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).
Pancreatic surgery is one of the most technically challenging types of surgery, and many questions remain unanswered; therefore, an overview of the global advancement in surgical research and ...clinical practice is fundamental in this field ....
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•A novel mouse model of intrahepatic cholangiocarcinoma (ICC) was established.•Hydrodynamic transfection of activated forms of AKT and Yap was used to induce ICC.•This model ...recapitulates many morphological and molecular features of human ICC.•MLN0128 may be superior to gemcitabine/oxaliplatin based chemotherapy to treat ICC.•The efficacy of MLN0128 is mainly attributed to induction of apoptosis of ICC cells.
Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy without effective treatment options. MLN0128, a second generation pan-mTOR inhibitor, shows efficacy for multiple tumor types. We evaluated the therapeutic potential of MLN0128 vs. gemcitabine/oxaliplatin in a novel ICC mouse model.
We established a novel ICC mouse model via hydrodynamic transfection of activated forms of AKT (myr-AKT) and Yap (YapS127A) protooncogenes (that will be referred to as AKT/YapS127A). Genetic approaches were applied to study the requirement of mTORC1 and mTORC2 in mediating AKT/YapS127A driven tumorigenesis. Gemcitabine/oxaliplatin and MLN0128 were administered in AKT/YapS127A tumor-bearing mice to study their anti-tumor efficacy in vivo. Multiple human ICC cell lines were used for in vitro experiments. Hematoxylin and eosin staining, immunohistochemistry and immunoblotting were applied for the characterization and mechanistic study.
Co-expression of myr-AKT and YapS127A promoted ICC development in mice. Both mTORC1 and mTORC2 complexes were required for AKT/YapS127A ICC development. Gemcitabine/oxaliplatin had limited efficacy in treating late stage AKT/YapS127A ICC. In contrast, partial tumor regression was achieved when MLN0128 was applied in the late stage of AKT/YapS127A cholangiocarcinogenesis. Furthermore, when MLN0128 was administered in the early stage of AKT/YapS127A carcinogenesis, it led to disease stabilization. Mechanistically, MLN0128 efficiently inhibited AKT/mTOR signaling both in vivo and in vitro, inducing strong ICC cell apoptosis and only marginally affecting proliferation.
This study suggests that mTOR kinase inhibitors may be beneficial for the treatment of ICC, even in tumors that are resistant to standard of care chemotherapeutics, such as gemcitabine/oxaliplatin-based regimens, especially in the subset of tumors exhibiting activated AKT/mTOR cascade.
Lay summary: We established a novel mouse model of intrahepatic cholangiocarcinoma (ICC). Using this new preclinical model, we evaluated the therapeutic potential of mTOR inhibitor MLN0128 vs. gemcitabine/oxaliplatin (the standard chemotherapy for ICC treatment). Our study shows the anti-neoplastic potential of MLN0128, suggesting that it may be superior to gemcitabine/oxaliplatin-based chemotherapy for the treatment of ICC, especially in the tumors exhibiting activated AKT/mTOR cascade.
Postoperative pancreatic fistula (POPF) is one of the most critical complications after pancreatic surgery. The relationship between sarcopenia and outcomes following this type of surgery is debated. ...The aim of this review was to assess the impact of sarcopenia on the risk of POPF. A literature search was performed using the PubMed database and the reference lists of relevant articles to identify papers about the impact of sarcopenia on POPF in pancreatic surgery. Twenty-one studies published between 2016 and 2021 with a total of 4068 patients were included. Some studies observed a significant difference in the incidence of POPF between the sarcopenic and non-sarcopenic patients undergoing pancreatoduodenectomy. Interestingly, there was a trend of a lower POPF rate in sarcopenic patients than in non-sarcopenic patients. Only one study included patients undergoing distal pancreatectomy specifically. The role of sarcopenia in surgical outcomes is still unclear. A combination of objective CT measurements could be used to predict POPF. It could be assessed by routine preoperative staging CT and could improve preoperative risk stratification in patients undergoing pancreatic surgery.
Patients with pancreatic ductal adenocarcinoma (PDCA) carrying impaired mismatch repair mechanisms seem to have an outcome advantage under treatment with conventional chemotherapy, whereas the role ...for the tumor mutation burden on prognosis is controversial. In this study, we evaluated the prognostic role of the mutated genes involved in genome damage repair in a real-life series of PDAC patients in a hospital-based manner from the main Institution deputed to surgically treat such a disease in North Sardinia.
A cohort of fifty-five consecutive PDAC patients with potentially resectable/border line resectable PDAC (stage IIB-III) or oligometastatic disease (stage IV) and tumor tissue availability underwent next-generation sequencing (NGS)-based analysis using a panel containing driver oncogenes and tumor suppressor genes as well as genes controlling DNA repair mechanisms.
Genes involved in the both genome damage repair (DR) and DNA mismatch repair (MMR) were found mutated in 17 (31%) and 15 (27%) cases, respectively. One fourth of PDAC cases (14/55; 25.5%) carried tumors presenting a combination of mutations in repair genes (DR and MMR) and the highest mutation load rates (MLR-H). After correction for confounders (surgery, adjuvant therapy, stage T, and metastasis), multivariate Cox regression analysis indicated that mutations in DR genes (HR = 3.0126, 95% CI 1.0707 to 8.4764, p = 0.0367) and the MLR (HR = 1.0018, 95%CI 1.0005 to 1.0032, p = 0.009) were significantly related to worse survival.
The combination of mutated repair genes and MLR-H, which is associated with a worse survival in our series of PDAC patients treated with conventional chemotherapy protocols, might become a predictive biomarker of response to immunotherapy in addition to its prognostic role in predicting survival.
