Regulation of VEGF expression. VEGF-A levels are increased in several hematologic malignancies, including MM. Factors modulating VEGF secretion include (A) secretion of IL-6 or VEGF by both BMSCs and tumor cells (paracrine/autocrine loop); (B) hypoxia and the presence of mutant oncogenes (ie, mutant Ras [mutRas] or Bcr-Abl, which up-regulate VEGF expression via HIF-1α protein); (C) secretion of IGF-1, which up-regulates VEGF production and secretion in tumor cells (paracrine loop); (D) c-maf–driven expression of tumor integrin β7; (E) tumor cell expression of ICAM1 and LFA1 modulating adhesion to ECM and BMSCs, thereby increasing VEGF production and secretion; and (F) CD40 activation, which induces p53-dependent VEGF secretion. Furthermore, VEGFR-1 expression is regulated, for instance, by IGF-1 via HIF-1α (C).