Angiogenesis in Breast Cancer Progression, Diagnosis, and Treatment

Abstract

Angiogenesis is a significant event in a wide range of healthy and diseased conditions. This process frequently involves vasodilation and an increase in vascular permeability. Numerous players referred to as angiogenic factors, work in tandem to facilitate the outgrowth of endothelial cells (EC) and the consequent vascularity. Conversely, angiogenic factors could also feature in pathological conditions. Angiogenesis is a critical factor in the development of tumors and metastases in numerous cancers. An increased level of angiogenesis is associated with decreased survival in breast cancer patients. Therefore, a good understanding of the angiogenic mechanism holds a promise of providing effective treatments for breast cancer progression, thereby enhancing patients' survival. Disrupting the initiation and progression of this process by targeting angiogenic factors such as vascular endothelial growth factor (Vegf)-one of the most potent member of the VEGF family- or by targeting transcription factors, such as Hypoxia-Inducible Factors (HIFs) that act as angiogenic regulators, have been considered potential treatment options for several types of cancers. The objective of this review is to highlight the mechanism of angiogenesis in diseases, specifically its role in the progression of malignancy in breast cancer, as well as to highlight the undergoing research in the development of angiogenesis-targeting therapies.

Keywords: Breast cancer; VEGF; angiogenesis; anti-angiogenic therapies; hypoxia; metastasis; vascular diseases.

Figure 1

Angiogenesis, the physiological process by which development of new blood vessels from preexisting vessels. New blood vessels form out of pre-existing capillaries. The new blood vessels, near and in the tumor, provide it with essential nutrients for growth. Angiogenesis in healthy tissues is regulated by the balance between anti- and pro-angiogenic factors (bottom), and this balance is destroyed by the prevalence of angiogenic factors in tumors, resulting in abnormal structure and function of blood vessels and leading to hypoxia. This reverts the balance and normalizes the vasculature.

Figure 2

Schematic diagram illustrating the balance hypothesis of the angiogenic switch. It is speculated that an angiogenesis switch mechanism tightly regulates normal angiogenesis (formation of new capillaries). This balance can be disrupted to favor increased blood vessel formation through inducers and inhibitors of angiogenesis, which activates the switch. Reducing the inhibitor concentration, e.g., thrombospondin-1, 16kD prolactin, Interferon αιβ, Platelet factor-4, Angiostatin, etc. or increasing the activator levels, e.g., aFGF, bFGF, VEGF, etc., can change the balance and activate the switch, which could lead to the growth of new blood vessels.

Figure 3

Schematic diagram of the receptor-binding specificity of vascular endothelial growth factor (VEGF) family members and their signaling pathways. VEGF family members bind to specific receptor tyrosine kinases: VEGFR-1, VEGFR-2, and VEGFR-3 respectively and through these signaling pathways activate different cascades and exert their various biologic effects.

Figure 4

Signaling of the VEGF Ligands, Receptors, and the Inhibitors of the VEGFA Pathway. The VEGF family of ligands and their receptor-binding patterns are shown at the top. VEGF ligand family members, VEGFA, -B, -C, -D, and placental growth factor (PIGF), selectively bind to three tyrosine kinase receptors, VEGFR1, VEGFR2, and VEGFR3. As co-receptors of VEGFR2 and VEGFR3, neuropilin 1 and 2 (NRP1 and NRP2) modulate their signaling pathways. The soluble VEGFR1 (sVEGFR1) inhibits the signaling of VEGFR1 and VEGFR2 by sequestering free ligands. The different VEGF pathway inhibitors and their targets are indicated with red. Downstream VEGFR signaling pathways are shown on the bottom. VEGFR activates many proteins through PKC or PI3K. The activation of downstream signal transduction molecules leads to numerous distinct biological processes as indicated in the diagram.

Figure 5

Chart of endogenous angiogenesis inhibitors. Several are fragments of a naturally occurring extracellular matrix (ECM) and basement membrane proteins. The endogenous inhibitors of angiogenesis are divided into two major categories.