Bcl-2 orchestrates a cross-talk between endothelial and tumor cells that promotes tumor growth.

The current understanding of the interaction between the endothelium and cancer cells is fundamentally based on the concept that endothelial cells are responsive to differentiation and survival signals originating from the tumor cells. Whereas the effect of tumor cell-secreted factors on angiogenesis is well established, little is known about the effect of factors secreted by endothelial cells on tumor cell gene expression and tumor progression. Here, we show that bcl-2 gene expression is significantly higher in the tumor-associated endothelial cells of patients with head and neck squamous cell carcinomas (HNSCC) as compared with endothelial cells from the normal oral mucosa. Bcl-2 induces vascular endothelial growth factor (VEGF) expression in neovascular endothelial cells through a signal transducer and activator of transcription 3 (STAT3)-mediated pathway. Endothelial cell-derived VEGF signals through VEGFR1 and induces expression of Bcl-2 and the proangiogenic chemokines CXCL1 and CXCL8 in HNSCC cells. Notably, inhibition of Bcl-2 expression in neovascular endothelial cells with RNA interference down-regulates expression of Bcl-2, CXCL8, and CXCL1 in HNSCC cells, and is sufficient to inhibit growth and decrease the microvessel density of xenografted HNSCC in immunodeficient mice. Together, these results show that Bcl-2 is the orchestrator of a cross-talk between neovascular endothelial cells and tumor cells, which has a direct effect on tumor growth. This work identifies a new function for Bcl-2 in cancer biology that is beyond its classic role in cell survival.

Adhesive resin and the hydrophilic monomer HEMA induce VEGF expression on dental pulp cells and macrophages.

Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis by inducing endothelial cell proliferation, migration and survival. Direct pulp capping with an adhesive resin system was shown to induce local increase in blood vessel density and lack of dentin bridging. However, the mechanisms involved in the increase in blood vessel density observed near the pulp exposures capped with an adhesive resin are largely unknown. OBJECTIVES.: To investigate the effect of an adhesive resin or one of its hydrophilic monomers (HEMA), in the expression of VEGF by pulp cells. METHODS.: Mouse odontoblast-like cells (MDPC-23), undifferentiated pulp cells (OD-21), gingival fibroblasts, and macrophages were exposed to SingleBond (3M) or to 0-1000nM HEMA. VEGF expression was evaluated by ELISA and semi-quantitative RT-PCR. RESULTS AND SIGNIFICANCE.: VEGF expression was upregulated in MDPC-23 cells exposed to HEMA (p<0.001) or to SingleBond (p<0.018), and in macrophages exposed to HEMA (p<0.001) or SingleBond (p=0.001). In contrast, VEGF expression remained unchanged in undifferentiated pulp cells (OD-21), or fibroblasts exposed to either HEMA or Single Bond (p>0.05). Treatment with SingleBond or HEMA did not affect VEGF expression at the mRNA level of any cell type evaluated here, suggesting that the induction of VEGF expression in these cells is regulated primarily at the post-transcriptional level. These findings suggest that VEGF is involved in the regulation of pulp neovascularization observed in response to the application of adhesive resins at site of pulp exposure.

Effect of ProRoot MTA on pulp cell apoptosis and proliferation in vitro.

ProRoot Mineral Trioxide Aggregate (MTA) has been indicated as a pulp capping material. The purpose of this study was to evaluate the effect of tooth-colored (white) MTA on pulp cell apoptosis and cell cycle. Mouse odontoblast-like cells (MDPC-23) and undifferentiated pulp cells (OD-21) were exposed to 0 to 100 mg MTA for 24 h. Propidium iodide staining followed by flow cytometry demonstrated that MTA did not induce apoptosis of MDPC-23 or OD-21 (p > 0.05). Cell cycle analysis showed that MTA induced a modest (but significant) increase in the percentage of MDPC-23 in the S and G2 phases, and OD-21 in the S phase of cell cycle, as compared to untreated controls (p

Effect of lipopolysaccharides on vascular endothelial growth factor expression in mouse pulp cells and macrophages.

Vascular endothelial growth factor (VEGF), a potent pro-angiogenic factor, might regulate the neovascularization observed in the pulp of teeth with deep caries. The purpose of this in vitro study was to evaluate the effect of bacterial lipopolysaccharides (LPS) on VEGF expression in dental pulp cells. Mouse odontoblast-like cells (MDPC-23) or undifferentiated pulp cells (OD-21) were exposed to 0-20 microg ml-1Escherichia coli LPS or 0-80 microg ml-1Prevotella intermedia LPS. As controls, mouse macrophages or gingival fibroblasts were exposed to LPS, since these cells are known to secrete VEGF. The VEGF expression was evaluated by reverse transcriptase polymerase chain reaction or enzyme-linked immunosorbent assay. The baseline expression levels of VEGF protein were higher in MDPC-23 and OD-21 than in fibroblasts or macrophages. Vascular endothelial growth factor protein expression was upregulated in MDPC-23 and macrophages exposed to E. coli LPS, but not in OD-21 cells or fibroblasts. Higher concentrations of P. intermedia LPS were required to induce VEGF expression in MDPC-23 cells. Treatment with LPS did not affect VEGF expression at the mRNA level in any of the cells evaluated. These results demonstrate that bacterial LPS upregulates VEGF expression in odontoblast-like cells and macrophages, and suggest that the regulation of VEGF expression occurs primarily at a post-transcriptional level.