Interrogating the interplay of angiogenesis and immunity in metastatic colorectal cancer

Abstract

Colon cancer is the third most common malignancy and the fifth most frequent cause of death from neoplastic disease worldwide. At the time of diagnosis, more than 20% of patients already have metastatic disease. In the last 20 years, the natural course of the disease has changed due to major changes in the management of metastatic disease such as the advent of novel surgical and local therapy approaches as well as the introduction of novel chemotherapy drugs and targeted agents such as anti-epidermal growth factor receptor, anti-BRAF and antiangiogenics. Angiogenesis is a complex biological process of new vessel formation from existing ones and is an integral component of tumor progression supporting cancer cells to grow, proliferate and metastasize. Many molecules are involved in this proangiogenic process, such as vascular endothelial growth factor and its receptors on endothelial cells. A well-standardized methodology that is applied to assess angiogenesis in the tumor microenvironment is microvascular density by using immunohistochemistry with antibodies against endothelial CD31, CD34 and CD105 antigens. Even smaller molecules, such as the microRNAs, which are small non-coding RNAs, are being studied for their usefulness as surrogate biomarkers of angiogenesis and prognosis. In this review, we will discuss recent advances regarding the investigation of angiogenesis, the crosstalk between elements of the immune microenvironment and angiogenesis and how a disorganized tumor vessel network affects the trafficking of CD8+ T cells in the tumor bed. Furthermore, we will present recent data from clinical trials that combine antiangiogenic therapies with immune checkpoint inhibitors in colorectal cancer.

ɑ-Solanine Affects the Apoptosis and Angiogenesis of M2-Like TAMs Cells by Regulating the PI3K/AKT/mTOR Signaling Pathway Under Hypoxia

“…Antiangiogenic therapy has been successfully applied to colorectal cancer and other tumor types. 28,29 Since its approval in 2004, bevacizumab, a humanized monoclonal antibody that binds VEGF-A , has been used as the first-line therapy in colorectal, non-small-cell lung, metastatic breast, and metastatic renal cell cancers. It is also used as the second-line therapy in glioblastoma multiforme.…”

How the Tumor Micromilieu Modulates the Recruitment and Activation of Colorectal Cancer-Infiltrating Lymphocytes

“…For instance, binding of Vascular Endothelial Growth Factor A (VEGF-A) to its receptor, VEGFR-2, represents a very relevant trigger for promoting angiogenesis and neovascularization in the context of colorectal cancer. However, this is again a highly complex scenario, as the newly formed vascular network induced under the influence of the intratumoral disbalance between pro- and anti-angiogenic factors often shows structural and functional abnormalities, resulting in insufficient tissue perfusion and the hampered delivery of chemokine-attracted effector T cells [ 144 , 145 ]. Moreover, VEGF-A has also been demonstrated to directly promote the proliferation of VEGFR-2-expressing regulatory T cells in colon tumor-bearing mice.…”

Diagnostic, Prognostic, and Therapeutic Role for Angiogenesis Markers in Head and Neck Squamous Cell Carcinoma: A Narrative Review

“…Mean microvessel density (MVD) has been tested in many human malignancy histological types, resulting as a powerful, even if often independent, prognostic indicator [ 19 , 20 , 21 ]. In addition, a significant association between one of the main regulators of angiogenesis, vascular endothelial growth factor (VEGF) expression, and prognosis has been reported [ 22 , 23 ]. In many studies, tissue expression levels of angiogenic factors are related to the potential for tumor spread; therefore, they are considered as predictive indicators in identifying high-risk patients with poor prognoses [ 24 , 25 , 26 ].…”