g vs. 2.75g and 2.82g, respectively). Ascites formation was absent in the P1E6-treated mice (0/5) compared to the vehicle-only (1/5) and P1B5 (2/5) controls. Importantly, metastases were reduced in the P1E6-treated mice (1/5) (two diaphragm metastases in one mouse), compared to the vehicle-only (5/5) (metastases were found variably in the liver, peritoneum, spleen, diaphragm, and GI) and P1B5 (4/5) (metastases were found variably in the liver, spleen, diaphragm, and GI) controls. Together with previous integrin subunit knockdown and antibody inhibition studies in vivo, which strongly implicate β1 integrins in pancreatic cancer progression, these data suggest that inhibiting α2β1 integrin-mediated interactions with type I collagen may have therapeutic value in the treatment of this recalcitrant disease.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 547. doi:10.1158/1538-7445.AM2011-547