FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2912201468> ?p ?o ?g. }

• W2912201468 endingPage "232" @default.
• W2912201468 startingPage "221" @default.
• W2912201468 abstract "Hepatocellular carcinoma (HCC) is swiftly increasing in prevalence globally with a high mortality rate. The progression of HCC in patients is induced with advanced fibrosis, mainly cirrhosis, and hepatitis. The absence of proper preventive or curative treatment methods encouraged extensive research against HCC to develop new therapeutic strategies. The Food and Drug Administration–approved Nexavar (sorafenib) is used in the treatment of patients with unresectable HCC. In 2017, Stivarga (regorafenib) and Opdivo (nivolumab) got approved for patients with HCC after being treated with sorafenib, and in 2018, Lenvima (lenvatinib) got approved for patients with unresectable HCC. But, owing to the rapid drug resistance development and toxicities, these treatment options are not completely satisfactory. Therefore, there is an urgent need for new systemic combination therapies that target different signaling mechanisms, thereby decreasing the prospect of cancer cells developing resistance to treatment. In this review, HCC etiology and new therapeutic strategies that include currently approved drugs and other potential candidates of HCC such as Milciclib, palbociclib, galunisertib, ipafricept, and ramucirumab are evaluated. Hepatocellular carcinoma (HCC) is swiftly increasing in prevalence globally with a high mortality rate. The progression of HCC in patients is induced with advanced fibrosis, mainly cirrhosis, and hepatitis. The absence of proper preventive or curative treatment methods encouraged extensive research against HCC to develop new therapeutic strategies. The Food and Drug Administration–approved Nexavar (sorafenib) is used in the treatment of patients with unresectable HCC. In 2017, Stivarga (regorafenib) and Opdivo (nivolumab) got approved for patients with HCC after being treated with sorafenib, and in 2018, Lenvima (lenvatinib) got approved for patients with unresectable HCC. But, owing to the rapid drug resistance development and toxicities, these treatment options are not completely satisfactory. Therefore, there is an urgent need for new systemic combination therapies that target different signaling mechanisms, thereby decreasing the prospect of cancer cells developing resistance to treatment. In this review, HCC etiology and new therapeutic strategies that include currently approved drugs and other potential candidates of HCC such as Milciclib, palbociclib, galunisertib, ipafricept, and ramucirumab are evaluated. Hepatocellular carcinoma (HCC) is the most prevalent malignancy of the liver, which is considered the second leading cause of cancer death in the US. It is considered as the fifth most detected cancer in men and the seventh most detected cancer in women in the USA and the third most leading cause of cancer death worldwide.1Mittal S. El-Serag H.B. Epidemiology of hepatocellular carcinoma: consider the population.J Clin Gastroenterol. 2013; 47: S2-S6Crossref PubMed Scopus (407) Google Scholar In many parts of the world including Europe, North America, and Latin America, the rate of liver cancer is increasing by 3.1% each year from 2008 to 2012, as reported by the database of the National Cancer Institute in the US.2Ryerson A.B. et al.Annual Report to the Nation on the Status of Cancer, 1975-2012, featuring the increasing incidence of liver cancer.Cancer. 2016; 122: 1312-1337Crossref PubMed Scopus (434) Google Scholar According to recent reports, the highest incidence rate of liver cancer in the world occurs in Africa and Asia. Hepatitis B virus (HBV) and hepatitis C virus (HCV) account for approximately 80% of HCC cases, of which HBV accounts for 50–80% of cases of virus-associated HCC, whereas HCV is known to be responsible for 10–25%.3McGlynn K.A. London W.T. The global epidemiology of hepatocellular carcinoma: present and future.Clin Liver Dis. 2011; 15 ([vii-x]): 223-243Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 4Sanyal A.J. Yoon S.K. Lencioni R. The etiology of hepatocellular carcinoma and consequences for treatment.Oncol. 2010; 15: 14-22Crossref Scopus (274) Google Scholar HCC is diagnosed more commonly in men than in women possibly due to a higher prevalence of HBV, HCV, and alcohol consumption in males that translate into increased carcinogenicity.1Mittal S. El-Serag H.B. Epidemiology of hepatocellular carcinoma: consider the population.J Clin Gastroenterol. 