Anticancer Role of PPARγ Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes

Figure 1

Molecular mechanisms of tumor-associated angiogenesis. Angiogenesis is essential for the persistence of solid tumor growth and, only recently, has it been appreciated that angiogenesis plays a role in progression of hematological malignancies as well. Cancer-associated angiogenesis in solid tumors begins once the tumor mass reaches a critical size such that the hypoxic environment inside the tumor leads to cancer cell-specific expression of proangiogenic factors including VEGF to shift the balance from endogenous antiangiogenic factors to tumor supplied proangiogenic factors—the angiogenic switch. Once proangiogenic factors overwhelm antiangiogenic factors, new blood vessels form in response to VEGF-induced endothelial permeability by EC sprouting, migration into the tumor mass, and proliferation from existing blood vessels—molecular mechanisms also induced by VEGF [64–67]. The tumor integrity of the vasculature is compromised in that it remains leaky with poor cell-to-cell adhesion, is abnormally branched and not well supported by pericytes (mural cells), the vascular smooth muscle cells that stabilize normal blood vessels [67, 68]. The chronic immaturity of tumor vessels has led Dvorak to characterize a tumor as a “wound that never heals” [69]. Notwithstanding, these features make tumor vessels viable targets for antitumor therapies. Benjamin et al. [70] demonstrated that removal of growth factors leads not only to the cessation of new vessel growth, but also to regression of the immature tumor vasculature [71].