Angiogenesis, the process of forming new blood vessels from existing ones, plays a pivotal role in tumor growth and metastasis. Tumors, in their quest for sustained growth, often exploit angiogenesis to ensure an adequate supply of nutrients and oxygen. Dr. Judah Folkman's proposal in the 1970s regarding the potential of targeting angiogenesis for cancer treatment laid the foundation for decades of research in this field. However, the comprehension of angiogenesis as a therapeutic target evolved significantly over the years.
Initially, the approach to angiogenesis inhibition was straightforward: starve tumors by blocking the formation of new blood vessels. This concept gained momentum with the discovery of vascular endothelial growth factor (VEGF) and its role in promoting angiogenesis. VEGF, along with other pro-angiogenic factors, orchestrates the complex process of angiogenesis, facilitating tumor progression. The development of drugs targeting VEGF and its receptors (VEGFRs) marked a significant milestone in cancer therapy, leading to the approval of numerous agents across various solid tumor types.
Related Products
VEGF/VEGFR Family
The VEGF/VEGFR family comprises crucial proteins involved in various physiological and pathological processes. VEGF, a 40-45 kDa homodimeric protein, is secreted by diverse cells. Besides VEGF-A, the family includes VEGF-B, VEGF-C, VEGF-D, and the placenta growth factor (PlGF). VEGF-A plays a pivotal role in endothelial cell functions like sprouting, mitogenesis, and migration, along with vasodilation and vascular permeability modulation. VEGF-B stimulates embryonic angiogenesis and perivascular cell coverage, affecting metastasis independently. VEGF-C and VEGF-D regulate lymphangiogenesis, while PlGF influences vasculogenesis, inflammation, and cancer cell survival. These ligands interact with VEGF receptors (VEGFRs), including VEGFR1, primarily bound by VEGF-A, VEGF-B, and PlGF. VEGFR2, expressed in blood and lymphatic vessels, interacts with VEGF-A and processed VEGF-C/VEGF-D. VEGFR3 binds VEGF-C and VEGF-D and is found in both blood and lymphatic endothelial cells. Neuropilins-1 and -2 (NRP-1 and NRP-2) act as co-receptors for VEGF ligands. VEGF undergoes alternative splicing, yielding various isoforms, notably VEGF165, predominant in normal and cancer cells. Anti-angiogenic isoforms like VEGFxxxb counteract pro-angiogenic ones, offering potential therapeutic avenues. Specific splicing factors regulating these isoforms present promising targets for inhibiting tumor angiogenesis.
Regulation of VEGF Expression
The expression of VEGF is tightly regulated at multiple levels. Hypoxia-inducible factor 1 (HIF-1) is a key transcription factor that upregulates VEGF expression in response to hypoxic conditions within the tumor microenvironment. Other factors, such as growth factors (e.g., EGF, FGF), cytokines (e.g., TNF-α), and oncogenes (e.g., Ras, Src), can also stimulate VEGF production through various signaling pathways. Moreover, epigenetic modifications, including DNA methylation and histone acetylation, contribute to the regulation of VEGF gene expression.
Downstream VEGF Signaling
VEGF family members bind to VEGFR on target cells, initiating downstream signaling pathways. VEGF-A predominantly binds to VEGFR-2, inducing receptor dimerization and auto-phosphorylation. This activation triggers PI3K, PLC-γ, Akt, Ras, and MAPK pathways, promoting various cellular responses including proliferation, survival, migration, and permeability changes. AXL mediates VEGF-A-induced PI3K/Akt signaling and vascular permeability. Co-receptors like NRP-1 and co-activating proteins modulate VEGFR signaling, while crosstalk with receptors like FGFR and the Hippo pathway further regulate its effects.
Fig. 1 The effect of VEGF on the function and growth of endothelial, tumor, and immune cells in the tumor microenvironment (Patel, S.A., et al. 2023).
