Pigment Epithelium-Derived Factor – An Angiostatic Factor with a Broader Function in Melanoma

Abstract

Metastatic spread is achieved through changes in the tissue microenvironment driven by tumor cells that allow the formation of various dissemination routes using a variety of mechanisms; such as angiogenesis and vasculogenesis (hematogeneous routes), lymphangiogenesis (lymphatic routes), and in some particular cases like melanoma, vasculogenic mimicry (vasculogenic channels lined by melanoma cells) (Carmeliet, 2005; Hendrix et al., 2003; Kopp et al., 2006; Tammela and Alitalo, 2010). Building of dissemination routes has to be coordinated with the acquisition of new capabilities by tumor cells that enable them to locally invade, intravasate into dissemination channels, survive in the circulation, extravasate, and ultimately adapt to a foreign territory. All this complex cascade of events is orchestrated by multiple cell types and diverse families of factors and signaling circuits controlling intracellular as well as intercellular key communication events (Nguyen et al., 2009b). Interestingly, a particular subset of extracellular factors have the dual capacity to simultaneously impinge on the formation of the dissemination routes and to modulate many of the properties that the tumor cells themselves have to acquire in order to fulfill all steps required to successfully colonize a foreign territory starting from a primary lesion in a drastically different environment. This chapter focuses on an angiostatic factor, pigment epithelium derived factor (PEDF), with a broader function in melanoma that allows it to dually impinge on destroying some of the more relevant dissemination routes and on counteracting key tumor cell properties that enable the metastatic spread of melanoma cells. Understanding of the molecular and cellular mechanisms controlling melanoma progression has become an active field of research over the last five years unveiling a complex intertwined relationship between melanoma cells and the diverse cell types present in the tumor microenvironment, as well as a number of key molecular mediators (Shackleton and Quintana, 2010; Villanueva and Herlyn, 2008). Plasticity of melanoma cells allows them for appropriate reprogramming underlying the decision making process that arbitrates