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1.
Gut microbiota alterations are distinct for primary colorectal cancer and hepatocellular carcinoma.
Jia, W, Rajani, C, Xu, H, Zheng, X
Protein & cell. 2021;(5):374-393
Abstract
Colorectal cancer (CRC) and hepatocellular carcinoma (HCC) are the second and third most common causes of death by cancer, respectively. The etiologies of the two cancers are either infectious insult or due to chronic use of alcohol, smoking, diet, obesity and diabetes. Pathological changes in the composition of the gut microbiota that lead to intestinal inflammation are a common factor for both HCC and CRC. However, the gut microbiota of the cancer patient evolves with disease pathogenesis in unique ways that are affected by etiologies and environmental factors. In this review, we examine the changes that occur in the composition of the gut microbiota across the stages of the HCC and CRC. Based on the idea that the gut microbiota are an additional "lifeline" and contribute to the tumor microenvironment, we can observe from previously published literature how the microbiota can cause a shift in the balance from normal → inflammation → diminished inflammation from early to later disease stages. This pattern leads to the hypothesis that tumor survival depends on a less pro-inflammatory tumor microenvironment. The differences observed in the gut microbiota composition between different disease etiologies as well as between HCC and CRC suggest that the tumor microenvironment is unique for each case.
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2.
Obesity and Liver Cancer in Japan: A Comprehensive Review.
Nishikawa, H, Fukunishi, S, Asai, A, Nishiguchi, S, Higuchi, K
Anticancer research. 2021;(5):2227-2237
Abstract
Lifestyle-related factors play a major role in the development of cancer. In recent years, obesity has become widespread in the world and has attracted attention not only as a cause of diabetes mellitus and atherosclerotic diseases but also as a factor in carcinogenesis. In Japan, the number of obesity-related malignancies has been increasing with the westernization of lifestyle. On the other hand, it is estimated that there are more than 10 million nonalcoholic fatty liver disease (NAFLD) patients in Japan. NAFLD is classified into simple fatty liver and nonalcoholic steatohepatitis (NASH), and 10-20% of NASH patients will progress to liver cirrhosis and 2-3% of them will develop hepatocellular carcinoma (HCC) per year. Research interest in metabolism-associated liver cancer has been increasing in recent years. Here in this review, we will comprehensively summarize the current knowledge with regard to the relationship between obesity and HCC in Japan.
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3.
Is transcatheter arterial chemoembolization plus sorafenib better than chemoembolization plus placebo in the treatment of hepatocellular carcinoma?
Xie, Y, Tian, H, Xiang, H
Tumori. 2021;(4):292-303
Abstract
OBJECTIVE To evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE) plus sorafenib compared with TACE plus placebo for hepatocellular carcinoma (HCC) using meta-analytical techniques. METHODS A search of PubMed, EMBASE, and Cochrane Library databases were done from inception to December 27, 2019. Published trials including a treatment group receiving TACE + sorafenib and a control group receiving TACE + placebo with data for at least 1-year survival or tumor response or time to progression were included. RESULTS Our study suggested that there was no evidence that TACE plus sorafenib was associated with a lower risk of disease progression compared with TACE plus placebo for treatment of HCC (hazard ratio 0.94 [95% confidence interval (CI), 0.84-1.05]), and no significant difference for treatment of HCC compared with TACE plus placebo in terms of 0.5-, 1-, 1.5-, and 2-year survival rates (risk ratio [RR] 1.01 [95% CI, 0.97-1.05]; RR 1.00 [95% CI, 0.92-1.08], RR 1.04 [95% CI, 0.89-1.23], RR 0.98 [95% CI, 0.72-1.34], respectively). The meta-analysis also showed that TACE + sorafenib seemed to have no significant difference for treatment of HCC compared with TACE + placebo in terms of complete response, partial response, stable disease, progressive disease, overall response rate, and disease control rate. There was an increased incidence of fatigue of grade 3/4 and elevation of aspartate aminotransferase and alanine aminotransferase of grade 3/4 in patients receiving TACE plus sorafenib compared with those receiving TACE plus placebo. CONCLUSIONS There is no additive benefit of TACE plus sorafenib compared to TACE plus placebo for HCC.
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4.
Gut-liver axis-mediated mechanism of liver cancer: A special focus on the role of gut microbiota.
