Anticancer Role of PPAR Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes
Tumor-associated angiogenesis is sustained through stromal microenvironment crosstalk. Most tumors are associated with the activation of tumor-promoting innate immune responses involving neutrophils, macrophages, and NK cells. Specific (adaptive) antitumor immune responses involving T- or B-lymphocytes are less efficient in suppressing tumor growth. Increased formation of blood and lymphatic vessels in bone marrow and lymph nodes provide oxygen and nutrients to malignant cells. Stromal cells, including ECs, inflammatory cells, and fibroblasts/myofibroblasts, produce cytokines and growth factors that act in a paracrine fashion to promote malignant cell proliferation or survival. In turn, malignant cells produce angiogenic factors and express their cognate receptors establishing functional autocrine loops to perpetuate their survival including signaling through the VEGF pathway [85–87, 107]. The secreted factors produced by and in response to those secreted by stromal and tumor cells include, but are not limited to VEGF, FGF-2, PDGF, IGF-1, HSF, TGF-α, TGF-β, TNF-α, IL-8, MCP-1/CCL2, MIF, IL-6, and IL-1 . The potent vasoconstrictor peptide endothelin-1 has been implicated in the pathophysiology of atherosclerosis and its complications , as well as tumor angiogenesis and lymphangiogenesis [109, 110]. Proteases important for invasion thorough the basement membrane and remodeling of the ECM, such as plasminogen  and MMPs, including MMP-2 and MMP-9 , and their inhibitors, PAI-1/2 and TIMPs, respectively, are produced by stromal and tumor cells. Downregulation of endogenous inhibitors of angiogenesis such as thrombospondin (TSP)-1 occurs in the stromal compartment as well to favor angiogenesis, cancer cell growth, and metastasis . In recent years, it has been recognized that a better understanding of the tumor-stromal microenvironment crosstalk may lead to elucidation of new therapeutic strategies for cancer therapy [99–102].