Amplification and/or activation of the c‐Myc proto‐oncogene is one of the leading genetic events along hepatocarcinogenesis. The oncogenic potential of c‐Myc has been proven experimentally by the ...finding that its overexpression in the mouse liver triggers tumor formation. However, the molecular mechanism whereby c‐Myc exerts its oncogenic activity in the liver remains poorly understood. Here, we demonstrate that the mammalian target of rapamycin complex 1 (mTORC1) cascade is activated and necessary for c‐Myc‐dependent hepatocarcinogenesis. Specifically, we found that ablation of Raptor, the unique member of mTORC1, strongly inhibits c‐Myc liver tumor formation. Also, the p70 ribosomal S6 kinase/ribosomal protein S6 and eukaryotic translation initiation factor 4E‐binding protein 1/eukaryotic translation initiation factor 4E signaling cascades downstream of mTORC1 are required for c‐Myc‐driven tumorigenesis. Intriguingly, microarray expression analysis revealed up‐regulation of multiple amino acid transporters, including solute carrier family 1 member A5 (SLC1A5) and SLC7A6, leading to robust uptake of amino acids, including glutamine, into c‐Myc tumor cells. Subsequent functional studies showed that amino acids are critical for activation of mTORC1 as their inhibition suppressed mTORC1 in c‐Myc tumor cells. In human hepatocellular carcinoma specimens, levels of c‐Myc directly correlate with those of mTORC1 activation as well as of SLC1A5 and SLC7A6. Conclusion: Our current study indicates that an intact mTORC1 axis is required for c‐Myc‐driven hepatocarcinogenesis; thus, targeting the mTOR pathway or amino acid transporters may be an effective and novel therapeutic option for the treatment of hepatocellular carcinoma with activated c‐Myc signaling. (Hepatology 2017;66:167–181).
Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems
. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects ...cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)-one such nociceptor-produced neuropeptide-directly increases the exhaustion of cytotoxic CD8
T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8
T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8
T cells, Ramp1
CD8
T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1-deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1-expressing CD8
T cells were more exhausted than their RAMP1-negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8
T cells.
Malignant mesothelioma (MM) is an aggressive tumor, mainly derived from the pleura, which is predominantly associated with exposure to asbestos fibers. The prognosis of MM patients is particularly ...severe, with a median survival of approximately 9–12 months and latency between exposure and diagnosis ranging from 20–50 years (median 30 years). Emerging evidence has demonstrated that tumor aggressiveness is associated with genome and gene expression abnormalities; therefore, several studies have recently focused on the role of microRNAs (miRNAs) in MM tumorigenesis. miRNAs are small non-protein coding single-stranded RNAs (17–22 nucleotides) involved in numerous cellular processes that negatively regulate gene expression by modulating the expression of downstream target genes. miRNAs are often deregulated in cancer; in particular, the differential miRNA expression profiles of MM cells compared to unaffected mesothelial cells have suggested potential roles of miRNAs as either oncogenes or tumor suppressor genes in MM oncogenesis. In this review, the mechanism of MM carcinogenesis was evaluated through the analysis of the published miRNA expression data. The roles of miRNAs as diagnostic biomarkers and prognostic factors for potential therapeutic strategies will be presented and discussed.
VeriStrat is a blood-based proteomic test with predictive and prognostic significance in second-line treatments for non-small cell lung cancer (NSCLC). This trial was designed to investigate the role ...of VeriStrat in first-line treatment of advanced NSCLC with standard chemotherapy. Here we present the results for 76 non-squamous patients treated with a combination of carboplatin or cisplatin with pemetrexed.
The test-assigned classifications of VeriStrat Good or VeriStrat Poor to samples collected at baseline. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and objective response. Exploratory analyses of end points separately in carboplatin/pemetrexed and cisplatin/pemetrexed subgroups were also conducted.
Patients classified as VeriStrat Good had longer PFS and OS than VeriStrat Poor: 6.5 vs 1.6 months and 10.8 vs 3.4 months, respectively; the corresponding hazard ratios (HRs) were 0.36 (P<0.0001) and 0.26 (P<0.0001); they were also more likely to achieve objective response. Prognostic significance of VeriStrat was confirmed in multivariate analysis. Significant differences in OS and PFS between Veristrat classifications were also found when treatment subgroups were analysed separately.
The trial demonstrated clinical utility of VeriStrat as a prognostic test for standard first-line chemotherapy of non-squamous advanced NSCLC.
COPD frequently coexists with HF with which shares several risk factors. A greater collaboration is required between cardiologists and pulmonologists to better identify and manage concurrent HF and ...COPD. This observational, retrospective study provides new data regarding the management of these patients.
from the Health Search Database which collects information generated by the routine activity of general practitioners, we selected 803 patients suffering from COPD or HF alone or combined analyzing similarities and differences regarding risk factors, diagnostic workup and therapeutic approaches.
Statistical analyses have evidenced significant differences regarding exposure to cigarette smoke and the prevalence of diabetes and hypertension in the three groups of patients. As regard to the diagnostic workup, it has been found that the 63,9% of COPD patients and the 57,1% of COPD + HF patients performed a spirometry vs the 95,4% of HF patients and the 95,2% of COPD + HF patients that performed an ECG.
Regarding the pharmacologic treatment, the 47% of COPD patients was treated with an ICS/LABA association and the 22% with ICS/LABA + LAMA. In the COPD + HF group, 47% of patients were treated with ICS/LABA association, while 32% of these patients were treated with ICS/LABA + LAMA. The pharmacologic treatment most prescribed in HF was β-blockers (68%), diuretics (92.8%), antiplatelet therapy (55.6%) and ACE inhibitors (38.1%). In the COPD + HF group, β-blockers (40.1%), diuretics (89.8%), antiplatelet therapy (57.1%) and ACE inhibitors (44.9%) were prescribed.
this study has evidenced a disparity in performing instrumental diagnosis between COPD and HF groups that persists when both conditions coexist. Moreover, the pharmacological treatment of the two conditions shows a consistent under treatment with bronchodilators in COPD patients and with β-blockers in HF patients.
•COPD and HF are highly incident in the general population.•Their coexistence lead to prognosis worsening and to high mortality.•General practitioners manage differently COPD and HF during diagnostic workup.•Therapy is characterized by:1)under treatment of COPD patients with bronchodilators.•2) Under treatment of COPD-HF patients with bronchodilators and β-blockers.
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