852093.fig.003
Figure 3: Cellular and molecular composition of premetastatic niche and metastatic microenvironment. premetastatic niche formation initiates by release of soluble factors, such as, VEGFA, TGF-beta, placental growth factor (PLGF), inflammatory chemokines S100, and Serum Amiloyd A3 (SAA3), as well as stromal-derived growth factor 1 (SDF1) by the primary tumor (1). As a result, bone marrow-derived hematopoietic progenitor cells (HPC) and immature myeloid cells are recruited to the premetastatic niche (2). Then, these bone marrow-derived cells start to populate the premetastatic niche with potent modified factors, such as tumor necrosis factor-α (TNFα), matrix metalloproteinase 9 (MMP9), and TGFβ, leading to stimulation of stromal cells that in turn modulate the extracellular matrix of the premetastatic microenvironment (3). For example, modified factors-mediated fibroblast activation initiates secretion of fibronectin, which constitutes an important adhesion protein in the niche. Additionally, other important extracellular matrix components such as hyaluronic acid, proteoglycans, glycosaminoglycan-modified enzymes, like heparanase and sulfatases are likely to be present (4), but it is yet to be confirmed and constitutes a new interesting area of research involving the premetastatic niche. Mature tumor microenvironment is composed by tumor cells, blood vessels, bone marrow-derived cells, proteoglycans, MMPs, hyaluronic acid, stromal cells, such as fibroblasts and several recruited cells like neutrophils, and macrophages. These cells, secrete several growth factors and cytokines that can drive epithelial to mesenchymal transition-mediated migration and invasion of tumor cells.