Ohtani, N, Hara, E
Cancer science. 2021;(11):4433-4443
Abstract
Gut microbiota and the mammalian host share a symbiotic relationship, in which the host provides a suitable ecosystem for the gut bacteria to digest indigestible nutrients and produce useful metabolites. Although gut microbiota primarily reside in and influence the intestine, they also regulate liver function via absorption and subsequent transfer of microbial components and metabolites through the portal vein to the liver. Due to this transfer, the liver may be continuously exposed to gut-derived metabolites and components. For example, short-chain fatty acids (SCFA) produced by gut microbiota, through the fermentation of dietary fiber, can suppress inflammation via regulatory T cell induction through SCFA-induced epigenetic mechanisms. Additionally, secondary bile acids (BA), such as deoxycholic acid, produced by gut bacteria through the 7α-dehydroxylation of primary BAs, are thought to induce DNA damage and contribute to the remodeling of tumor microenvironments. Other substances that are also thought to influence liver function include lipopolysaccharides (components of the outer membrane of gram-negative bacteria) and lipoteichoic acid (cell wall component of Gram-positive bacteria), which are ligands of innate immune receptors, Toll-like receptor-4, and Toll-like receptor-2, respectively, through which inflammatory signaling is elicited. In this review, we focus on the role of gut microbiota in the liver microenvironment, describing the anatomy of the gut-liver axis, the role of gut microbial metabolites, and the relationships that exist between gut microbiota and liver diseases, including liver cancer.
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5.
Understanding the Role of Perilipin 5 in Non-Alcoholic Fatty Liver Disease and Its Role in Hepatocellular Carcinoma: A Review of Novel Insights.
Mass Sanchez, PB, Krizanac, M, Weiskirchen, R, Asimakopoulos, A
International journal of molecular sciences. 2021;(10)
Abstract
Consumption of high-calorie foods, such as diets rich in fats, is an important factor leading to the development of steatohepatitis. Several studies have suggested how lipid accumulation creates a lipotoxic microenvironment for cells, leading cells to deregulate their transcriptional and translational activity. This deregulation induces the development of liver diseases such as non-alcoholic fatty liver disease (NAFLD) and subsequently also the appearance of hepatocellular carcinoma (HCC) which is one of the deadliest types of cancers worldwide. Understanding its pathology and studying new biomarkers with better specificity in predicting disease prognosis can help in the personalized treatment of the disease. In this setting, understanding the link between NAFLD and HCC progression, the differentiation of each stage in between as well as the mechanisms underlying this process, are vital for development of new treatments and in exploring new therapeutic targets. Perilipins are a family of five closely related proteins expressed on the surface of lipid droplets (LD) in several tissues acting in several pathways involved in lipid metabolism. Recent studies have shown that Plin5 depletion acts protectively in the pathogenesis of liver injury underpinning the importance of pathways associated with PLIN5. PLIN5 expression is involved in pro-inflammatory cytokine regulation and mitochondrial damage, as well as endoplasmic reticulum (ER) stress, making it critical target of the NAFLD-HCC studies. The aim of this review is to dissect the recent findings and functions of PLIN5 in lipid metabolism, metabolic disorders, and NAFLD as well as the progression of NAFLD to HCC.
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6.
Retinoids in health and disease: A role for hepatic stellate cells in affecting retinoid levels.
Haaker, MW, Vaandrager, AB, Helms, JB
Biochimica et biophysica acta. Molecular and cell biology of lipids. 2020;(6):158674
Abstract
Vitamin A (retinol) is important for normal growth, vision and reproduction. It has a role in the immune response and the development of metabolic syndrome. Most of the retinol present in the body is stored as retinyl esters within lipid droplets in hepatic stellate cells (HSCs). In case of liver damage, HSCs release large amounts of stored retinol, which is partially converted to retinoic acid (RA). This surge of RA can mediate the immune response and enhance the regeneration of the liver. If the damage persists activated HSCs change into myofibroblast-like cells producing extracellular matrix, which increases the chance of tumorigenesis to occur. RA has been shown to decrease proliferation and metastasis of hepatocellular carcinoma. The levels of RA and RA signaling are influenced by the possibility to esterify retinol towards retinyl esters. This suggests a complex regulation between different retinoids, with an important regulatory role for HSCs.
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7.
Nanophytomedicine Based Novel Therapeutic Strategies in Liver Cancer.
