Tumor angiogenesis: causes, consequences, challenges and opportunities

Abstract

Tumor vascularization occurs through several distinct biological processes, which not only vary between tumor type and anatomic location, but also occur simultaneously within the same cancer tissue. These processes are orchestrated by a range of secreted factors and signaling pathways and can involve participation of non-endothelial cells, such as progenitors or cancer stem cells. Anti-angiogenic therapies using either antibodies or tyrosine kinase inhibitors have been approved to treat several types of cancer. However, the benefit of treatment has so far been modest, some patients not responding at all and others acquiring resistance. It is becoming increasingly clear that blocking tumors from accessing the circulation is not an easy task to accomplish. Tumor vessel functionality and gene expression often differ vastly when comparing different cancer subtypes, and vessel phenotype can be markedly heterogeneous within a single tumor. Here, we summarize the current understanding of cellular and molecular mechanisms involved in tumor angiogenesis and discuss challenges and opportunities associated with vascular targeting.

Keywords: Angiogenesis; Anti-angiogenic therapy; Cancer; Endothelial; VEGF; Vascular targeting.

Fig. 1

Mechanisms of blood vessel formation. Neo-vascularization in normal tissues and tumors occur through one or more of the following mechanisms: a Sprouting angiogenesis: a process involving formation and outgrowth of sprouts (tip cells), which eventually fuse with an existing vessel or newly formed sprout. b Intussusceptive angiogenesis: the formation of new vasculature where a pre-existing vessel splits in two. c Vasculogenesis: prenatal neo-vascularization from endothelial progenitor cells. The endothelial progenitor cells proliferate and form lumens, eventually assembling into new blood vessels. d Recruitment of endothelial progenitor cells: vessel formation in tumors by recruitment of circulating endothelial progenitor cells. e Vascular mimicry: a matrix-embedded fluid-conducting meshwork formed by tumor cells. f Trans-differentiation of cancer stem cells (CSC): neo-vascularization in tumors through differentiation of CSCs to endothelial cells

Fig. 2

Morphological and functional characteristics of tumor vessels as compared to normal vessels. a Normal vessels display an organized and hierarchical branching pattern of arteries, veins, and capillaries. In healthy vessels, endothelial cells are supported by basal membrane and pericytes coverage and they are tightly connected by stable cell-cell junctions. b Tumor vessels are morphologically and functionally different from normal vessels. In response to persistent and imbalanced expression of angiogenic factors and inhibitors, tumor vessels display an unorganized network lacking of a hierarchical vessel division. Tumor vessels are characterized by reduced blood flow, endothelial cell sprouting, disruption of endothelial cell junctions, loss of pericytes coverage and increased vessel leakiness resulting in increased tissue hypoxia and intravasation of tumor cells. Moreover, tumor endothelial cell basal membrane is abnormal, including loose associations with endothelial cells and variable thickness. c Tumor vessel abnormalization shown by immunofluorescent staining for the vessel marker CD31 (green) in an orthotopic syngeneic mouse model of glioma growing in the brain

Fig. 3

Effects of anti-angiogenic therapy. The mechanism of actions of angiogenesis inhibitors on tumor blood vessels can be classified into three categories: a vessel depletion, b vessel normalization, and c immune activation. a Vessel depletion result in tumor cell starvation and an increased tissue hypoxia. Enhanced hypoxia may promote the recruitment of pro-angiogenic myeloid cells and the mobilization of tumor cell from the hypoxic tissue to the normal tissue as well as co-option of normal vessels. In addition, the depletion of tumor vessels results in an inefficient delivery of anti-cancer drugs. b Normalization of tumor blood vessels achieved by restored endothelial cell junctions, increased pericytes coverage and re-established blood flow result in decrease tissue hypoxia and increased drugs delivery. In addition, vessel normalization promote the expression of endothelial adhesion molecule facilitating immune cell infiltration. c Immune activation, induced by anti-angiogenic drugs include dendritic cell (DC) maturation, activation and infiltration of T-cell as well as the polarization of tumor associated macrophages (TAM) towards an M1-like phenotype. In addition, a decrease in regulatory T-cells (Treg), myeloid derived suppressor cells (MDSCs) and mast cells have been observed in response to anti-angiogenic therapy