Neutralizing Murine TGFβR2 Promotes a Differentiated Tumor Cell Phenotype and Inhibits Pancreatic Cancer Metastasis

Abstract

Elevated levels of TGF-β are a negative prognostic indicator for patients diagnosed with pancreatic cancer; as a result the TGF-β pathway is an attractive target for therapy. However, clinical application of pharmacologic inhibition of TGF-β remains challenging because TGF-β has tumor suppressor functions in many epithelial malignancies including pancreatic cancer. In fact, direct neutralization of TGF-β promotes tumor progression of genetic murine models of pancreatic cancer. Here we report that neutralizing the activity of murine TGF-β receptor 2 using a monoclonal antibody (2G8) has potent anti-metastatic activity in orthotopic human tumor xenografts, syngenic tumors and a genetic model of pancreatic cancer. 2G8 reduced activated fibroblasts, collagen deposition, microvessel density and vascular function. These stromal specific changes resulted in tumor cell epithelial differentiation and a potent reduction in metastases. We conclude that TGF-β signaling within stromal cells participates directly in tumor cell phenotype and pancreatic cancer progression. Thus, strategies that inhibit TGF-β dependent effector functions of stromal cells could be efficacious for the therapy of pancreatic tumors.

Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer

“…For example, TGF-␤ functions as a tumor suppressor under normal conditions and during early tumorigenesis; however, mutations are commonly acquired in this pathway that switch TGF-␤ to a factor that promotes tumor progression. Blocking TGF-␤ receptor activity in preclinical models of PDA has shown a robust effect in reducing metastatic spread (30). Our studies reveal that a possible and underappreciated method by which blocking TGF-␤ may reduce tumor burden and metastasis is by inhibiting the synthesis of pro-tumorigenic ECM molecules such as Fbln5.…”

“…Enhanced expression and activity of TGF-␤ has been reported in many models and human cases of PDA (5,30,(45)(46)(47)(48). To confirm that TGF-␤ signaling is critical for Fbln5 expression in pancreatic tumors, we examined Fbln5 levels in tumor tissue from KPC mice that had been treated with TGF-␤ inhibitors.…”

“…To confirm that TGF-␤ signaling is critical for Fbln5 expression in pancreatic tumors, we examined Fbln5 levels in tumor tissue from KPC mice that had been treated with TGF-␤ inhibitors. KPC mice were treated with LY2157299 as well as an inhibitor of TGF-␤ receptor 2 (2G8) (30). Immunohistochemical analysis of frozen tumor sections revealed a significant decrease in Fbln5 expression in tumors of treated mice (Fig.…”

“…However, it is unclear whether hypoxia induces Fbln5 in a TGF-␤-dependent manner and whether these factors regulate Fbln5 expression in an in vivo context. Hypoxia and TGF-␤ expression and activity are elevated in a number of advanced solid tumors, including PDA (5,30). Therefore, through biochemical and immunohistological analyses, we sought to elucidate a mechanism by which pancreatic tumors stimulate Fbln5 expression in vivo.…”

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“…Tumor cell extrinsic activities include induction and increased tumor vascularization, modulation of the stromal extracellular matrix, and inhibition of immune surveillance and antitumor immunity [4,15]. Studies in genetically engineered mouse models and preclinical studies using TGFβ pathway antagonists support the pro-metastatic function of TGFβ, although this activity may depend on multiple factors, such as the nature of the tumor-initiating mutation, the precise mechanism of TGFβ inactivation, and the timing of TGFβ signaling [4,[12][13]16]. Small molecule TGFβRI inhibitors as well as antibodies directed to the type II receptor have been shown to block EMT and tumor cell migration in cancer cells [16][17][18].…”