Kumar, S, Fayaz, F, Pottoo, FH, Bajaj, S, Manchanda, S, Bansal, H
Current topics in medicinal chemistry. 2020;(22):1999-2024
Abstract
Liver cancer is the fifth (6.3% of all cancers i.e., 548,000 cases/year) and ninth (2.8% of all cancers i.e., 244,000 cases/year) most prevalent cancer worldwide in men and women, respectively. Although multiple choices of therapies are offered for Hepatocellular Carcinoma (HCC) like liver resection or transplant, radiofrequency ablation, transarterial chemoembolization, radioembolization, and systemic targeted agent, by the time of diagnosis, most of the cases of HCC are in an advanced stage, which renders therapies like liver transplant or resection and local ablation impractical; and targeted therapy has its shortcomings like general toxicity, imprecise selectivity, several adversative reactions, and resistance development. Therefore, novel drugs with specificity and selectivity are needed to provide the potential therapeutic response. Various researches have shown the potential of phytomedicines in liver cancer by modulating cell growth, invasion, metastasis, and apoptosis. However, their therapeutic potential is held up by their unfavorable properties like stability, poor water solubility, low absorption, and quick metabolism. Nonetheless, the advancement of nanotechnology-based innovative nanocarrier formulations has improved the phytomedicines' profile to be used in the treatment of liver cancer. Nanocarriers not only improve the solubility and stability of phytomedicines but also extend their residence in plasma and accomplish specificity. In this review, we summarize the advancements introduced by nanotechnology in the treatment of liver cancer. In particular, we discuss quite a few applications of nanophytomedicines like curcumin, quercetin, epigallocatechin-3-gallate, berberine, apigenin, triptolide, and resveratrol in liver cancer treatment.
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8.
Tyrosine Kinase Inhibitors and Hepatocellular Carcinoma.
da Fonseca, LG, Reig, M, Bruix, J
Clinics in liver disease. 2020;(4):719-737
Abstract
Sorafenib was the first tyrosine kinase inhibitor (TKI) that showed success in extending survival in patients with advanced hepatocellular carcinoma (HCC). In recent years, additional TKIs have been shown to improve survival and expanded the armamentarium for treating this malignancy. The current landscape includes other classes of drugs, such as immune checkpoint inhibitors and monoclonal antibodies. The challenge is now placed on how to best select, combine, and sequence drugs with the goal of improving efficacy and minimizing toxicities to deliver better outcomes for HCC patients.
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9.
Sorafenib in pediatric hepatocellular carcinoma from a clinician perspective.
Pearson, H, Marshall, LV, Carceller, F
Pediatric hematology and oncology. 2020;(5):412-423
Abstract
Hepatocellular Carcinoma (HCC) is a rare tumor in children and normally carries poor outcomes. The most frequently employed chemotherapy regimen includes cisplatin and doxorubicin (PLADO), but this combination offers limited efficacy. Sorafenib is a multi-tyrosine kinase inhibitor which, following positive studies in adults with HCC, has begun to be introduced in conjunction with PLADO in pediatric oncology with some encouraging results. Based on these findings, the use of sorafenib is become more common in children with unresectable and/or metastatic HCC. The care of patients receiving sorafenib requires appropriate expertise and standardized pediatric guidelines are lacking. An increasing number of children with HCC are expected to receive sorafenib in the years to come. Pediatric oncology clinicians have a key role in identifying side effects early and clinicians caring for children receiving sorafenib need to be familiar with these. This review article provides suitable and practical information on sorafenib for educational development to optimize clinical care and facilitate enhanced patient/parent education. The article addresses specific areas including mechanisms of action, pre-clinical and clinical evidence, dosing and drug administration and toxicities of sorafenib. Clinical research and recommendations for managing sorafenib-related side effects are discussed. Underpinned by research, this article provides pediatric oncology clinicians with the knowledge required to deliver optimal care to children receiving sorafenib.
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10.
Targeted Molecular Therapeutic Options for Hepatocellular Carcinoma.
Sridhar, S, Sharma, I, Sankpal, UT, Ghabach, B, Narra, K, Neerukonda, L, Basha, R
Critical reviews in oncogenesis. 2020;(1):47-55
Abstract
Liver cancer is the 6th leading cause of cancer related deaths in the US even though it ranks 14th in incidence. More men are diagnosed with liver cancer than women, and the number of projected deaths among men (20,020) is almost double that among women (10,140) in the US. Infections like hepatitis and metabolic conditions like obesity are believed to be major risk factors for the onset of liver cancer. Hepatocellular carcinoma (HCC), the most common type of liver cancer, accounts for 75% of all cases. Chemotherapy has not been effective in treating HCC. Targeted therapies are being used in advanced HCC patients due to a better survival and less side effects when compared to traditional chemotherapy. Therapeutic agents targeting the regulators of growth factor signaling pathways and the mediators of downstream signaling-for example, inhibitors of the tyrosine kinase receptor-are used as targeted molecular therapies. Kinase inhibitors that modulate growth signals, such as sorafenib and lenvatinib, are commonly employed in targeted molecular therapy for HCC patients. This review covers these agents, highlighting modes of action and providing details on clinical trials.