Activated mammalian target of rapamycin is a potential therapeutic target in gastric cancer

<p>Abstract</p> <p>Background</p> <p>The mammalian target of rapamycin (mTOR) plays a key role in cellular growth and homeostasis. The purpose of our present study is to investigate the expression of activated mTOR (p-mTOR) in gastric cancer patients, their prognostic significance and the inhibition effect of RAD001 on tumor growth and to determine whether targeted inhibition of mTOR could be a potential therapeutic strategy for gastric cancer.</p> <p>Methods</p> <p>The expression of p-mTOR was detected in specimens of 181 gastric cancers who underwent radical resection (R0) by immunohistochemistry. The correlation of p-mTOR expression to clinicopathologic features and survival of gastric cancer was studied. We also determined the inhibition effect of RAD001 on tumor growth using BGC823 and AGS human gastric cancer cell lines.</p> <p>Results</p> <p>Immunostaining for p-mTOR was positive in 93 of 181 (51.4%) gastric cancers, closely correlated with lymph node status and pTNM stage. Patients with p-mTOR positive showed significantly shorter disease-free survival (DFS) and overall survival (OS) rates than those with p-mTOR-negative tumors in univariable analyses, and there was a trend toward a correlation between p-mTOR expression and survival in multivariable analyses. RAD001 markedly inhibited dose-dependently proliferation of human gastric carcinoma cells by down-regulating expression of p70s6k, p-p70s6k, C-myc, CyclinD1 and Bcl-2, up-regulating expression of P53.</p> <p>Conclusions</p> <p>In gastric cancer, p-mTOR is a potential therapeutic target and RAD001 was a promising treatment agent with inducing cell cycle arrest and apoptosis by down-regulating expression of C-myc, CyclinD1 and Bcl-2, up-regulating expression of P53.</p

The phosphatase and tensin homologue deleted on chromosome 10 mediates radiosensitivity in head and neck cancer

BACKGROUND: For locally advanced squamous cell carcinoma of the head and neck (HNSCC), the recurrence rate after surgery and postoperative radiotherapy is between 20 and 40%, and the 5- year overall survival rate is similar to 50%. Presently, no markers exist to accurately predict treatment outcome. Expression of proteins in the human epidermal growth factor receptor (EGFR) pathway has been reported as a prognostic marker in several types of cancer. METHODS: The aim of this study was to investigate the prognostic value of proteins in the EGFR pathway in HNSCC. For this purpose, we collected surgically resected tissue of 140 locally advanced head and neck cancer patients, all treated with surgery and postoperative radiotherapy. RESULTS: In a multivariate analysis, expression of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was significantly related to worse locoregional control (LRC; HR: 2.2, 95% CI: 1.1-4.6; P = 0.03), independent of lymph node metastases (HR: 5.6, 95% CI: 1.2-27.4; P = 0.03) and extranodal spread (HR: 2.7; 95% CI: 1.2- 6.5; P = 0.02). In vitro clonogenic radiosensitivity assays confirmed that overexpression of PTEN resulted in increased radioresistance. CONCLUSION: Our study is the first report showing that expression of PTEN mediates radiosensitivity in vitro and that increased expression in advanced HNSCC predicts worse LRC. British Journal of Cancer (2010) 102, 1778-1785. doi: 10.1038/sj.bjc.6605707 www.bjcancer.com Published online 25 May 2010 (C) 2010 Cancer Research U

Alteration of EGFR Spatiotemporal Dynamics Suppresses Signal Transduction

The epidermal growth factor receptor (EGFR), which regulates cell growth and survival, is integral to colon tumorigenesis. Lipid rafts play a role in regulating EGFR signaling, and docosahexaenoic acid (DHA) is known to perturb membrane domain organization through changes in lipid rafts. Therefore, we investigated the mechanistic link between EGFR function and DHA. Membrane incorporation of DHA into immortalized colonocytes altered the lateral organization of EGFR. DHA additionally increased EGFR phosphorylation but paradoxically suppressed downstream signaling. Assessment of the EGFR-Ras-ERK1/2 signaling cascade identified Ras GTP binding as the locus of the DHA-induced disruption of signal transduction. DHA also antagonized EGFR signaling capacity by increasing receptor internalization and degradation. DHA suppressed cell proliferation in an EGFR-dependent manner, but cell proliferation could be partially rescued by expression of constitutively active Ras. Feeding chronically-inflamed, carcinogen-injected C57BL/6 mice a fish oil containing diet enriched in DHA recapitulated the effects on the EGFR signaling axis observed in cell culture and additionally suppressed tumor formation. We conclude that DHA-induced alteration in both the lateral and subcellular localization of EGFR culminates in the suppression of EGFR downstream signal transduction, which has implications for the molecular basis of colon cancer prevention by DHA