2013; 47: S2-S6Crossref PubMed Scopus (407) Google Scholar Other factors that contribute to the escalation of HCC include increased occurrence of obesity, aflatoxin exposure, and nonalcoholic fatty liver disease around the world.1Mittal S. El-Serag H.B. Epidemiology of hepatocellular carcinoma: consider the population.J Clin Gastroenterol. 2013; 47: S2-S6Crossref PubMed Scopus (407) Google Scholar Several factors associated with the etiology of HCC have a direct influence on disease progression and on the characteristic of patients.4Sanyal A.J. Yoon S.K. Lencioni R. The etiology of hepatocellular carcinoma and consequences for treatment.Oncol. 2010; 15: 14-22Crossref Scopus (274) Google Scholar The greatest global HCC incidence has been reported from sub-Saharan Eastern and Western Africa, Mongolia, China, and Asia-pacific regions.5Zamor P.J. deLemos A.S. Russo M.W. Viral hepatitis and hepatocellular carcinoma: etiology and management.J Gastrointest Oncol. 2017; 8: 229-242Crossref PubMed Scopus (9) Google Scholar However, the pervasiveness of HCC is lower in developed countries excluding France, Japan, and Italy. HBV, HCV, and hepatitis D virus (HDV) have a strong link with the progression of HCC; therefore, the global incidence of HCC mirrors the occurrence of these infectious viral diseases. Liver cirrhosis progresses to HCC in ∼80–90% of the cases.6Ghouri Y.A. Mian I. Rowe J.H. Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis.J Carcinog. 2017; 16: 1Crossref PubMed Scopus (195) Google Scholar The paramount risk element for HCC to flourish is cirrhosis, and HCV and HBV are regarded as the crucial causes of cirrhosis. As a matter of fact, cirrhosis happens when hepatocytes undergo necrosis resulting in fibrosis-forming scar tissue in cirrhosis.7Bataller R. Brenner D.A. Liver fibrosis.J Clin Invest. 2005; 115: 209-218Crossref PubMed Google Scholar It is well known that HCC is the mainspring of HBV infection.8Di Bisceglie A.M. Hepatitis B and hepatocellular carcinoma.Hepatology. 2009; 49: S56-S60Crossref PubMed Scopus (159) Google Scholar To a large extent, HCC linked to HBV occurs in patients who are suffering from HBV infection nearly all their lives, namely chronic hepatitis B.8Di Bisceglie A.M. Hepatitis B and hepatocellular carcinoma.Hepatology. 2009; 49: S56-S60Crossref PubMed Scopus (159) Google Scholar HBV infections may develop into HCC in the presence or absence of cirrhosis due to the genetic mutation induced by HBV.9Liu S. et al.Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis.J Natl Cancer Inst. 2009; 101: 1066-1082Crossref PubMed Scopus (247) Google Scholar The HBV genetic material infiltrates normal hepatocytes and interrupts their function, which result in cancerous cells. Fragments of the HBV genome are often detected in these hepatocarcinoma cells.10Jiang Z. et al.The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients.Genome Res. 2012; 22: 593-601Crossref PubMed Scopus (0) Google Scholar HBV has a partly double-stranded DNA that incorporates virus associated to the Hepadnaviridae family.11Gowans E.J. et al.Patterns of single- and double-stranded hepatitis B virus DNA and viral antigen accumulation in infected liver cells.J Gen Virol. 1983; 64: 1229-1239Crossref PubMed Scopus (33) Google Scholar HCC is induced by this virus through both direct and indirect pathways. HBV infection in the liver is the cause of hepatocyte lesion and chronic necroinflammation ensuing hepatocyte proliferation, fibrosis, and cirrhosis.12Brown A. Goodman Z. Hepatitis B-associated fibrosis and fibrosis/cirrhosis regression with nucleoside and nucleotide analogs.Expert Rev Gastroenterol Hepatol. 2012; 6: 187-198Crossref PubMed Scopus (24) Google Scholar, 13Arora G. Keeffe E.B. Chronic hepatitis B with advanced fibrosis or cirrhosis: impact of antiviral therapy.Rev Gastroenterol Disord. 2007; 7: 63-73PubMed Google Scholar, 14Fung J. et al.Prevalence of fibrosis and cirrhosis in chronic hepatitis B: implications for treatment and management.Am J Gastroenterol. 