Tumor Specific VEGF-A and VEGFR2/KDR Protein are Co-expressed in Breast Cancer

Abstract

Angiogenesis is a prognostic indicator in primary breast cancer regulated by specific angiogenic factors and their receptors. Vascular endothelial growth factor-A (VEGF-A), so far considered the most important, acts through dimerization of the receptor VEGFR2/KDR within the receptor tyrosine kinase family of VEGF receptors. In order to study the interplay between VEGF-A and VEGFR2/KDR in breast cancer we evaluated their expression by immunohistochemistry in 102 breast cancers organized in a tumor tissue array system allowing semi-quantitative evaluation of cytoplasmatic staining intensity. In addition, VEGF-A165 was analyzed by an enzyme immuno assay (ELISA) in protein extracts prepared from frozen tissue from 98 of 102 tumors included in the array. Cytoplasmatic staining of VEGF of varying intensity was observed in all samples and correlated with the ELISA results of VEGF content (p = 0.007). Interestingly, VEGFR2/KDR expression correlated with VEGF expression using immunohistochemistry, indicating that VEGF and VEGFR2/KDR may be co-expressed in breast cancer. Furthermore, high levels of VEGF-A165 in the protein extracts was associated with impaired short time survival but not long term survival whereas immunohistochemically assessed VEGF and VEGFR2/KDR were not significantly associated with survival. In summary, immunohistochemically based analysis of VEGF using a tumor tissue array system seems to be a useful method for VEGF quantification in breast cancer here validated using an ELISA based method. The tumor tissue array system enables opportunities of simultaneous analysis of markers engaged in angiogenesis justifying further studies using larger series of tumors.

Potential autocrine function of vascular endothelial growth factor in head and neck cancer via vascular endothelial growth factor receptor-2

“…36 However, it is quite possible that its action is not limited in the paracrine, endothelial dependent, angiogenic pathway, but also extends towards a potential autocrine action between cancer cells in various malignancies. [19][20][21][22][23][24] VEGF activities are mediated via two tyrosine kinase receptors VEGFR-1 (also known as flt-1) and VEGFR-2 (also known as Flk-1/KDR). Although VEGF binds with VEGFR-1 with higher affinity, it is well known that mitogenic and proliferating actions of VEGF in endothelial cells are mediated via VEGFR-2.…”

“…[17][18][19][20][21][22][23][24] There are also studies describing the existence of VEGF receptors in cancer cell lines and in limited number of tissue samples in head and neck squamous cell carcinoma. 25,26 These observations suggest that VEGF can function as an autocrine growth factor.…”

Sequence-dependent inhibition of human colon cancer cell growth and of prosurvival pathways by oxaliplatin in combination with ZD6474 (Zactima), an inhibitor of VEGFR and EGFR tyrosine kinases

“…Treatment with ZD6474 alone for 48 hours resulted in a dosedependent inhibition of growth with an IC 50 …”

Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells

“…However, more recent studies have noted these tyrosine kinase receptors on hematopoietic stem cells, monocytes, and osteoblasts (Bellamy et al, 1999;Mayr-Wohlfart et al, 2002;Lalla et al, 2003). VEGF receptors have also been noted on tumor cells, including leukemic cells, Kaposi's sarcoma, and breast carcinoma (Arora et al, 1999;Dias et al, 2000;Hasan and Jayson, 2001;Price et al, 2001;Ryden et al, 2003). The novel VEGF co-receptor, neuropilin, has also been shown to be present on tumor cells and may mediate cell survival signals in breast carcinoma (Bachelder et al, 2003).…”