GNS561, a New Autophagy Inhibitor Active against Cancer Stem Cells in Hepatocellular Carcinoma and Hepatic Metastasis from Colorectal Cancer.
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ABSTRACT:
SUBMITTER: Brun S
PROVIDER: S-EPMC8364651 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The liver is the most common site of metastasis in patients with colorectal cancer due to its anatomical situation regarding its portal circulation. About 14 to 18% of patients with colorectal cancer present metastasis at the first medical consultation, and 10 to 25% at the time of the resection of the primary colorectal cancer. The incidence is higher (35%) when a computed tomography (CT) scan is used. In the last decades, a significant increase in the life expectancy of patients with colorectal cancer has been achieved with different diagnostic and treatment programs. Despite these improvements, the presence of metastasis, disease recurrence, and advanced local tumors continue to remain poor prognostic factors. Median survival without treatment is <8 months from the moment of its presentation, and a survival rate at 5 years of 11% is the best prognosis for those who present with local metastasis. Even in patients with limited metastatic disease, 5-year survival is exceptional. Patients with hepatic metastasis of colorectal cancer have a median survival of 5 to 20 months with no treatment. Approximately 20 to 30% of patients with colorectal metastasis have disease confined to the liver, and this can be managed with surgery. Modern surgical strategies at the main hepatobiliary centers have proved that hepatectomy of 70% of the liver can be performed, with a mortality rate of <5%. It is very important to have knowledge of predisposing factors, diagnostic methods, and treatment of hepatic metastasis. However, the establishment of newer, efficient, preventive screening programs for early diagnosis and adequate treatment is vital. How to cite this article: Valderrama-Treviño AI, Barrera-Mera B, Ceballos-Villalva JC, Montalvo-Javé EE. Hepatic Metastasis from Colorectal Cancer. Euroasian J Hepato-Gastroenterol 2017;7(2):166-175.
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Project description:Colorectal cancer (CRC) is one of the most common cancers in the world. About two third of patients with CRC will develop distant recurrence at some point in time. Liver is the most common site where distant metastasis takes place. While the overall survival (OS) of patients with metastatic CRC was poor about 3 decades ago, there has been tremendous improvement in this area in the recent years. With the advent of effective systemic chemotherapy and biologic agents and better understanding of the biological behaviour of the tumour, aggressive treatment strategies such as metastatectomy of the liver metastases (or lung metastases) are now acceptable. More importantly, it has transformed the way how stage IV CRCs are being managed. From predominantly palliative as the primary aim, a comprehensive multidisciplinary approach is now the mainstay of treatment with very successful outcomes. Combination of systemic therapies with liver resection has been shown to be effective in providing promising survival benefits. In addition, other adjunctive modalities in targeting the liver metastases such as ablation, combining resection and ablation, transarterial chemoembolization, stereotactic body radiotherapy (SBRT), hepatic artery perfusion, etc. have also been demonstrated variable outcome in treating colorectal liver metastasis (CRLM). Very recently, transplant oncologists have also explored using liver transplantation as a treatment modality for unresectable CRLM, which has demonstrated very good long-term survival in well selected cases. The new paradigm in the treatment of metastatic CRC has dawned.
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Project description:Hepatocellular carcinoma is the most frequent primary liver cancer. Macroautophagy/autophagy inhibitors have been extensively studied in cancer but, to date, none has reached efficacy in clinical trials. In this study, we demonstrated that GNS561, a new autophagy inhibitor, whose anticancer activity was previously linked to lysosomal cell death, displayed high liver tropism and potent antitumor activity against a panel of human cancer cell lines and in two hepatocellular carcinoma in vivo models. We showed that due to its lysosomotropic properties, GNS561 could reach and specifically inhibited its enzyme target, PPT1 (palmitoyl-protein thioesterase 1), resulting in lysosomal unbound Zn2+ accumulation, impairment of cathepsin activity, blockage of autophagic flux, altered location of MTOR (mechanistic target of rapamycin kinase), lysosomal membrane permeabilization, caspase activation and cell death. Accordingly, GNS561, for which a global phase 1b clinical trial in liver cancers was just successfully achieved, represents a promising new drug candidate and a hopeful therapeutic strategy in cancer treatment.Abbreviations: ANXA5:annexin A5; ATCC: American type culture collection; BafA1: bafilomycin A1; BSA: bovine serum albumin; CASP3: caspase 3; CASP7: caspase 7; CASP8: caspase 8; CCND1: cyclin D1; CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; CQ: chloroquine; iCCA: intrahepatic cholangiocarcinoma; DEN: diethylnitrosamine; DMEM: Dulbelcco's modified Eagle medium; FBS: fetal bovine serum; FITC: fluorescein isothiocyanate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HCC: hepatocellular carcinoma; HCQ: hydroxychloroquine; HDSF: hexadecylsulfonylfluoride; IC50: mean half-maximal inhibitory concentration; LAMP: lysosomal associated membrane protein; LC3-II: phosphatidylethanolamine-conjugated form of MAP1LC3; LMP: lysosomal membrane permeabilization; MALDI: matrix assisted laser desorption ionization; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MKI67: marker of proliferation Ki-67; MTOR: mechanistic target of rapamycin kinase; MRI: magnetic resonance imaging; NH4Cl: ammonium chloride; NtBuHA: N-tert-butylhydroxylamine; PARP: poly(ADP-ribose) polymerase; PBS: phosphate-buffered saline; PPT1: palmitoyl-protein thioesterase 1; SD: standard deviation; SEM: standard error mean; vs, versus; Zn2+: zinc ion; Z-Phe: Z-Phe-Tyt(tBu)-diazomethylketone; Z-VAD-FMK: carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone.