2008; 103: 1421-1426Crossref PubMed Scopus (33) Google Scholar The unceasing regeneration in cirrhosis persuades hepatocyte multiplication, turnover, and buildup of mutations in the host genome, resulting in genetic changes, chromosomal rearrangements, inactivation of tumor suppressor genes, and activation of oncogenes.14Fung J. et al.Prevalence of fibrosis and cirrhosis in chronic hepatitis B: implications for treatment and management.Am J Gastroenterol. 2008; 103: 1421-1426Crossref PubMed Scopus (33) Google Scholar Nevertheless, in the absence of cirrhosis, HBV can also induce HCC.4Sanyal A.J. Yoon S.K. Lencioni R. The etiology of hepatocellular carcinoma and consequences for treatment.Oncol. 2010; 15: 14-22Crossref Scopus (274) Google Scholar However, HBV may behave as a mutagenic factor by resulting in secondary chromosomal rearrangement and escalate genomic mutability via integrating its DNA into host cells.4Sanyal A.J. Yoon S.K. Lencioni R. The etiology of hepatocellular carcinoma and consequences for treatment.Oncol. 2010; 15: 14-22Crossref Scopus (274) Google Scholar While most HCC cases evolve in cirrhotic livers, a crucial fragment of HBV-associated HCC may take place in the setting of chronic hepatitis B in the lack of liver cirrhosis. The fact that a lower rate of cirrhosis in HBV-associated HCC is analogous to other etiologies, thus argues for a more direct role of HBV in the tumor formation process. Furthermore, different gene expression profiles have been diagnosed in the nontumoral livers of chronic HBV carriers. For instance, activating expression of genes linked in proapoptotic, inflammatory, and DNA repair responses indicate definite pathways activated by chronic hepatitis B.15McGaughan G.W. Shackel N.A. Gorrell M.D. Discussion on differential gene expression between chronic hepatitis B and C hepatic lesion.Gastroenterology. 2001; 121: 1263-1264Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 16Neuveut C. Wei Y. Buendia M.A. Mechanisms of HBV-related hepatocarcinogenesis.J Hepatol. 2010; 52: 594-604Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Hepatitis B virus X (HBx) gene plays an essential role in HBV-associated HCC development. In addition, HBx functions as an activator for an enormous variety of viral promoters. Hence, HBx gene expression is of foremost significance for viral reproduction within living cells.17Ayub A. Ashfaq U.A. Haque A. HBV induced HCC: major risk factors from genetic to molecular level.BioMed Res Int. 2013; 2013: 810461Crossref PubMed Scopus (35) Google Scholar, 18Zhang X. Zhang H. Ye L. Effects of hepatitis B virus X protein on the development of liver cancer.J Lab Clin Med. 2006; 147: 58-66Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 19Hwang G.Y. et al.Detection of the hepatitis B virus X protein (HBx) antigen and anti-HBx antibodies in cases of human hepatocellular carcinoma.J Clin Microbiol. 2003; 41: 5598-5603Crossref PubMed Scopus (59) Google Scholar, 20Forgues M. et al.Interaction of the hepatitis B virus X protein with the Crm1-dependent nuclear export pathway.J Biol Chem. 2001; 276: 22797-22803Crossref PubMed Scopus (69) Google Scholar, 21Weil R. et al.Direct association and nuclear import of the hepatitis B virus X protein with the NF-kappaB inhibitor IkappaBalpha.Mol Cell Biol. 1999; 19: 6345-6354Crossref PubMed Google Scholar, 22Sirma H. et al.Cytosol is the prime compartment of hepatitis B virus X protein where it colocalizes with the proteasome.Oncogene. 1998; 16: 2051-2063Crossref PubMed Scopus (93) Google Scholar HBx protein of HBV or NS5A protein of HCV can cause chronic infections that trigger the PI3K/Akt/STAT3 pathway in tumor cells.23Choudhari S.R. et al.Deactivation of Akt and STAT3 signaling promotes apoptosis, inhibits proliferation, and enhances the sensitivity of hepatocellular carcinoma cells to an anticancer agent.Atiprimod. Mol Cancer Ther. 2007; 6: 112-121Crossref PubMed Scopus (58) Google Scholar HCV is associated with the Hepacivirus genus of Flaviviridae descent, and it infects approximately 170 million people globally per year.24de Oliveria Andrade L.J. et al.Association between hepatitis C and hepatocellular carcinoma.J Global Infect Dis. 2009; 1: 33-37Crossref PubMed Google Scholar As compared to uninfected subjects, a 15- to 20-fold increased threat for HCC exists in HCV-infected individuals.24de Oliveria Andrade L.J. et al.Association between hepatitis C and hepatocellular carcinoma.J Global Infect Dis. 2009; 1: 33-37Crossref PubMed Google Scholar Throughout the extent of 30 years of persistent infection, the momentum of HCC in cohort studies of HCV-affected persons extends from 1% to 3%. After HCV-associated cirrhosis is confirmed, HCC evolves at a yearly rate from 1% to 8% at an average of 3.5%.24de Oliveria Andrade L.J. et al.Association between hepatitis C and hepatocellular carcinoma.J Global Infect Dis. 2009; 1: 33-37Crossref PubMed Google Scholar, 25El-Serag H.B. Kanwal F. Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?.Hepatology. 2014; 60: 1767-1775Crossref PubMed Scopus (302) Google Scholar Unlike HBV that can integrate into the host genome resulting in the direct carcinogenic activity, HCV is known to be an RNA virus with the restricted incorporation of its genetic information into the host genome.26Goossens N. Hoshida Y. Hepatitis C virus-induced hepatocellular carcinoma.Clin Mol Hepatol. 2015; 21: 105-114Crossref PubMed Scopus (54) Google Scholar Consequently, the carcinogenic prospective of HCV is linked to indirect mechanisms.26Goossens N. Hoshida Y. Hepatitis C virus-induced hepatocellular carcinoma.Clin Mol Hepatol. 2015; 21: 105-114Crossref PubMed Scopus (54) Google Scholar Although HCV elimination can play a role in preventing the progression of HCC, other factors that play a major role in HCC progression are iron overload, oxidative stress, endoplasmic reticulum stress, steatosis in hepatocytes, and inflammation.27Kanda T. Yokosuka O. Omata M. Hepatitis C virus and hepatocellular carcinoma.Biology. 2013; 2: 304-316Crossref PubMed Scopus (7) Google Scholar Nevertheless, HCV may also directly progress to HCC by amending various host regulatory pathways that are required in epithelial–mesenchymal transition, angiogenesis, apoptosis, proliferation, and DNA repair. Recent studies have identified direct targets of HCV proteins such as retinoblastoma protein (Rb) that is responsible to restrain cell proliferation primarily by suppressing the activation of E2F, a transcription factor required for S-phase ingression in the cell cycle.28Vescovo T. et al.Molecular mechanisms of hepatitis C virus-induced hepatocellular carcinoma.Clin Microbiol Infect. 2016; 22: 853-861Abstract Full Text Full Text PDF PubMed Google Scholar, 29Mitchell J.K. Lemon S.M. McGivern D.R. How do persistent infections with hepatitis C virus cause liver cancer?.Curr Opin Virol. 2015; 14: 101-108Crossref PubMed Google Scholar, 30Heim M.H. Thimme R. Innate and adaptive immune responses in HCV infections.J Hepatol. 2014; 61: S14-S25Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 31Arzumanyan A. Reis H.M. Feitelson M.A. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma.Nat Rev Canc. 2013; 13: 123-135Crossref PubMed Scopus (476) Google Scholar, 32Bartosch B. et al.Hepatitis C virus-induced hepatocarcinogenesis.J Hepatol. 2009; 51: 810-820Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar There are several salient similarities shared by HBV and HCV such as the modes of transmission, large diffusion globally, and the ability to trigger a chronic infection that may progress to cirrhosis and hepatocellular carcinoma.33Perz J.F. et al.The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide.J Hepatol. 2006; 45: 529-538Abstract Full Text Full Text PDF PubMed Scopus (1656) Google Scholar Gathered epidemiological data suggest that coinfection with HBV and HCV escalates the risk for the progression of HCC. A massive body of data revealed that the pervasiveness of esoteric HBV infection that is the enduring persistence of HBV genomes in person negative for HBV surface antigen (HBsAg) is specifically raised in HCV individuals.34Raimondo G. et al.Statements from the Taormina expert meeting on occult hepatitis B virus infection.J Hepatol. 2008; 49: 652-657Abstract Full Text Full Text PDF PubMed Scopus (544) Google Scholar, 35Cacciola I. et al.Occult hepatitis B virus infection in patients with chronic hepatitis C liver disease.N Engl J Med. 1999; 341: 22-26Crossref PubMed Scopus (561) Google Scholar, 36Torbenson M. Thomas D.L. Occult hepatitis B.Lancet Infect Dis. 2002; 2: 479-486Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar Recent studies have demonstrated that coinfection has long-term acute evolution as compared to HBV or HCV monoinfection. Furthermore, dual infection is linked with an elevated risk of development of fibrosis and the progression of cirrhosis and is a discrete predictor of HCC progression.37Donato F. Boffetta P. Puoti M. A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma.Int J Canc. 1998; 75: 347-354Crossref PubMed Scopus (0) Google Scholar, 38Cho L.Y. et al.Coinfection of hepatitis B and C viruses and risk of hepatocellular carcinoma: systematic review and meta-analysis.Int J Canc. 2011; 128: 176-184Crossref PubMed Scopus (0) Google Scholar Thus, coinfection with HBV or HCV is an intricate clinical/virological form39European Association For The Study Of The L. EASL clinical practice guidelines: management of chronic hepatitis B virus infection.J Hepatol. 