VEGF165 is mainly secreted, whereas VEGF189 is cell-associated and is almost completely sequestered in the extracellular matrix [23]. These VEGF isoforms probably have different functions in cancer tissues. Although several types of tumor cells express VEGF-A and its receptors, the VEGF-A receptor BIRB 796 in vivo neuropilin-1 (NRP-1) is only expressed in the pancreatic carcinoma cell lines Panc-1 and MIA PaCa-2 [29]. Because NRP-1 only binds to VEGF165, one of the several isoforms of VEGF-A [21], it is possible that the binding of VEGF165 to NRP-1 causes cell progression in these pancreatic carcinoma cells. Furthermore, the results of studies on VEGF inhibition using Je-11 suggested that VEGF enhances cell proliferation

(Figure 3A). selleck chemicals However, the inhibition of VEGF by Je-11 partially relieved the TZD-induced cells from growth arrest. Therefore, we believe that TZD treatment cause the growth arrest of NSCLC cells

by the mechanism containing VEGF-A (VEGF165) and NRP-1 interaction. High VEGF expression has been reported to be associated with poor prognosis in patients with breast carcinoma [30], prostate carcinoma [31], melanoma CBL-0137 research buy [32, 33], and lung carcinoma [20]. Thus, VEGF is a prognostic biomarker for NSCLC. On the other hand, lung cancer risk among subjects administered with TZDs is reduced by 33% [34] and in vitro studies indicate that TZDs inhibit the growth of NSCLC cells [27, 35]. Purified VEGF189 and VEGF165 induced cell progression in human umbilical vascular endothelial cells (HUVEC), the human metastatic breast cancer cell line MDA-MB-231, and the human pancreatic carcinoma cell line Panc-1 [36]. These reports indicated that one of the mechanisms as an anti-cancer effect of TZDs

was depressing the VEGF expression. However, some reports contradict the inductive effect Cyclooxygenase (COX) of TZDs on VEGF [12–19], and this was also observed in the present study. Our results indicate that the interaction of the induced VEGF and NRP-1 may inhibit the growth of NSCLC cells. Taken together, these results suggest that rather than being a growth factor for NSCLC cells, troglitazone-induced VEGF may mediate cell growth arrest. It has been recently reported that the mechanism of VEGF action is complicated [37]. Deletion of myeloid-cell VEGF-A in multiple subcutaneous isograft models and in an autochthonous transgenic model of mammary tumorigenesis resulted in accelerated tumor progression; this process was accompanied by less overall tumor cell death and decreased tumor hypoxia. Administration of TZD to a lung cancer patient induces VEGF expression and prevents the maturation of the surrounding blood vessels, thereby leading to tumor suppression by hypoxia and lack of nutrition. Further, in this study, we showed that TZD-induced VEGF expression inhibited the growth of tumor cells. We think that both these effects prolong the survival of the lung cancer patients.