The longitudinal relationship between circulating concentrations of C-reactive protein, interleukin-6 and interleukin-10 in patients undergoing resection for renal cancer

The systemic inflammatory response, as evidenced by elevated circulating concentrations of C-reactive protein, is a stage-independent prognostic factor in patients undergoing curative nephrectomy for localised renal cancer. However, it is not clear whether the systemic inflammatory response arises from the tumour per se or as a result of an impaired immune cytokine response. The aim of the present study was to examine C-reactive protein, interleukin-6 and interleukin-10 concentrations before and following curative resection of renal cancer. Sixty-four patients with malignant renal disease and 12 with benign disease, undergoing resection were studied. Preoperatively, a blood sample was collected for routine laboratory analysis with a further sample stored before analysis of interleukin-6 and interleukin-10 using an enzyme-linked immunosorbent assay (ELISA) technique. The blood sampling procedure and analyses were repeated at approximately 3 months following resection. Circulating concentrations of both interleukin-6 and interleukin (P&#8804;0.01) were higher and a greater proportion were elevated (P&#60;0.05) in malignant compared with benign disease. The renal cancer patients were grouped according to whether they had evidence of a systemic inflammatory response. In the inflammatory group T stage was higher (P&#60;0.01), both interleukin-6 and interleukin-10 concentrations were higher (P&#60;0.001) and elevated (P&#60;0.10) compared with the non-inflammatory group. Tumour volume was weakly correlated with C-reactive protein (r&lt;sup&gt;2&lt;/sup&gt;=0.20, P=0.002), interleukin-6 (r2=0.20, P=0.002) and interleukin-10 (r&lt;sup&gt;2&lt;/sup&gt;=0.24, P=0.001). Following nephrectomy the proportion of patients with elevated C-reactive protein, interleukin-6 and interleukin-10 concentrations did not alter significantly. An elevated preoperative C-reactive protein was associated with increased tumour stage, interleukin-6 and interleukin-10 concentrations. However, resection of the primary tumour did not appear to be associated with significant normalisation of circulating concentrations of C-reactive protein, interleukin-6 or interleukin-10. Therefore, the presence of systemic inflammatory response is unlikely to be solely be determined by the tumour itself, but may be as a result of an impaired immune cytokine response in patients with renal cancer

Abdominal spilled stones: ultrasound findings

Laparoscopic cholecystectomy (LC) is the treatment of choice for uncomplicated symptomatic gallstones. Spillage of stones due to gallbladder rupture has been reported in up to 33% of all LCs, but clinical sequelae caused by dropped gallstones are uncommon. We recently observed two patients with retained stones after LC. Correct diagnosis was made by abdominal ultrasonography (US) in both cases. In the first patient, who presented with fever, malaise, and weight loss 18 months after LC, abdominal US revealed hypoechoic focal lesions containing hyperechoic images with posterior shadowing of the liver and spleen. US-guided aspiration biopsies of these lesions yielded purulent material, and the injection and aspiration of saline solution provoked rolling movements of the hyperechoic images. Laparotomy confirmed the diagnosis of abscess-containing spilled gallstones. In the second patient, multiple hyperechoic images with posterior shadowing were observed in the Morison pouch during a routine US examination. The diagnosis of retained stones was consistent with the history of gallstone spillage during LC performed 2 months previously and was confirmed by computed tomographic findings of hyperdense images in the Morison pouch. The patient was asymptomatic, and treatment was thus deferred. Our experience suggests that US can be very useful in the detection of gallstones spilled during LC