Tumor Angiogenesis: How Cancer Hijacks Blood Vessel Formation

VEGF acts through autocrine signaling, where it is synthesized within the cell and binds to receptors on the same cell. When monoclonal antibodies block VEGF, tumor cells respond by upregulating VEGF receptor expression and increasing PI(4,5)P2 expression, which serves as a GPI anchor attaching receptor tyrosine kinases to the plasma membrane. This mechanism allows tumors to overcome antibody suppression by increasing functional receptor density. Anti-angiogenesis therapy began in 1971 when Folkman observed tumors were restricted until neovascularization occurred. Bevacizumab proved effective for metastatic colon cancer (2004), NSCLC (2006), and cervical cancer (2014). Small molecule TKIs like sunitinib showed benefits in renal carcinoma (2005). However, meta-analyses showed limited efficacy as monotherapy and required combination with conventional chemotherapy.

This segment presents the scientific findings on why antiangiogenic treatments fail long-term. Tumors cannot grow beyond 1-2 mm without blood supply, inducing angiogenesis through soluble factors. Despite FDA approval of Bevacizumab in 2004 and subsequent small molecule inhibitors, clinical efficacy remains modest with many patients showing resistance. Researchers developed a mouse model recapitulating human treatment resistance, where tumors regrow aggressively after treatment cessation. Using omics technologies, they discovered metabolic reprogramming: during treatment, tumors become glycolytic (glucose-consuming) to survive hypoxia; after treatment, they switch to oxidative metabolism with accelerated Krebs cycle and lipid synthesis. Combining antiangiogenic therapy with lipid synthesis inhibitors (pharmacologically or via shRNA) completely prevents tumor regrowth, offering a promising strategy to improve cancer treatment efficacy.

Patients show heterogeneous responses ranging from profound tumor shrinkage to disease progression. Resistance mechanisms include: tumors expressing alternative pro-angiogenic factors (basic FGF, PDGF, HGF, angiopoietin-1) that compensate for VEGF inhibition; transformed endothelial cells derived from tumor stem cells that may be resistant; recruitment of normal cells like myeloid cells and endothelial progenitors; and vessel co-option where tumors grow around pre-existing vessels instead of inducing new ones. Preclinical studies confirm that FGF can maintain endothelial survival even when VEGF signaling is blocked.

Anti-angiogenic drugs like bevacizumab face challenges in identifying predictive biomarkers due to the complex and dynamic nature of angiogenesis pathways, where multiple pro-angiogenic ligands beyond VEGF-A may contribute to treatment resistance, making it difficult to predict which patients will respond to these therapies; current research indicates that effective anti-angiogenic strategies may require targeting multiple pathways simultaneously rather than relying on single-agent approaches, and the development of better biomarkers remains an active area of investigation.

Antiangiogenic therapy targets the VEGF pathway through two primary mechanisms: monoclonal antibodies (like bevacizumab) that bind VEGF ligands outside the cell to prevent receptor activation, and tyrosine kinase inhibitors (TKIs) that block the intracellular kinase domain of VEGF receptors; while monoclonal antibodies inhibit the pathway earlier by trapping ligands, clinical data suggests receptor-targeting approaches may be more effective in certain cancers like gastric cancer, demonstrating that empirical evidence often determines optimal therapeutic strategies rather than purely theoretical predictions.

Vasculogenic mimicry is a pathological phenomenon where tumor cells organize themselves to form vessel-like hollow channels that normal blood vessels hook up to, mimicking the vascular genesis process seen in normal physiology; this differs from angiogenesis (new vessel growth from existing vessels) and requires different treatment approaches since anti-angiogenic therapies may not effectively target this alternative vascularization mechanism in tumors.

In the COBIT group, there was new blood vessel growth primarily through a process known as intussusceptive angiogenesis. Angiogenesis means the formation of new blood vessels. The term 'intussusceptive' refers to something telescoping inside itself—in this context, new blood vessels are formed by a pillar of tissue within another blood vessel, effectively splitting that vessel into two. This process contributes to more problems with clotting and inflammation of the lining of the blood vessels compared to influenza. Angiogenesis was much more prevalent in the COVID group compared to the influenza group and there wasn't any angiogenesis in the control group.

Tumors develop their own blood supply through angiogenesis, a process where hypoxic tumor cells release factors that recruit endothelial cells from surrounding tissues to form new blood vessels; however, this strategy faces fundamental challenges because tumors are complex adaptive systems that can develop alternative vasculature strategies, including vasculogenic mimicry where tumor cells themselves form vessel-like structures, and the resulting abnormal vasculature remains highly permeable, facilitating metastasis while providing poor oxygenation.

