Knockdown of the β₁ integrin subunit reduces primary tumor growth and inhibits pancreatic cancer metastasis

Abstract

To address the role of β1 integrins in pancreatic cancer progression, we stably knocked down β1 integrin subunit expression in human FG-RFP pancreatic cancer cells using lentiviral-based RNA interference. We then examined the effects of β1 integrin subunit knockdown on pancreatic cancer cell adhesion, migration, and proliferation on tumor microenvironment-specific ECM proteins in vitro, and on tumor progression in vivo using a clinically-relevant fluorescent orthotopic mouse model of pancreatic cancer. Knockdown of the β1 integrin subunit inhibited cell adhesion, migration, and proliferation on types I and IV collagen, fibronectin, and laminin in vitro. In vivo, knockdown of the β1 integrin subunit reduced primary tumor growth by 50% and completely inhibited spontaneously occurring metastasis. These observations indicate a critical role for the β1 integrin subunit in pancreatic cancer progression, and metastasis in particular. Our results suggest the β1 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.

Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver

“…Several studies have correlated KC 49–51 and ECM changes 52–54 with circulating tumor cell arrest and liver metastasis. In addition, myeloid cell recruitment to the liver was also shown to precede liver metastasis 55–58 .…”

β1 Integrin Targeting Potentiates Antiangiogenic Therapy and Inhibits the Growth of Bevacizumab-Resistant Glioblastoma

“…This hypothesis warrants further study. Indeed, β1 integrin has proved to be a viable oncological target in animal models of solid and blood-borne cancers for multiple processes, including (i) prevention and growth of metastasis (37); (ii) overcoming resistance to radiation (35) and chemotherapy (38–42); and (iii) inhibition of local carcinoma spread. In addition, β1 integrin upregulation has been shown to be prognostic for breast (38, 43), lung (44), and pancreatic (37) cancers.…”

Pharmacological Inhibition and Genetic Knockdown of Exchange Protein Directly Activated by cAMP 1 Reduce Pancreatic Cancer Metastasis In Vivo

“…The expression, distribution, trafficking, and function of integrins are frequently altered in tumor cells in a manner that promotes cancer migration (Caswell and Norman, 2006). Itgb1 is particularly important for invasion of PDA and plays an essential role in facilitating its metastasis (Vogelmann et al, 1999;Grzesiak et al, 2011). Several reports have implicated EPAC1 and its effector Rap1 in Itgb1-mediated adhesion and migration of endothelial progenitor and immune cells (Lorenowicz et al, 2006;Carmona et al, 2008).…”