Studies on the molecular mechanism of osteopontin regulated promatrix metalloproteinase 9 activation and tumor growth

Abstract

Cell migration and degradation of the extracellular matrix are some of the crucial steps involved in tumor progression. Several proteinases including matrix metalloproteinases (MMPs) play important roles in degradation of extracellular matrix (ECM) components and hence contribute to cancer cell motility, tumor growth and metastasis. MMPs are highly regulated by several growth factors, cytokines and ECM components. Osteopontin (OPN) is a secreted, non-collagenous, sialic acid rich, chemokine like calcified ECM protein that plays a significant role in determining the metastatic potential of various cancers. Since its first identification in bone by biochemical means, OPN has been reported to play a multifaceted role in regulating a number of physiological and pathophysiological processes like atherosclerosis, bone remodeling, angiogenesis, wound healing and tissue injuries as well as certain diseases such as restenosis, arterial neointimal hyperplasia, myocardinal necrosis, renal tubulointerstitial fibrosis, kidney stone formation and autoimmune diseases. It exerts its pro-metastatic effects by interacting with various integrins and CD44 receptors. Thus OPN and its receptors figure prominently in a wide spectrum of malignancies. Further studies in a variety of human cancers have correlated the high levels of OPN expression with the advanced stages of tumors. The pivotal role of OPN in tumor dissemination has been highlighted by gene transfer experiments. Overexpression of OPN results in an increase in malignant phenotype, whereas transfection with antisense oligonucleotides yields population with reduced malignant potential. Thus OPN has been recognized as a potential marker in the processes of tumorigenicity and metastasis.