Decoding tumor angiogenesis: pathways, mechanisms, and future directions in anti-cancer strategies

Abstract

Angiogenesis, a crucial process in tumor growth and metastasis, necessitates targeted therapeutic intervention. This review reviews the latest knowledge of anti-angiogenesis targets in tumors, with emphasis on the molecular mechanisms and signaling pathways that regulate this process. We emphasize the tumor microenvironment's role in angiogenesis, examine endothelial cell metabolic changes, and evaluated potential therapeutic strategies targeting the tumor vascular system. At the same time, we analyzed the signaling pathway and molecular mechanism of tumor angiogenesis in detail. In addition, this paper also looks at the development trend of tumor anti-angiogenesis drugs, including their future development direction and challenges, aiming to provide prospective insight into the development of this field. Despite their potential, anti-angiogenic therapies encounter challenges like drug resistance and side effects, necessitating ongoing research to enhance cancer treatment strategies and the efficacy of these therapies.

Keywords: Anti-angiogenic therapy; Cancer; Endothelial; Molecular Pathways; Tumor Angiogenesis; Tumor microenvironment; Vascular targeting.

Fig. 1

The most prevalent pattern of tumor angiogenesis. a Sprouting angiogenesis: this process involves the growth of new blood vessels from the existing vasculature; b Intussusceptive angiogenesis: the lumen of the existing blood vessel splits and eventually the blood vessel splits into two; c Vasculogenesis: It refers to the process of angiogenesis from scratch, the differentiation of EPCs in the bone marrow into ECs, and finally the construction of a new vascular system; d Vascular mimicry: tumor cells form a vascular structure that directs oxygen and nutrients to the tumor tissue; e Vessel co-option: tumor cells utilize the existing vasculature for their own growth needs instead of inducing new blood vessels; f Trans-differentiation of cancer stem cells (CSCs): CSCs transform into ECs, which in turn participate in the formation of new vascular network supporting tumor growth. In normal tissues and tumors, the first three patterns were common. The subsequent three were specifically associated with tumor angiogenesis

Fig. 2

Tumor blood vessels characteristics. Abnormal tumor vascular structure: compared with normal blood vessels, tumor vascular perfusion dysfunction, disordered, distorted shape, and excessive branching; hyperpermeability: an increase in the number of abnormal pores (such as endothelial Spaces, vesicles, and transcellular channels) in the vascular walls of the tumor, widening of connections between endothelial cells, broken or missing basement membranes, and abnormal shapes of endothelial cells that overlap and sometimes protrusion into lumen; Increased vascular leakage: due to the above changes, vascular leakage is aggravated, which disrupts the metabolic balance between the tumor area and the surrounding normal lymphatic system, causes the increase of hydrostatic pressure within the tumor tissue, and aggravates the deterioration of the tumor growth environment; Reduced endothelial surface markers: ECs in tumor vessels may exhibit low levels of surface markers, such as cell adhesion molecules, which may affect the function of the vessel; Pericellular sparsity: Tumor blood vessels may lack pericellular cells, which are critical for maintaining the"resting"state of blood vessels and ensuring proper vascular activity to meet metabolic needs

Fig. 3

Angiogenesis related factors secreted by various components of the tumor microenvironment

Fig. 4

ESM1 and ANGPTL4 promote tumor angiogenesis signaling pathways

Fig. 5

Mechanisms and consequences of anti-angiogenic therapy in tumor vascular targeting. a Key molecular targets of anti-angiogenesis include tyrosine kinase signaling pathways (such as VEGF-VEGFR, FGR-FGFR axis, etc.), angiopoietins, ESM1, Notch ligands, and integrins to trigger vessel sprouting by regulating EC proliferation, migration, and survival; b The efficacy of anti-angiogenic therapy depends on the tumor growth stage and angiogenesis status, with early tumors being more sensitive to this treatment; c The dynamic effect of vascular budding inhibition induces transient vascular pruning that reduces tumor growth through starvation. Moderate anti-angiogenic agents promote vascular normalization (strengthening, stabilizing blood vessels) to improve perfusion and adjunctive therapy. However, excessive pruning can aggravate tumor hypoxia and necrosis, triggering resistance mechanisms such as vascular co-selection, metastasis, and invasive recurrence. Vascular normalization is only a transient phase, as long-term treatment eventually leads to hypoxia-driven tumor progression

Fig. 6

Vascular facilitation Therapy. This strategy promotes functional angiogenesis to improve tumor drug delivery by combining low-dose vascular remodeling drugs with chemotherapy. Low-dose cilengitide, which targets αVβ3 integrin, can increase vascular density and improve perfusion when combined with gemcitabine and verapamil. Epirubicin inhibits microtubule dynamics and, when combined with paclitaxel or capecitabine, reduces hypoxia and enhances antitumor immunity. Lysophosphatidic acid (LPA) activates LPA4 receptor to promote the localization of VE-cadherin, forming a dense vascular network to improve the delivery efficiency of 5-fluorouracil/oxaliplatin