Angiogenic signaling pathways and anti-angiogenic therapy for cancer

Abstract

Angiogenesis, the formation of new blood vessels, is a complex and dynamic process regulated by various pro- and anti-angiogenic molecules, which plays a crucial role in tumor growth, invasion, and metastasis. With the advances in molecular and cellular biology, various biomolecules such as growth factors, chemokines, and adhesion factors involved in tumor angiogenesis has gradually been elucidated. Targeted therapeutic research based on these molecules has driven anti-angiogenic treatment to become a promising strategy in anti-tumor therapy. The most widely used anti-angiogenic agents include monoclonal antibodies and tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) pathway. However, the clinical benefit of this modality has still been limited due to several defects such as adverse events, acquired drug resistance, tumor recurrence, and lack of validated biomarkers, which impel further research on mechanisms of tumor angiogenesis, the development of multiple drugs and the combination therapy to figure out how to improve the therapeutic efficacy. Here, we broadly summarize various signaling pathways in tumor angiogenesis and discuss the development and current challenges of anti-angiogenic therapy. We also propose several new promising approaches to improve anti-angiogenic efficacy and provide a perspective for the development and research of anti-angiogenic therapy.

Fig. 1

The progression of the canceration through angiogenesis. The rapid expansion of tumor results in a reduction in the oxygen supply. The consequent hypoxic tumor microenvironment stimulates excessive angiogenesis via increasing various angiogenic pro-factors including VEGF, PDGF, FGF, and angiopoietin. Later, new blood vessels facilitate the transportation of oxygen and nutrients to further support the survival, growth and proliferation of tumor cells. When tumor cells develop a more aggressive phenotype, they continue to proliferate, spread and induce angiogenesis, with the invasion and metastasis of tumor cells into distant tissues through blood circulation

Fig. 2

Most common modes in tumor angiogenesis. a Sprouting angiogenesis: main way in both physiological and pathological angiogenesis, which is induce by proliferation and migration of endothelial tip cells. b Intussusception: the existing blood vessel is divided into two vessels under mediation of cell reorganization. c Vasculogenesis: bone-marrow-derived endothelial progenitor cells differentiate into endothelial cells, participating in the formation of new vascular lumen. d Vessel co-option: tumor cells approach and hijack the existing blood vessels. e Vessel mimicry: tumor cells form a vessel-like channel around normal blood vessels to direct the transport of oxygen and nutrients into tumor tissue. f Trans-differentiation of cancer cells: cancer stem-like cells differentiate into endothelial cells, which participate in the formation of new blood vessels. (Modified from Carmeliet, P. & Jain, R. K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).)

Fig. 3

Schematic diagram showing crosstalk of multiple signaling pathways during tumor angiogenesis. Pointed arrows indicate activation whereas flat arrows indicate inhibition

Fig. 4

The transduction of HIF-1α in normal and hypoxic conditions. Under normal conditions, HIF-1α is degraded by protease and loses transcription function. In hypoxic environment, lack of enzyme degradation leads to efficient transcription of HIF-1α, resulting in over-expression of pro-angiogenic factors including VEGF, PDGF, and MMPs

Fig. 5

MMP-expressing stromal cells and functions of MMPs in tumor microenvironment. MMP precursors which are secreted by endothelial cells, fibroblasts, and lymphocytes et al. converted into active MMPs through enzymolysis. Subsequently, active MMPs participate in different biological processes including angiogenesis and tissue invasion by degrading specific extracellular matrix components

Fig. 6

Diagramatic illustrations of the relationship between tumor blood vessels, pro-angiogenic and anti-angiogenic factors. a Blood vessels with regularity and completeness depend on dynamic balance of pro-factors and anti- factors in normal tissues. b Abnormal vessels with chaos, leakage and feeble blood circulation are caused by imbalance of mediators in tumor tissue. c Blood vessels are repaired through neutralizing abundant pro-factors or increasing anti-factors under the guidance of angiogenic inhibitors. d Blood vessels in tumor tissue are destroyed by excessive inhibitors, which aggravates hypoxia within tumor tissue and hinders drug transportation

Fig. 7

Timeline of the milestones regarding the research on tumor angiogenesis

Fig. 8

Mechanisms of drug resistance in anti-angiogenic therapy. Some patients are intrinsically non-responsive to anti-angiogenic therapy while other patients who are initially responsive acquire adaptive resistance. The mechanisms that manifest acquired resistance to anti-angiogenic therapy include: compensatory upregulation of alternative pro-angiogenic factors such as bFGF, PDGF, and PlGF within the tumor; recruitment of bone marrow-derived endothelial progenitor cells to facilitate neovascularization; increased pericyte coverage protects tumor blood vessels; autophagy helps tumor cells thrive in a hypoxic environment; increased invasiveness of the tumor promotes the distant metastasis and invasion of tumor cells through blood and lymphatic circulation. In addition, genetic mutations, vessel mimicry, vessel co-option, and intussusception angiogenesis also contribute to drug resistance