Anticancer Role of PPAR Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes
Autocrine production of VEGF in CLL B cells is regulated by miRNA-92-1 inhibition of pVHL production. Expression of high levels of VEGF by tumor cells is critical to promote and sustain the angiogenesis needed for cancer progression. Under normal oxygen tension, the HIF-1α subunit of the transcription factor, HIF-1, is constitutively produced and rapidly degraded by pVHL-induced proteasomal degradation, which prevents transcription of the VEGF gene. In solid tumors, HIF-1-induced VEGF expression occurs when tumor growth exceeds the dimensions where existing blood vessels can feed the tumor and carry away waste products. The resulting hypoxia leads to stabilization of HIF-1α and activation of the HIF-1 heterodimer resulting in high VEGF production by tumor cells. Although solid tumors do not develop in hematological malignancies, angiogenesis is an important process of disease progression. CLL B cells constitutively express high levels of VEGF and VEGFRs leading to autocrine signaling and increased resistance to apoptosis. Recently, Ghosh et al.  discovered that HIF-1 is stabilized in CLL B cells due to low levels of pVHL as a result of miR-92-1 overexpression and subsequent repression of translation of the VHL transcript. Therefore, HIF-1 accumulates and translocates to the nucleus where it forms an active complex with the transcriptional coactivator p300 and phosphorylated Stat3 and, together with the basal transcription machinery, transactivates the VEGF promoter. PPAR agonists could potentially inhibit overexpression of VEGF by inhibiting Stat3 signaling in CLL B cells. The schematic in this figure was adapted from .