2012; 57: 167-185Abstract Full Text Full Text PDF PubMed Scopus (2225) Google Scholar that seems to be linked with the various manifestation of chronic liver disease, and it is a major risk factor for HCC progression.40Huang Y.T. et al.Lifetime risk and sex difference of hepatocellular carcinoma among patients with chronic hepatitis B and C.J Clin Oncol. 2011; 29: 3643-3650Crossref PubMed Scopus (88) Google Scholar, 41Weltman M.D. et al.Coinfection with hepatitis B and C or B, C and delta viruses results in severe chronic liver disease and responds poorly to interferon-alpha treatment.J Viral Hepat. 1995; 2: 39-45Crossref PubMed Google Scholar The human immunodeficiency virus (HIV) is considered as another major modulator of HCC. Studies have revealed that HIV coinfection can hasten the clinical progression of chronic HBV or HCV infection and enlarge the risk of liver cirrhosis and HCC.42Thio C.L. et al.HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS).Lancet. 2002; 360: 1921-1926Abstract Full Text Full Text PDF PubMed Scopus (788) Google Scholar, 43Soriano V. et al.Viral hepatitis and HIV co-infection.Antivir Res. 2010; 85: 303-315Crossref PubMed Scopus (143) Google Scholar The impact of HBV or HCV on HIV are, however, contentious, and some studies have described that HIV-positive patients coinfected with HCV and/or HBV have the more swift development of AIDS and associated death than patients without coinfection.44Joshi D. et al.Increasing burden of liver disease in patients with HIV infection.Lancet. 2011; 377: 1198-1209Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Furthermore, HIV and HBV share a similar course of transmission as the prevalence of anti–hepatitis B core antibody (HBcAb) and HBsAg in HIV-positive patients are exceptionally elevated. Discrete, usually vital, virological profiles may be perceived that is particularly associated with the proceedings of either one or both the viruses over time.45Italian Association for the Study of the, L., T.D. Italian Society of InfectiousD. Italian Society for the Study of Sexually TransmittedPractice guidelines for the treatment of hepatitis C: recommendations from an AISF/SIMIT/SIMAST Expert Opinion Meeting.Dig Liver Dis. 2010; 42: 81-91Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar For the accurate diagnosis and therapeutic approach, it is obligatory to perform a cautious longitudinal assessment of the HBV and HCV titers. Patient heterogeneity is a part of the natural alterations that can be assigned to the attributes of those patients.46Ramaekers B.L. Joore M.A. Grutters J.P. How should we deal with patient heterogeneity in economic evaluation: a systematic review of national pharmacoeconomic guidelines.Value Health. 2013; 16: 855-862Abstract Full Text Full Text PDF PubMed Google Scholar, 47Grutters J.P. et al.Acknowledging patient heterogeneity in economic evaluation : a systematic literature review.Pharmacoeconomics. 2013; 31: 111-123Crossref PubMed Scopus (0) Google Scholar Interpatient heterogeneity is described by the discrepancy of tumor cell populations within patients.48Baeriswyl V. Christofori G. The angiogenic switch in carcinogenesis.Semin Canc Biol. 2009; 19: 329-337Crossref PubMed Scopus (208) Google Scholar, 49Bedard P.L. et al.Tumour heterogeneity in the clinic.Nature. 