The mTOR pathway is aberrantly stimulated in many cancer cells, including pancreatic ductal adenocarcinoma (PDAC), and thus it is a potential target for therapy. However, the mTORC1/S6K axis also mediates negative feedback loops that attenuate signaling via insulin/IGF receptor and other tyrosine kinase receptors. Suppression of these feed-back loops unleashes over-activation of upstream pathways that potentially counterbalance the antiproliferative effects of mTOR inhibitors. Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic cancer cells with either rapamycin or active-site mTOR inhibitors suppressed S6K and S6 phosphorylation induced by insulin and the GPCR agonist neurotensin. Rapamycin caused a striking increase in Akt phosphorylation at Ser473 while the active-site inhibitors of mTOR (KU63794 and PP242) completely abrogated Akt phosphorylation at this site. Conversely, active-site inhibitors of mTOR cause a marked increase in ERK activation whereas rapamycin did not have any stimulatory effect on ERK activation. The results imply that first and second generation of mTOR inhibitors promote over-activation of different pro-oncogenic pathways in PDAC cells, suggesting that suppression of feed-back loops should be a major consideration in the use of these inhibitors for PDAC therapy. In contrast, metformin abolished mTORC1 activation without over-stimulating Akt phosphorylation on Ser473 and prevented mitogen-stimulated ERK activation in PDAC cells. Metformin induced a more pronounced inhibition of proliferation than either KU63794 or rapamycin while, the active-site mTOR inhibitor was more effective than rapamycin. Thus, the effects of metformin on Akt and ERK activation are strikingly different from allosteric or active-site mTOR inhibitors in PDAC cells, though all these agents potently inhibited the mTORC1/S6K axis.

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Recently, many studies have been conducted to explore prognostic value of platelet to lymphocyte ratio (PLR) for patients with lung cancer, while the results remain controversial. We collected pretreatment, clinicopathological and follow-up data of 1388 lung cancer patients receiving surgery between 2006 and 2011 in our hospital, and reviewed relevant articles from Embase, Pubmed, Web of science databases, then performed a meta-analysis to clarify the relationship between PLR and prognosis of lung cancer patients. Finally, 11 articles with our study were included, results indicated elevated PLR was negatively related to overall survival (HR = 1.33, 95% CI: 1.10–1.62), but not related to progress-free survival (HR = 1.21, 95% CI: 0.97–1.49). Subgroup analysis suggested high PLR was correlated with poor survival in non-small cell lung cancer (HR = 1.43, 95% CI: 1.14–1.78), but not in small cell lung cancer (HR = 1.10, 95% CI: 0.76–1.58). Besides, for patients treated by chemotherapy or radiotherapy (HR = 1.66, 95% CI: 1.15–2.38) and patients in late stage (HR = 1.41, 95% CI: 1.19–1.68), PLR had significantly prognostic value. Additionally, the result was significant for patients when cut-off value of PLR was between 150 and 200 (HR = 1.47, 95% CI: 1.18–1.82). In Conclusion, this meta-analysis revealed that elevated PLR was associated with poor prognosis in lung cancer.

FAP-α is highly expressed in cancer stroma and also a predictor of poor survival of NSCLC patients. Elevated FAP-α expression may be associated with inflammation and suppressed lymphocyte-dependent immune response, which then result in the tumor progression. Therefore, FAP-α plays an important role in the progression of NSCLC, and its high expression is a predictor of poor survival. Targeting FAP-α may be a novel strategy for NSCLC therapy.

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PurposeGastric carcinoma (GC) is a highly aggressive cancer and one of the leading causes of cancer-related deaths worldwide. Histopathological evaluation pertaining to invasiveness is likely to provide additional information in relation to patient outcome. In this study, we aimed to evaluate the prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma.Materials and methodsHematoxylin and eosin-stained slides generated from 296 gastric adenocarcinoma patients with full clinical and pathological and follow-up information were systematically reviewed. The patients were grouped on the basis of tumor budding, single cell invasion, large cell invasion, mitotic count, and fibrosis. The association between histopathological parameters, different classification systems, and overall survival (OS) was statistically analyzed.ResultsAmong the 296 cases that were analyzed, high-grade tumor budding was observed in 49.0% (145) of them. Single cell invasion and large cell invasion were observed in 62.8% (186) and 16.9% (50) of the cases, respectively. Following univariate analysis, patients with high-grade tumor budding had shorter OS than those with low-grade tumor budding (hazard ratio [HR]: 2.260, P<0.001). Similarly, the OS of patients with single cell invasion and large cell invasion was reduced (single cell invasion, HR: 3.553, P<0.001; large cell invasion, HR: 2.466, P<0.001). Following multivariate analysis, tumor budding and single cell invasion were observed to be independent risk factors for gastric adenocarcinoma (P<0.05). According to the Lauren classification, patients with intestinal-type adenocarcinoma had better outcomes than those with diffuse-type adenocarcinoma (HR: 2.563, P<0.001).ConclusionTumor budding and single cell invasion in gastric adenocarcinoma are associated with an unfavorable prognosis.

We concluded that sublobectomy might achieve similar survival rates when compared with lobectomy in elderly stage I NSCLC patients, especially for patients with low %FEV1 and stage IA tumours less than 2 cm in diameter.

MicroRNAs (miRNAs), as a class of naturally occurring small non-coding RNAs, play profound and pervasive roles in cancer initiation and progression. Extensive decrease in miRNA levels are frequently observed in human cancers, indicating that miRNAs may function intrinsically in tumor suppression. However, the underlying mechanisms of miRNA interactions with cellular pathways are still unclear. The expression of miR-34b in non-small cell lung cancer (NSCLC) tissues was detected using quantitative real-time PCR. The relations between miR-34b expression levels and pathological stage or lymph node metastasis were assessed using the Spearman correlation test. For in vitro studies, lung cancer cells were transfected with double stranded synthetic miRNA mimics (syn-hsa-miR-34b miScript miRNA) and scrambled controls. Immunohistochemistry was used to validate the related downstream proteins of miR-34b. The expression of miR-34b was lower in NSCLC tissues compared to that in pericarcinous tissues of lung cancer. Additionally, the Spearman correlation test showed that lower miR-34b expression was correlated with higher lymph node metastasis. In vitro gain-of-function experiments indicated that miR-34b suppressed cell proliferation by inducing cell apoptosis. IHC results showed association between lower miR-34b and overexpression of phospho-Met, p53 (phospho S392) and Mdm2. Consistent with the opposing correlation between the expression of miR-34b and lymph node metastasis in NSCLC, miR-34b may play an important role in NSCLC progression. Furthermore, miR-34b downregulates Met, with subsequent changes of downstream p53 (phospho S392) and Mdm2, and inversely p53 upregulates miR-34b in a feedback loop, which provides new insights into the roles of miR-34 family members in the regulation of signaling pathways of NSCLC.