Lupeol suppresses cisplatin-induced nuclear factor-κB activation in head and neck squamous cell carcinoma and inhibits local invasion and nodal metastasis in an orthotopic nude mouse model

A poor prognosis in head and neck squamous cell carcinoma (HNSCC) patients is commonly associated with the presence of regional metastasis. Cisplatin-based chemotherapy concurrent with radiation therapy is commonly used in the treatment of locally advanced HNSCC. However, the result is dismal due to common acquisition of chemoresistance and radioresistance. Epidemiologic studies have shown the importance of dietary substances in the prevention of HNSCC. Here, we found that lupeol, a triterpene found in fruits and vegetables, selectively induced substantial HNSCC cell death but exhibited only a minimal effect on a normal tongue fibroblast cell line in vitro. Down-regulation of NF-κB was identified as the major mechanism of the anticancer properties of lupeol against HNSCC. Lupeol alone was not only found to suppress tumor growth but also to impair HNSCC cell invasion by reversal of the NF-κB-dependent epithelial-to-mesenchymal transition. Lupeol exerted a synergistic effect with cisplatin, resulting in chemosensitization of HNSCC cell lines with high NF-κB activity in vitro. In in vivo studies, using an orthotopic metastatic nude mouse model of oral tongue squamous cell carcinoma, lupeol at a dose of 2 mg/animal dramatically decreased tumor volume and suppressed local metastasis, which was more effective than cisplatin alone. Lupeol exerted a significant synergistic cytotoxic effect when combined with low-dose cisplatin without side effects. Our results suggest that lupeol may be an effective agent either alone or in combination for treatment of advanced tumors. ©2007 American Association for Cancer Research.link_to_OA_fulltex

Fascin over-expression is associated with aggressiveness of oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is associated with a high potential of tumor recurrence and metastasis, leading to poor prognosis. Cell motility is an important factor in the progression and metastasis of cancers. Recently, Fascin has been linked to tumor progression by induction of cell motility. However, the precise roles of Fascin in OSCC have not been elucidated clearly. The aim of this study was to analyze the roles of Fascin in OSCC progression using OSCC clinical samples. We demonstrated that Fascin over-expression was found in OSCC clinical samples and its expression was significantly associated with nodal metastasis (p = 0.027), tumor recurrence (p < 0.001) and poor patients' overall survival (p = 0.013). Consistently, Fascin proteins were detected in all OSCC cell lines with the expression level corresponding to the invasion ability. To specifically investigate the mechanism of Fascin in OSCC, we examined the E-cadherin expression in the same set of OSCC specimens. Fascin was negatively correlated with E-cadherin expression (p = 0.018, r = -0.513). In conclusion, our findings suggested that Fascin over-expression might enhance OSCC aggressiveness, possibly by interacting with E-cadherin expression. © 2007 Elsevier Ireland Ltd. All rights reserved.link_to_subscribed_fulltex

Id-1 promotes angiogenesis in hepatocellular carcinoma through HIF-1α-mediated VEGF upregulation

Session - Tumor Biology 14: Tumor Angiogenesis and the Microenvironment 2: no. 1860BACKGROUND: Hepatocellular carcinoma (HCC) is a highly vascularized tumor associated with poor prognosis. Angiogenesis plays a critical role in rapid growth and metastasis of HCC. Vascular endothelial growth factor (VEGF) is one of the most important angiogenic factors in HCC. A better understanding of the regulatory mechanisms of VEGF expression in HCC may reveal novel targets for treatment of this cancer. Recently, Id-1 (inhibitor of differentiation/DNA synthesis) has been suggested to play a role in cancer angiogenesis but the molecular mechanism remains unknown. Given the central role of VEGF in cancer angiogenesis, we performed a study to elucidate whether overexpression of Id-1 promotes angiogenesis in HCC by interacting with VEGF. METHODOLOGY: In this study, we examined the expression of Id-1 and its relationship with expression of VEGF in HCC by performing immunohistochemistry on HCC tissue microarray. The role of Id-1 in regulating angiogenesis in HCC was evaluated in vitro by ectopic Id-1 transfection, and the effect of inhibition of Id-1 expression on angiogenesis and tumor growth of HCC was studied in vitro and in vivo. RESULTS: Id-1over-expression correlated with HCC metastasis (p<0.001), and its expression significantly correlated with VEGF expression (p<0.001, r=0.47) by tissue microarray. Ectopic transfection of Id-1 into HCC cell lines induced VEGF secretion, and the culture medium of the Id-1 transfectants could induce morphological change and proliferation of human umbilical vein endothelial cells. Furthermore, the angiogenic effect of the culture medium of the Id-1 transfectants was reversed by treatment with an Flk-1 inhibitor, SU1498, or with a VEGF neutralizing antibody. Id-1 induced transcriptional activation of VEGF by upregulating its promoter harboring hypoxia inducible factor-1α (HIF-1α) binding site. Id-1 was able to increase HIF-1α protein but not mRNA expression. In hypoxic condition, Id-1 increased VEGF expression by stabilizing HIF-1α protein. By anti-sense approach, Id-1 downregulation led to suppression of HIF-1α-mediated VEGF production, and resulted in reduced tumor growth and vascularity when the HCC cells were injected subcutaneously in nude mice. CONCLUSION: Id-1 promoted angiogenesis in HCC through stabilization of HIF-1α protein and increased VEGF expression. Downregulation of Id-1 may be a novel target to inhibit angiogenesis in HCC. ©American Association for Cancer Researc

Upper urinary tract infection with extended-spectrum beta-lactamase positive organisms: prevalence and risk factors of infection in a tertiary centre

Abstract and Oral Presentation: Oral (Free Paper) Session III: abstract no. OP.3-