Brain-derived neurotrophic factor plus vascular endothelial growth factor additively promotes early growth of the transitional cell carcinoma cell line BFTC905 in vitro and in vivo

AbstractObjectiveThe attempt to block one type of receptor tyrosine kinase (RTK) signaling has been considered a main strategy for cancer therapy; however, cancer cells may survive using alternative RTK signaling. Thus, targeting multiple RTKs simultaneously may be a better treatment strategy. Previously, we demonstrated that brain-derived neurotrophic factor (BDNF) via activating tropomyosin receptor kinase B (TrkB) is a survival factor for transitional cell carcinoma (TCC). Others have reported that autocrine vascular endothelial growth factor (VEGF) pathways also play a crucial role in TCC growth. We aim to examine the in vitro and in vivo effects of BDNF plus VEGF on the TCC cell line BFTC905 derived from the bladder cancer of a Taiwanese patient with black foot disease.Materials and MethodsCell numbers were counted after administration of 50 nM BDNF and/or VEGF to the BFTC905 or primary human urothelial cell (HUC) cultures for 96 hours. The volumes of the xenograft tumors were measured 6 weeks after weekly injections of 100 ng BDNF and/or VEGF into the cancer cell-loading site of NOD.CB17-Prkdcscid/Tcu mice. The expression of TrkB in HUCs and VEGF receptor FLT-1 in BFTC905 cells and HUCs, as well as CD34 and Ki-67 in the xenograft tumors was determined by Western blotting.ResultsThe effects of increasing BFTC905 cell numbers were as follows: BDNF + VEGF > BDNF > VEGF > control after 96 hours of treatment. The VEGF receptor FLT-1 was expressed in BFTC905 cells. Exogenous BDNF and/or VEGF did not promote the proliferation of HUCs. In addition, TrkB and FLT-1 were very weakly expressed in HUCs. After treatment for 5 weeks, the effects of exogenously administered BDNF and/or VEGF on the xenograft tumor volume were as follows: BDNF + VEGF > BDNF > VEGF > control. However, similar tumor sizes with few metastases were found in the four groups of mice after treatment for 6 weeks. The expression levels of the angiogenic marker CD34 and proliferative marker Ki-67 were also similar among these four groups of xenograft tumors.ConclusionExogenous BDNF plus VEGF additively promotes the early growth of BFTC905 in vitro and in vivo without affecting the normal urothelium. Targeted blockade of both TrkB and VEGF signaling might be an effective treatment for adjuvant bladder cancer therapy or in the early stage of high-grade TCC