Vascular Endothelial Growth Factor Receptors VEGFR-2 and VEGFR-3 Are Localized Primarily to the Vasculature in Human Primary Solid Cancers

Abstract

Purpose: Vascular endothelial growth factor (VEGF) signaling is key to tumor angiogenesis and is an important target in the development of anticancer drugs. However, VEGF receptor (VEGFR) expression in human cancers, particularly the relative expression of VEGFR-2 and VEGFR-3 in tumor vasculature versus tumor cells, is poorly defined. Experimental Design: VEGFR-2– and VEGFR-3–specific antibodies were identified and used in the immunohistochemical analysis of human primary cancers and normal tissue. The relative vascular localization of both receptors in colorectal and breast cancers was determined by coimmunofluorescence with vascular markers. Results: VEGFR-2 and VEGFR-3 were expressed on vascular endothelium but not on malignant cells in 13 common human solid tumor types (n > 400, bladder, breast, colorectal, head and neck, liver, lung, skin, ovarian, pancreatic, prostate, renal, stomach, and thyroid). The signal intensity of both receptors was significantly greater in vessels associated with malignant colorectal, lung, and breast than adjacent nontumor tissue. In colorectal cancers, VEGFR-2 was expressed on both intratumoral blood and lymphatic vessels, whereas VEGFR-3 was found predominantly on lymphatic vessels. In breast cancers, both receptors were localized to and upregulated on blood vessels. Conclusions: VEGFR-2 and VEGFR-3 are primarily localized to, and significantly upregulated on, tumor vasculature (blood and/or lymphatic) supporting the majority of solid cancers. The primary clinical mechanism of action of VEGF signaling inhibitors is likely to be through the targeting of tumor vessels rather than tumor cells. The upregulation of VEGFR-3 on tumor blood vessels indicates a potential additional antiangiogenic effect for dual VEGFR-2/VEGFR-3–targeted therapy. Clin Cancer Res; 16(14); 3548–61. ©2010 AACR.

Combination of anti‐angiogenic therapies reduces osteolysis and tumor burden in experimental breast cancer bone metastasis

“…5 In human breast carcinomas, the primary signaling receptor for VEGF, VEGFR2, is confined to the surface of endothelial cells of angiogenic tumor vasculature. 5,6 VEGFR1 is expressed on the tumor endothelium as well, but is also expressed by breast cancer cells. [5][6][7][8] VEGF acts as a survival factor for VEGFR1-expressing breast cancer cells.…”

“…5,6 VEGFR1 is expressed on the tumor endothelium as well, but is also expressed by breast cancer cells. [5][6][7][8] VEGF acts as a survival factor for VEGFR1-expressing breast cancer cells. 7 Neuropilin-1 (which is also expressed by tumor cells) supports VEGF autocrine effects on breast cancer cell migration and invasion.…”

Distinct patterns of angiogenic factor expression as a predictive factor of response to chemotherapy in stage IIIA non-small-cell lung cancer patients

“…Expression of VEGFR-2 in combination with VEGFR-3 is significantly upregulated in the tumour vascular endothelium of the most common human solid tumours. VEGFR-3 is largely confined to the lymphatic endothelium in adult tissues, but its expression also plays a fundamental role in the tumour microenvironment by promoting the sprouting of new lymphatic vessels from pre-existing ones (7,9,10 Microvessel density (MVD), as determined by the expression of the endothelial antigens CD34 and CD105, is a direct neoangiogenesis marker and an important prognostic indicator in NSCLC. MVD has been shown to be correlated with the concentration and expression of VEGF; it is also associated with enzymes involved in the early stages of angiogenesis, tumour growth and occurrence of distant metastasis (11)(12)(13).…”

Lactate Dehydrogenase-5 (Ldh-5) Immunohistochemical Expression as Predictor of Efficacy of First-Line Therapy in Patients with Advanced Colorectal Cancer Treated with Chemotherapy and Bevacizumab

“…Identification of molecular markers capable of predicting patients' prognosis and the response to cytostatic and anti-angiogenic treatments is a challenging task, since these potential markers would allow selecting the patients who would benefit the most from each of the drugs available. Unfortunately, despite the different attempts carried out, there has been no success to relate several molecular markers with tumour response to the treatment with bevacizumab; therefore, currently there is no way to predict in advance which patients will benefit from this treatment [13]. It is still unknown the place where anti-VWGF therapies produce its main effect, they might have a direct effect on the tumour cell, but it could also base its activity on the endothelial cells of the blood vasculature and/or the lymphatic vessels supporting the tumour, where it has been detected a overexpression of VEGFR-2 (KDR) and VEGFR-3 (13) receptors.…”