Vascular endothelial growth factor signaling in acute myeloid leukemia

Abstract

This review is designed to provide an overview of the current literature concerning vascular endothelial growth factor signaling (VEGF) in acute myeloid leukemia (AML). Aberrant VEGF signaling operates in the bone marrow of AML patients and is related to a poor prognosis. The altered signaling pathway demonstrated to interfere in several autocrine and paracrine signaling pathways. VEGF signaling promotes autocrine AML blast cell proliferation, survival, and chemotherapy resistance. In addition, VEGF signaling can mediate paracrine vascular endothelial cell-controlled angiogenesis in AML. Both effects presumably explain the association of high VEGF levels and poor therapeutic outcome. More recently, researches focusing on bone marrow stem cell niches demonstrate a role for VEGF signaling in the preservation of several cell types within these niches. The bone marrow niches are proposed to be a protective microenvironment for AML cells that could be responsible for relapses in AML patients. This implies the need of sophisticated VEGF-targeted therapeutics in AML therapy strategies. This review highlights our current understanding of aberrant VEGF signaling in AML, appoints the interference of VEGF signaling in the AML-associated microenvironment, and reflects the novelty of current VEGF-targeted therapeutics used in clinical trails for the treatment of AML.

Fig. 1

Autocrine VEGF signaling in AML cells. VEGF-A, VEGF-C, VEGFR-2, and VEGFR-3 are overexpressed by AML blasts. VEGF-A and VEGF-C proteins can pass the cell membrane through active transport using secretory vesicles. Studies in endothelial cells demonstrated that VEGFR-2 in the cytoplasm is captured within the endosomes, which is also likely for VEGFR-3 [82]. The cytoplasmic VEGFR-2 retains its signaling activity, even when trapped within the endosomes. Excretion of VEGF-A/C enables the AML cell to bind VEGF-A/C to the VEGFR-2, residing on the cell membrane (external loop). Moreover, VEGF-A/C can also signal internally through binding to VEGFR-2 and VEGFR-3 that reside in the cytoplasm (internal loop). The role of VEGFR-2 within the nucleus is unknown

Fig. 2

Summarized model for classical downstream VEGF/VEGFR signaling in AML cells. The VEGF receptor phosphorylates upon binding of either VEGF-A or VEGF-C. Phosphorylation of the VEGF receptor results in the activation of downstream signaling proteins involved in the PI3 kinase and MAPK signaling pathways. Chemotherapy-resistant mechanisms are regulated through VEGF receptor-mediated activation of Bcl-2 and HSPs. The MAPK route can induce transcription of COX-2. This protein is a pro-angiogenic factor, which in turn can induce paracrine VEGF signaling. The blue proteins evidently demonstrated to be important downstream proteins of the VEGF/VEGFR signaling for the proliferation, survival, and chemotherapy resistance of AML blast cells

Fig. 3

Autocrine and paracrine VEGF signaling in AML. VEGF signaling in AML patients demonstrates two separate signaling pathways that co-operate and promote the pathogenesis of AML. Via autocrine signaling, the AML cells activate the VEGF receptors to induce self-renewal, proliferation, survival, and chemotherapy resistance. Paracrine VEGF signaling promotes angiogenesis and lymph angiogenesis. Through these signaling pathways, the leukemic blasts can increase the vessel formation and their own stem cell maintenance. VEGF-A and VEGF-C can bind to activate AML cells as well as to endothelial cells

Fig. 4

Stem cell niches. Leukemic stem cell niches are thought to protect the leukemic stem cells from therapeutic agents. Stem cells reside in a quiescent state in the endosteal bone marrow niche, which makes the AML cells unsusceptible for therapeutics that targets proliferating cells. Moreover, cells that reside in the vascular bone marrow niche can be mobilized by extrinsic factors to attract them into the bloodstream for organ infiltration, which is commonly observed in AML patients. Secreted VEGF-A and VEGF-C are essential for the supportive cells from which the stem cell niches are formed