Abstract
BackgroundAngiogenesis represents a highly multi-factorial and multi-cellular complex (patho-) physiologic event involving endothelial cells, tumor cells in malignant conditions, as well as bone marrow derived cells and stromal cells. One main driver is vascular endothelial growth factor (VEGFA), which is known to interact with endothelial cells as a survival and mitogenic signal. The role of VEGFA on tumor cells and /or tumor stromal cell interaction is less clear. Condition specific (e.g. hypoxia) or tumor specific expression of VEGFA, VEGF receptors and co-receptors on tumor cells has been reported, in addition to the expression on the endothelium. This suggests a potential paracrine/autocrine loop that could affect changes specific to tumor cells.MethodsWe used the monoclonal antibody against VEGFA, bevacizumab, in various in vitro experiments using cell lines derived from different tumor entities (non small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer (BC) and renal cell carcinoma (RCC)) in order to determine if potential VEGFA signaling could be blocked in tumor cells. The experiments were done under hypoxia, a major inducer of VEGFA and angiogenesis, in an attempt to mimic the physiological tumor condition. Known VEGFA induced endothelial biological responses such as proliferation, migration, survival and gene expression changes were evaluated.ResultsOur study was able to demonstrate expression of VEGF receptors on tumor cells as well as hypoxia regulated angiogenic gene expression. In addition, there was a cell line specific effect in tumor cells by VEGFA blockade with bevacizumab in terms of proliferation; however overall, there was a limited measurable consequence of bevacizumab therapy detected by migration and survival.ConclusionThe present study showed in a variety of in vitro experiments with several tumor cell lines from different tumor origins, that by blocking VEGFA with bevacizumab, there was a limited autocrine or cell-autonomous function of VEGFA signaling in tumor cells, when evaluating VEGFA induced downstream outputs known in endothelial cells.
Highlights
Tumor cells are dependent on consistent oxygen and nutrient supply to promote tumor progression
We showed that VEGF receptors are expressed by tumor cells and by endothelial cells, which highlights the prospect of complex angiogenic pathway/signaling cross talk between various cell types
Cell line selection As vascular endothelial growth factor (VEGFA) is thought to work primarily through activation of one of the known VEGF receptors VEGFR1, VEGFR2 and co-receptor Neuropilin1, in general two cell lines per tumor type were selected from the NCI-60 panel of solid tumors (NSCLC: H522, HOP62, colorectal cancer (CRC): HCT-116, HT-29, KM12, breast cancer (BC): HS-578 T, MDA-MB-231 and one renal cell carcinoma (RCC): A498), according to high relative expression levels from publicly available microarray data [26], published data and our own preliminary gene expression data related to angiogenesis pathway genes
Summary
Tumor cells are dependent on consistent oxygen and nutrient supply to promote tumor progression. The first approved therapeutic agent to target the tumor associated vessels of solid tumors was bevacizumab, a monoclonal antibody against all isoforms of VEGFA [6]. One main driver is vascular endothelial growth factor (VEGFA), which is known to interact with endothelial cells as a survival and mitogenic signal. The role of VEGFA on tumor cells and /or tumor stromal cell interaction is less clear. Condition specific (e.g. hypoxia) or tumor specific expression of VEGFA, VEGF receptors and co-receptors on tumor cells has been reported, in addition to the expression on the endothelium. This suggests a potential paracrine/autocrine loop that could affect changes specific to tumor cells
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