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Project description:Hepatic metastasis is the major cause of mortality in colorectal cancer (CRC) patients. Using proteomic analysis, we found sciellin (SCEL) to be specifically expressed in hepatic metastatic CRC cell lines. SCEL knockdown increased CRC cell migration and invasion, while overexpression had the opposite effect. SCEL knockdown also caused cancer cells to form more invasive structures within 3D cultures, increased the mesenchymal marker vimentin, and attenuated the epithelial marker E-cadherin. SCEL increased WNT signaling by activating β-catenin and its downstream target c-myc, and activated mesenchymal-to-epithelial transition (MET) through a SCEL-β-catenin-E-cadherin axis. SCEL showed higher expression in late stage primary CRC than in its hepatic metastatic counterpart. SCEL expression is dynamically modulated by TGF-β1 and hypoxia, revealing a plastic MET mechanism for tumor colonization. Intrahepatic injection in immunodeficient mice revealed that SCEL is necessary for metastatic CRC tumor growth in the liver. These results demonstrate that SCEL is a MET inducer dynamically regulated through the metastasis process. They suggest SCEL may be a useful therapeutic target for preventing or eliminating CRC hepatic metastasis.
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Project description:Purpose: Colorectal liver metastasis (CRLM) is the major cause of death due to colorectal cancer. Although great efforts have been made in treatment of CRLM, about 60-70% of patients will develop hepatic recurrence. Hepatic steatosis was reported to provide fertile soil for metastasis. However, whether hepatic steatosis predicts higher incidence of CRLM recurrence is not clear. Therefore, we aimed to determine the role of hepatic steatosis in CRLM recurrence in the present study. Methods: Consecutive CRLM patients undergoing curative treatment were retrospectively enrolled and CT liver-spleen attenuation ratio was used to detect the presence of hepatic steatosis. In patients with hepatic steatosis, we also detected the presence of fibrosis. Besides, a systematic literature search was performed to do meta-analysis to further analyze the association between hepatic steatosis and CRLM recurrence. Results: A total of 195 eligible patients were included in our center. Patients with hepatic steatosis had a significantly worse overall (P = 0.0049) and hepatic recurrence-free survival (RFS) (P = 0.0012). Univariate and multivariate analysis confirmed its essential role in prediction of RFS. Besides, hepatic fibrosis is associated with worse overall RFS (P = 0.039) and hepatic RFS (P = 0.048). In meta-analysis, we included other four studies, with a total of 1,370 patients in the case group, and 3,735 patients in the control group. The odds ratio was 1.98 (95% CI: 1.25-3.14, P = 0.004), indicating that patients with steatosis had a significantly higher incidence of CRLM recurrence. Conclusion: In summary, patients with hepatic steatosis had a significantly worse overall and hepatic RFS and it's associated with higher incidence of CRLM recurrence.
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Project description:Colorectal cancer is the second leading cause of death from cancer in the United States. Metastases in the liver, the most common metastatic site for colorectal cancer, are found in one-third of the patients who die of colorectal cancer. Currently, the genes and molecular mechanisms that are functionally critical in modulating colorectal cancer hepatic metastasis remain unclear. Here, we report our studies using functional selection in an orthotopic mouse model of colorectal cancer to identify a set of genes that play an important role in mediating colorectal cancer liver metastasis. These genes included APOBEC3G, CD133, LIPC, and S100P. Clinically, we found these genes to be highly expressed in a cohort of human hepatic metastasis and their primary colorectal tumors, suggesting that it might be possible to use these genes to predict the likelihood of hepatic metastasis. We have further revealed what we believe to be a novel mechanism in which APOBEC3G promotes colorectal cancer hepatic metastasis through inhibition of miR-29-mediated suppression of MMP2. Together, our data elucidate key factors and mechanisms involved in colorectal cancer liver metastasis, which could be potential targets for diagnosis and treatment.
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Project description:BACKGROUND Colorectal cancer (CRC) is one of the most common cancers worldwide, and more than half of CRC patients have CRC liver metastasis (CRCLM). Mounting evidence indicates that high mobility group protein A1(HMGA1) is overexpressed in many cancer types, but its role in CRCLM has been obscure. MATERIAL AND METHODS Using immunohistochemistry, we assessed the expression of HMGA1 in 73 patients with CRCLM, and compared HMGA1 mRNA in 17 pairs of CRCs, CRCLM tissues, and normal liver tissues. The clinical significance of HMGA1 was evaluated by analyzing its correlation with the clinicopathological factors and overall survival (OS) rates. The function of HMGA1 in CRC invasion was investigated and the underlying mechanism of HMGA1-induced invasion was explored with in vitro experiments. RESULTS In CRCLMs, the high-HMGA1 and low-HMGA1 patients accounted for 53.42% and 46.58% of all patients, respectively. High HMGA1 expression in CRCLM was significantly associated with low OS rates. In vitro experiments demonstrated that HMGA1 promoted glucose transporter 3 (GLUT3) transcription and expression in CRC cells. GLUT3 was required in HMGA1-involved invasion, and GLUT3 expression was associated with poor prognosis of CRCLM. CONCLUSIONS High HMGA1 and GLUT3 expression in CRCLM was significantly correlated with poor prognosis of CRCLM. HMGA1 promoted CRC invasion by elevating GLUT3 transcription and expression.
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