Trenton Glaser

Introduction. Colorectal cancer (CRC) is the third most common cancer in the United States and the number of cases is increasing due to a variety of factors.¹ Developing countries have seen an increase in CRC cases due to increase population age and modifiable lifestyle habits.^1&2 While several new treatment options are available the survival rate and prognosis is worse for cases that have metastasized. CRC symptoms are typically not apparent until the tumor has progressed enough to cause obstructions. ^1-3 This emphasizes the necessity for regular screenings via colonoscopies that drastically reduce the mortality rate of CRC.² Around 20% of CRC are metastatic requiring further adjunctive therapy to treat and prevent metastasis.¹ Vascular endothelial growth factor (VEGF) is upregulated very early on in CRC progression and contributes to early tumor growth, microvascular network extension (MNE), and tumor immune escape.^4-6 The VEGF pathway is implicated in several different types of cancers and could act as an effective therapeutic target for CRC.⁷ Methods. An azoxymethane (AOM) and dextran sulphate sodium salt CRC mouse model was used to determine the impact of VEGF overexpression on CRC progression. An adenovirus expressing VEGF was administered to these mice with and without anti-VEGF antibody (mF431C1). These mice were analyzed for level of tumor growth, tumor associated macrophage population (TAMs), differentiated M1 vs M2 subtype, and lymphatic vessel density.⁴ Subcutaneously grown tumors (CT26-GFP tumor cells) were transplanted into the colon of mice models and treated with Pazopanib (VEGFR inhibitor) to determine its effects on inhibition of tumor and lymphatic vessel growth.⁵ 76 patients with CRC were analyzed via immunohistochemistry to determine if there was a correlation between TAM population and MNE.⁶ Results. Inhibition of the VEGF pathway in the AOM model restored antitumor immunity (Increased levels of CD8+ T-cells), reduced lymphangiogenesis, increased factors involved in inflammation, and decreased tumor volumes. Macrophage depletion in these mice also showed decreased tumor volumes and increased CD8+ T-cells showing that TAMs and VEGF cooperate to induce tumor immune escape.⁴ TAM population is strongly associated with MNE, and TAM infiltration likewise strongly correlated with angiogenic markers such as VEGF.⁶ Pazopanib treatment resulted in significantly reduced tumor volumes, lymphatic vessel density, and lymphatic spread of tumor cells.⁵ Conclusions. These studies show that VEGF plays a role not only in tumor progression but also TAM recruitment allowing for tumor immune escape. The effects Anti-VEGF therapy has on the MNE and anti-tumor immunity could provide an effective adjunctive or neo-adjunctive therapy for CRC.

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