Studies on the role of osteopontin (opn) in the regulation of cyclooxygenase-2 (cox-2) expression, tumor growth, and angiogenesis in prostate cancer

Abstract

Tumor progression requires interplay among several cytokines, growth factors and enzymes, all contributing to an integrated sequence of events regulated in the tumor microenvironment. The process of tumor progression is characterized by various events including deregulated growth control, proliferation, adhesion, ECM degradation, angiogenesis and metastasis. Among men, prostate cancer is the most common cancer diagnosed, and the second leading cause of death from cancer in United States. Metastasis or migration of malignant cells from prostate tumor to the distant sites makes prostate cancer one of the deadly diseases. Therefore, understanding the molecular mechanism underlying prostate cancer metastasis will be helpful for the diagnosis and treatment of cancer. Osteopontin (OPN) is a chemokine like phospho-glycosialoprotein known to express in a variety of tissues. Enhanced expression of OPN has been detected at the tumor sites as well as plasma and serum of patients with various types of cancer. Studies have shown that OPN acts as a crucial oncogenic molecule and its enhanced expression is not only associated with tumor progression, it also acts as a lead marker for various types of cancer. Research from various laboratories have demonstrated the multifaceted role of OPN in the broad array of physiological as well as pathophysiological processes such as tissue remodeling, bone resorption, wound healing, immunological responses, restenosis, atherosclerosis, and autoimmune diseases. However, the molecular mechanism by which OPN regulates tumor growth, metastasis and angiogenesis is not clearly understood. In this study, using multiple in vitro and in vivo models, we have demonstrated the molecular mechanism implicated in OPN-regulated prostate tumor growth, metastasis and angiogenesis. We have shown that OPN regulates prostate tumor progression via cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2)-mediated autocrine and paracrine pathways. OPN stimulates the activation of protein kinase C α (PKCα)/nuclear factor-inducing kinase (NIK)/nuclear factor- κB (NF-κB)-dependent signaling that induces COX-2 expression, which in turn regulates the PGE2 production, matrix metalloproteinase-2 (MMP-2) activation, tumor cell motility, invasion and angiogenesis.