Colorectal cancer (CRC) is a leading cause of cancer death worldwide, and about 20% is metastatic at diagnosis and untreatable. Increasing evidence suggests that the heterogeneous nature of CRC is ...related to colorectal cancer stem cells (CCSCs), a small cells population with stemness behaviors and responsible for tumor progression, recurrence, and therapy resistance. Growing knowledge of stem cells (SCs) biology has rapidly improved uncovering the molecular mechanisms and possible crosstalk/feedback loops between signaling pathways that directly influence intestinal homeostasis and tumorigenesis. The generation of CCSCs is probably connected to genetic changes in members of signaling pathways, which control self-renewal and pluripotency in SCs and then establish function and phenotype of CCSCs. Particularly, various deregulated CCSC-related miRNAs have been reported to modulate stemness features, controlling CCSCs functions such as regulation of cell cycle genes expression, epithelial-mesenchymal transition, metastasization, and drug-resistance mechanisms. Primarily, CCSC-related miRNAs work by regulating mainly signal pathways known to be involved in CCSCs biology. This review intends to summarize the epigenetic findings linked to miRNAome in the maintenance and regulation of CCSCs, including their relationships with different signaling pathways, which should help to identify specific diagnostic, prognostic, and predictive biomarkers for CRC, but also develop innovative CCSCs-targeted therapies.
Colorectal cancer (CRC) ranks as the most frequent carcinoma worldwide. CRC patients show strong prognostic differences and responses to treatment, and 20% have incurable metastatic disease at ...diagnosis. We considered it essential to investigate mechanisms that control cellular regulatory networks, such as the miRNA-mRNA interaction, known to be involved in cancer pathogenesis. We conducted a human miRNome analysis by TaqMan low density array, comparing CRC to normal colon tissue (NCT, and experimentally identified gene targets of miRNAs deregulated, by anti-correlation analysis, with the CRC whole-transcriptome profile obtained from RNASeq experiments. We identified an integrated signature of 20 deregulated miRNAs in CRC. Enrichment analyses of the gene targets controlled by these miRNAs brought to light 25 genes, members of pathways known to lead to cell growth and death (
etc.), such as cell metabolism (
). A screening of prognosis-mediated miRNAs underlined that the overexpression of miR-224 promotes CRC metastasis, and is associated with high stage and poor survival. These findings suggest that the biology and progression of CRC depend on deregulation of multiple miRNAs that cause a complex dysfunction of cellular molecular networks. Our results have further established miRNA-mRNA interactions and defined multiple pathways involved in CRC pathogenesis.
Background: The literature is conflicting regarding oncological outcome and morbidity associated to portal–mesenteric resection during pancreaticoduodenectomy (PD) in patients with pancreatic head ...adenocarcinoma (PHAC). Methods: A meta-analysis of studies comparing PD plus venous resection (PD+VR) and standard PD exclusively in patients with adenocarcinoma of the pancreatic head was conducted. Results: Twenty-three cohort studies were identified, which included 6037 patients, of which 28.6% underwent PD+VR and 71.4% underwent standard PD. Patients who received PD+VR had lower 1-year overall survival (OS) (odds radio OR 0.79, 95% CI 0.67–0.92, p = 0.003), 3-year OS (OR 0.72, 95% CI 0.59–0.87, p = 0.0006), and 5-year OS (OR 0.57, 95% CI 0.39–0.83, p = 0.003). Patients in the PD+VR group were more likely to have a larger tumor size (MD 3.87, 95% CI 1.75 to 5.99, p = 0.0003), positive lymph nodes (OR 1.24, 95% CI 1.06–1.45, p = 0.007), and R1 resection (OR 1.74, 95% CI 1.37–2.20, p < 0.0001). Thirty-day mortality was higher in the PD+VR group (OR 1.93, 95% CI 1.28–2.91, p = 0.002), while no differences between groups were observed in rates of total complications (OR 1.07, 95% CI, 0.81–1.41, p = 0.65). Conclusions: Although PD+VR has significantly increased the resection rate in patients with PHAC, it has inferior survival outcomes and higher 30-day mortality when compared with standard PD, whereas postoperative morbidity rates are similar. Further research is needed to evaluate the role of PD+VR in the context of multimodality treatment of PHAC.
Purpose: Cryoablation (CrA) is a minimally invasive treatment that can be used in primary and metastatic liver cancer. The purpose of this study was to assess the effectiveness of CrA in patients ...with hepatocellular carcinoma (HCC) and liver metastases. Methods: We retrospectively evaluated the patients who had CrA for HCC or liver metastases between 2015 and 2020. Technical success, complete ablation, CrA-related complications, local tumor progression, local recurrences, and distant metastases were evaluated in the study population. In patients with HCC, the median survival was also estimated. Results: Sixty-four liver tumors in 49 patients were treated with CrA (50 metastases and 14 HCC). The mean tumor diameter was 2.15 cm. The mean follow-up was 19.8 months. Technical success was achieved in the whole study population. Complete tumor ablation was observed after one month in 92% of lesions treated with CrA (79% and 96% in the HCC Group and metastases Group, respectively, p < 0.001). Local tumor progression occurred in 12.5 of lesions, with no difference between the study groups (p = 0.105). Sixteen patients (33%) developed local recurrence (45% and 29% in the HCC Group and metastases Group, respectively, p = 0.477). Seven patients (14%) developed distant metastases in the follow-up period. Ten patients (20.8%) underwent redo CrA for local recurrence or incomplete tumor ablation. Minor complications were observed in 14% of patients. In patients with HCC, the median survival was 22 months. Conclusions: CrA can be safely used for treatment of HCC and liver metastases not amenable of surgical resection. Further studies are necessary to better define the role of CrA in the multidisciplinary treatment of liver malignancies.
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