Patients show heterogeneous responses ranging from profound tumor shrinkage to disease progression. Resistance mechanisms include tumors expressing alternative pro-angiogenic factors (basic FGF, PDGF, HGF, angiopoietin-1) that compensate for VEGF inhibition; transformed endothelial cells derived from tumor stem cells that may be resistant; recruitment of normal cells like myeloid cells and endothelial progenitors; and vessel co-option where tumors grow around pre-existing vessels instead of inducing new ones. Vessel co-option has been observed in liver, lung, and brain metastases, where tumors maintain vascular architecture identical to host tissue. No validated biomarkers currently predict response—circulating VEGF levels and cytokine panels show promise but require validation. Critical evidence shows continuous therapy maintenance is essential—removing anti-VEGF drugs allows vascular density to recover within two weeks. Retrospective analysis demonstrated improved survival for colorectal cancer patients continuing bevacizumab beyond first progression, supporting uninterrupted therapy for sustained benefit.

Lung cancer remains a leading cause of mortality, with traditional platinum-based chemotherapies causing adverse effects and developing resistance. Immunotherapy shows limited efficacy, with 70% of patients unresponsive, particularly those with low CD8+ T cells and PD-L1. Tumors require blood vessels for oxygen and nutrients, developing them through angiogenesis (new vessel creation) or vascular co-option (using pre-existing vessels). Tumors utilizing co-option develop therapy resistance. Experimental models with Kras and p53 mutant cells showed mixed vascular patterns, with platinum-based treatments inducing resistance linked to hypoxia. The research concludes that chemotherapy triggers tumors to switch from angiogenic to co-option vascularization patterns, mediated by unknown cytokines, representing a key mechanism of treatment resistance.

Perfusion MRI monitors treatment response through functional changes preceding morphological alterations. In chemotherapy, washout patterns become less pronounced post-treatment. For anti-angiogenic therapy, perfusion and permeability changes occur before tumor size reduction, making traditional RECIST criteria inadequate. Baseline perfusion correlates with prognosis—hypervascular tumors respond better to anti-angiogenic drugs—establishing perfusion as a potential surrogate endpoint in clinical trials.

CT perfusion evaluates tissue blood flow by measuring contrast uptake over time, calculating blood flow, blood volume, mean transit time, and permeability surface area product. This technique characterizes tumors by assessing angiogenesis, which correlates with tumor vascularity and aggressiveness. PET (Positron Emission Tomography) is a functional imaging technique using radiolabeled substrates like FDG (fluorodeoxyglucose) to detect metabolic activity. Areas of high metabolic activity appear as 'hot spots' on PET images, useful for detecting tumors, infections, and inflammatory processes.

Anti-angiogenic therapy targets tumor neovascularization by blocking VEGF receptors, with over 200 approved drugs and 800 in development. However, most drugs target the same receptor, creating a critical need for biomarkers to select optimal treatments. Traditional RECIST criteria fail because anti-angiogenic drugs cause tumor necrosis without volumetric changes—patients show no size reduction even after 9 months, while functional imaging immediately reveals necrosis. Functional imaging quantifies biological changes (necrosis, vascularization) rather than anatomy, correlating with progression-free and overall survival. This enables earlier drug selection, saves patient time, and reduces healthcare costs by avoiding unnecessary treatments.

Since 2004 when anti-angiogenic therapies became available, there has been a 70-100% improvement in survival for patients with kidney cancer, multiple myeloma, colorectal cancer, and gastrointestinal stromal tumors. However, for other tumor types, improvements have only been modest. The reason for limited effectiveness in some cancers may be that treatment often begins too late, after cancer has already spread or metastasized.

Anti-angiogenic therapies reduce tumor vascularization by targeting VEGF pathways, producing vascular normalization effects where central tumor vasculature normalizes while peripheral vessels remain intact. Dynamic contrast enhanced MRI quantifies these effects through parameters including transfer constant (Ktrans) reflecting permeability and blood flow. However, size change is an inappropriate endpoint for anti-angiogenic drugs - clinical trials demonstrate modest anatomical responses but significant survival benefits, leading to approvals for hepatocellular carcinoma, colorectal cancer, renal cancer, and glioblastoma. Time-to-progression endpoints do not reliably predict overall survival benefits, necessitating better biomarkers to identify patients who will benefit versus those who will experience harm.