VEGF is an important pathway in cancer treatment. In many solid tumor VEGF is a target of anti-tumor agents. VEGF is correlated with the agiogenesis, proliferation, migration, and survival of tumor cells.
Functional blood vessels provide the basis of tissue homeostasis and growth with the supply of oxygen and nutrients and the elimination of metabolic degradation products. Therefore, the establishment of a vascular system was essential in organisms. During development, endothelial progenitor cells form a primitive network expands by a process termed “angiogenesis”, in which endotheliad cells (ECs) sprout and form a more complex and elaborated vascular system. Finally, in a process termed “arteriogenesis”, the coverage of EC channels with pericytes and smooth muscle cells provides vessel maturation and stabilization.
The process of angiogenesis is initiated in conditions under which cells experience low oxygen tension and mount a hypoxia inducible factor 1α(HIF-1α)-mediated response. HIF-1α is a transcription factor that is stabilized in hypoxic conditions and activates several genes, including the prototypic angiogenic VEGF-A. VEGF family can bind and signal through the tyrosine kinase (TK) receptors VEGFR.
Once initially angiogenesis was considered to not or only minimally contribute to the pathogenesis of leukemia. But now it has become apparent that the BM vasculature plays an important role in hematopoiesis in health and disease. Endothelial and mural cells (pericytes and smooth muscle cells) provide a specialized “vascular niche” for hematopoietic stem cells (HSCs). Different from the “osteoblastic niche”, which provides a microenvironment for long-term quiescent HSCs, the vascular niche supports proliferation and differentiation of short-term hematopoietic progenitors. It is postulated that HSCs first leave the osteoblastic niche and are then mobilized to the vascular niche before being released into the bloodstream.
Similarly to HSCs, a small fraction of leukemic stem cells possess stem-cell properties with long-term self-renewal, especially in chronic myeloid leukemia (CML). Both the osteoblastic and vascular niche are of importance for the support and maintenance of leukemic stem cells. BM ECs in this vascular niche are capable of secreting several soluble cytokines such as G-CSF, GM-CSF, VEGF, and IL-6, which promote leukemia cell proliferation and survival.
The microvascular capillary network consists of thin-walled, fenestrated sinusoidal ECs (SECs), allowing access, transport, and egression of nutrients and cells across the microvascular wall. These SECs have a unique VE-cadherin+VEGFR2+VEGF3+Scal– signature. Due to the unique expression of adhesion molecules, SECs allow hematopoietic stem and progenitor cells to home and traffic through the BM. This sinusoidal network consists only of a thin basal lamina with a single layer of ECs, but typical pericytes are missing; instead, they can be covered by SDF-1+ reticular cells and clusters of myeloid F4/80+ cells. The abundant densely packed surrounding hematopoietic cells and adipocytes further support this fragile network of SECs. Despite its extensively branched vascular netwrok, the adult BM is relatively hypoxic, with oxygen tensions approximating only 20 mmHg.
Leukemia cells can secrete VEGF, which can activate VEGF receptors on both the leukemia cells and ECs. VEGF is also able to induce the proliferation of these cells and can chemoprotect leukemia cells against cytoxic agents such as etoposide and doxorubicin. In CML, the disease-causing Bcr-Abl1 fusion kinase up-regulates the expression levels of VEGF, whereas the Bcr-Abl1 TK inhibitor imatinib down-regulates VEGF.
PIGF is a member of VEGF family, which binds and signals through Flt1 (VEGFR) in various cell types including ECs, smooth muscle cells, fibroblasts, myeloid progenitor cells, macrophages, and tumor cells. PIGF binding then signaling promote tumor angiogenesis, tumor growth, and the formation of the premetastatic niche.
However, there is still controversy. Initial human studies have shown that bevacizumab is ineffective as monotherapy in patients with refractory pretreated AML, whereas combination therapy with cytostatic agents provided only a slight survival advantage in ALL (Acute Lymphoblastic Leukemia). Despite formidable progess in our current understanding of angioigenesis with the successful translation of anti-angiogenic therapy “from the bench to the bedside” in clinical practice, there are still many outstanding challenges. Parallelisms between angiogenesis in solid tumors and in hematological diseases have been recognized in recent years, but we are still lacking fundamental insight into how vessels support hematological diseases and how this can be successfully targeted in clinical settings.