Molecular mechanisms and clinical applications of angiogenesis

Abstract

Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.

Figure 1. Modes of vessel formation

There are several known methods of blood vessel formation in normal tissues and tumours. a–c, Vessel formation can occur by sprouting angiogenesis (a), by the recruitment of bone-marrow-derived and/or vascular-wall-resident endothelial progenitor cells (EPCs) that differentiate into endothelial cells (ECs; b), or by a process of vessel splitting known as intussusception (c). d–f, Tumour cells can co-opt pre-existing vessels (d), or tumour vessels can be lined by tumour cells (vascular mimicry; e) or by endothelial cells, with cytogenetic abnormalities in their chromosomes, derived from putative cancer stem cells (f). Unlike normal tissues, which use sprouting angiogenesis, vasculogenesis and intussusception (a–c), tumours can use all six modes of vessel formation (a–f).

Figure 2. Molecular basis of vessel branching

The consecutive steps of blood vessel branching are shown, with the key molecular players involved denoted in parentheses. a, After stimulation with angiogenic factors, the quiescent vessel dilates and an endothelial cell tip cell is selected (DLL4 and JAGGED1) to ensure branch formation. Tip-cell formation requires degradation of the basement membrane, pericyte detachment and loosening of endothelial cell junctions. Increased permeability permits extravasation of plasma proteins (such as fibrinogen and fibronectin) to deposit a provisional matrix layer, and proteases remodel pre-existing interstitial matrix, all enabling cell migration. For simplicity, only the basement membrane between endothelial cells and pericytes is depicted, but in reality, both pericytes and endothelial cells are embedded in this basement membrane. b, Tip cells navigate in response to guidance signals (such as semaphorins and ephrins) and adhere to the extracellular matrix (mediated by integrins) to migrate. Stalk cells behind the tip cell proliferate, elongate and form a lumen, and sprouts fuse to establish a perfused neovessel. Proliferating stalk cells attract pericytes and deposit basement membranes to become stabilized. Recruited myeloid cells such as tumour-associated macrophages (TAMs) and TIE-2-expressing monocytes (TEMs) can produce pro-angiogenic factors or proteolytically liberate angiogenic growth factors from the ECM. c, After fusion of neighbouring branches, lumen formation allows perfusion of the neovessel, which resumes quiescence by promoting a phalanx phenotype, re-establishment of junctions, deposition of basement membrane, maturation of pericytes and production of vascular maintenance signals. Other factors promote transendothelial lipid transport.

Figure 3. Potential mechanisms of resistance to targeted VEGF therapy in cancer

Different mechanisms underlie the resistance to VEGF blockade seen in some patients with cancer. These mechanisms are not exclusive, and it is likely that several occur simultaneously in a single tumour. a, In established tumours, VEGF blockade aggravates hypoxia, which upregulates the production of other angiogenic factors or increases tumour cell invasiveness. Tumour cells that have acquired other mutations can also become hypoxia tolerant. The more malignant tumour cells are shown as dark green, blue and purple cells. b, Other modes of tumour vascularization, including intussusception, vasculogenic mimicry, differentiation of putative cancer stem cells (CSCs) into endothelial cells (ECs), vasculogenic vessel growth and vessel co-option (all denoted by the mosaic red–purple vessels), may be less sensitive to VEGF blockade. c, Tumour vessels covered by pericytes (green) are less sensitive to VEGF blockade. d, Recruited pro-angiogenic BMDCs (yellow), macrophages (blue and purple) or activated cancer-associated fibroblasts (CAFs; orange) can rescue tumour vascularization by the production of pro-angiogenic factors.