Tumor microenvironment extracellular matrix

In this chapter, the consequences of the irregular structure and function of the tumor microcirculation and the self-perpetuating hostile pathophysiological microenvironment (via a vicious circle) will be described. This overview considers, inter alia, many metabolic, biophysical, and physico-biochemical parameters of the tumor microenvironment rather than focusing on the complex composition of the tumor stroma, the cells therein, and their factors secreted, the key components of the tumor stroma, and the interactions between tumor cells, the extracellular matrix, and stromal cells (for reviews see, e.g., Mueller and Fusenig 2004 Witz and Levy-Nissenbaum 2006 Weinberg 2008 Ariztia etal. 2006 Cunha etal. 2003 Park etal. 2000 Liotta and Kohn 2001 Fidler 2002 Unger and Weaver 2003 Denko et al. 2003). 

Expression and secretion of proteases by the tumor microenvironment is critical both for support of tumor progression and metastasis, activation of growth factors and promotion of angiogenesis and invasion by digestion of the extracellular matrix (matrix metalloproteinases, MMPs, are collagenases) [114], The dominant cancer proteases are cathepsins and MMPs with both extracellular secreted MMPs and membrane type MMPs (MT-MMPs). This has promoted the use of cathepsin and MMP substrate peptides for tumor imaging and/or therapy [ 115,116]. 

Tumor migration, invasion, extravasation, circulation with blood, interaction with endothelium, and establishment of a microenvironment are aU dependent on specific adhesive interactions of tumor cells with other cells and components of the extracellular matrix. Some of these important interactions are mediated by selectins and their ligands—sialyl Lewis and sialyl Lewis [122-124]. Selectins are adhesion receptors expressed on activated platelets (P-selectin), leukocytes (L-selectin), and endothelial cells (E-selectin) [125]. Unlike normal healthy endothelial cells which do not express E-selectin, primary tumors in patients secrete inflammatory cytokines such as TNF a, which induce E-selectin on endothelial cells [126]. Sialyl Lewis and sialyl Lewis are ligands for E-selectin, and therefore responsible for the adhesion of human tumor cells to endothelium [ 127]. With platelets and leukocytes, tumor cells can form multicellular complexes (via P-selectin) and then settle down in the microvasculature (via L-selectin) of distant organs and eventually extravasate and establish metastatic colonies [128] (Fig. lc,d). 

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