VEGF/VEGFR in Cancer Therapy
Initially, therapeutic interventions targeting the VEGF/VEGFR pathway were pioneered by Ferrara and colleagues through the use of a monoclonal antibody against VEGF-A. It was observed that inhibiting VEGF led to a reduction in tumor vessels, supporting the hypothesis that impeding tumor angiogenesis and subsequent reduction in tumor perfusion could hinder tumor growth. However, subsequent studies uncovered a more intricate role of VEGF-A inhibition. Contrary to earlier beliefs, anti-VEGF-A therapy demonstrated the ability to enhance the effectiveness of concurrent cytotoxic therapy, which relies on blood vessels for drug delivery. This was attributed to the "vascular normalization" model, suggesting that VEGF-A inhibitors could transiently normalize abnormal tumor vessels, enhancing oxygen and drug delivery temporarily. Despite initial skepticism, extensive preclinical and clinical studies supported this concept, indicating improved progression-free survival (PFS) and overall survival (OS) in patients experiencing increased tumor perfusion with anti-VEGF/R agents.
VEGF-A exerts direct effects on various cells within the tumor microenvironment, including endothelial cells, tumor cells, and immune cells. Initially recognized for its role in regulating endothelial sprouting, migration, and differentiation primarily through VEGF-A/VEGFR-2 binding, VEGF-A's overexpression in tumors, often due to hypoxia, leads to the formation of aberrant and tortuous vessels. Additionally, VEGF-A increases microvascular permeability, and endothelial fenestrations, and supports endothelial cell network development, crucial for tumor growth. Moreover, VEGF-A facilitates the recruitment of circulating endothelial progenitor cells (CEPs) from the bone marrow, further promoting tumor angiogenesis.
Beyond its effects on endothelial cells, VEGF-A directly influences tumor cells, promoting aggressiveness and survival. It induces epithelial-mesenchymal transition (EMT), stemness, invasiveness, and migration through various signaling pathways. Furthermore, VEGF-A signaling in tumor cells activates survival pathways and confers resistance to chemotherapy.
VEGF-A also acts as an immunosuppressive cytokine within the tumor microenvironment, impairing the function of immune cells. It inhibits dendritic cell maturation and antigen presentation, thereby suppressing T cell-mediated cytotoxicity. Additionally, VEGF-A affects macrophage polarization, promoting an immunosuppressive M2 phenotype, which supports tumor vascularization and remodeling. Moreover, VEGF-A attracts myeloid-derived suppressor cells (MDSCs) to the tumor site, further contributing to immunosuppression. Overall, VEGF-A fosters an immunosuppressive microenvironment through various mechanisms, hindering antitumor immunity.
Despite the initial optimism surrounding VEGF/VEGFR targeting, resistance mechanisms have emerged, involving both tumor cell-intrinsic and microenvironmental factors. Tumor genomic alterations, such as p53 inactivation and loss of LKB1 protein, can promote resistance by rendering tumor cells less sensitive to hypoxia-induced apoptosis and altering angiogenesis-related pathways. Acquired resistance mechanisms involve treatment-induced hypoxia, upregulation of alternative pro-angiogenic signaling molecules, and changes in the tumor microenvironment.
Host factors, including estrogen levels and altered blood vessel development, also influence response to VEGF-targeted therapies. Moreover, resistance can arise from increased pericyte coverage of tumor blood vessels, upregulation of factors promoting tumor invasiveness, and enhanced autophagy induced by hypoxia.
In summary, understanding the multifaceted impact of VEGF signaling in tumor biology is crucial for developing effective therapeutic strategies. Despite challenges posed by resistance mechanisms, ongoing research continues to elucidate the complex interplay between VEGF signaling, tumor cells, and the microenvironment, offering opportunities for innovative combination therapies and biomarker discovery.
Reference
- Patel, S.A., et al. 2023. Molecular mechanisms and future implications of VEGF/VEGFR in cancer therapy. Clinical Cancer Research. 29(1), pp.30-39.
.