2013; 501: 355-364Crossref PubMed Scopus (531) Google Scholar Hepatocellular carcinoma has diverse modifications that rely on tumor size and histological grade. Recent studies demonstrated that HCCs approximately 1.0 cm in size have artery-like vessels that are not properly grown with vague capillarization of the blood expanse and the main portal supply within cancerous nodules.48Baeriswyl V. Christofori G. The angiogenic switch in carcinogenesis.Semin Canc Biol. 2009; 19: 329-337Crossref PubMed Scopus (208) Google Scholar At distinct phases of tumor development, angiogenic shifts come from the balance between proangiogenic and antiangiogenic elements. Hence, angiogenic heterogeneity is related to angiogenic molecules such as VEGF, PEDF, and HIF-1 alpha. Therapy against angiogenic elements is crucial in restraining the recurrence in patients with HCC.50Wu X.Z. Xie G.R. Chen D. Hypoxia and hepatocellular carcinoma: the therapeutic target for hepatocellular carcinoma.J Gastroenterol Hepatol. 2007; 22: 1178-1182Crossref PubMed Scopus (130) Google Scholar There are various antiangiogenesis targets such as VEGF, VEGFR, bFGF, platelet-derived growth factor receptor (PDGFR), and angiopoietin Ang-1 and Ang-2. A Food and Drug Administration (FDA)–approved kinase inhibitor, Sorafenib, could lessen the expression of VEGFR-2, VEGFR-3, and PDGFR.51Chiang I.T. et al.Sorafenib inhibits TPA-induced MMP-9 and VEGF expression via suppression of ERK/NF-kappaB pathway in hepatocellular carcinoma cells.In Vivo. 2012; 26: 671-681PubMed Google Scholar The angiogenic heterogeneity of HCC is required to be taken into deliberation because angiogenic elements could be distinct among different tumor sizes and time span throughout the course of hepatocarcinogenesis.50Wu X.Z. Xie G.R. Chen D. Hypoxia and hepatocellular carcinoma: the therapeutic target for hepatocellular carcinoma.J Gastroenterol Hepatol. 2007; 22: 1178-1182Crossref PubMed Scopus (130) Google Scholar The connective tissue growth factor (CTGF) is overexpressed in individuals with HCC, but it is also known that the downregulation of CTGF could hamper HCC development.52Jia X.Q. et al.Inhibition of connective tissue growth factor overexpression decreases growth of hepatocellular carcinoma cells in vitro and in vivo.Chin Med J (Engl). 2011; 124: 3794-3799PubMed Google Scholar It could potentially be a future therapeutic target for HCC treatment. Epithelial–mesenchymal transition (EMT) is a vital course of action in hepatocarcinogenesis, which includes the association between cells and extracellular matrix (ECM) mediated by transforming growth factor-1 (TGF 1) or PDGFR signaling. It is an onerous point to inhibit ECM proteins due to several ECM proteins and intricate mechanisms, and thus, it is important to consider it for target therapy.53Riener M.O. et al.Expression of the extracellular matrix protein periostin in liver tumours and bile duct carcinomas.Histopathology. 2010; 56: 600-606Crossref PubMed Scopus (38) Google Scholar The immune microenvironment in HCC also appears to be heterogeneous. Cell types enclosed within surrounding tumors incorporate CD8+ cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg), natural killer (NK) cells, natural killer T (NKT) cells, and myeloid-derived suppressor cells (MDSCs).54Junttila M.R. de Sauvage F.J. Influence of tumour micro-environment heterogeneity on therapeutic response.Nature. 2013; 501: 346-354Crossref PubMed Scopus (1026) Google Scholar The cells can be involved in developing or inhibiting HCC development.55Jenne C.N. Kubes P. Immune surveillance by the liver.Nat Immunol. 2013; 14: 996-1006Crossref PubMed Scopus (343) Google Scholar The development of immunotherapy requires a comprehension of the heterogeneous microenvironment, regulation of cytokines at various stages of HCC, the functional activity of CTLs and NK cells, etc.54Junttila M.R. de Sauvage F.J. Influence of tumour micro-environment heterogeneity on therapeutic response.Nature. 2013; 501: 346-354Crossref PubMed Scopus (1026) Google Scholar The heterogeneity of HCC cells comes from distinctive gene expression and genetic variations that modify signaling pathways and protein function.49Bedard P.L. et al.Tumour heterogeneity in the clinic.Nature. 2013; 501: 355-364Crossref PubMed Scopus (531) Google Scholar In one study, it was found that intratumor heterogeneity was detectable in 87% of HCC cases. The same study also suggested that on the basis of tumor morphology alone, 26% of the cases were heterogenic.56Friemel J. et al.Intratumor heterogeneity in hepatocellular carcinoma.Clin Canc Res. 2015; 21: 1951-1961Crossref PubMed Scopus (0) Google Scholar Various kinase inhibitors have been under development or reviewed for their clinical significance. Besides, it is important to develop a novel therapy averse to drug-resistant cancer stem cells. For subsequent clinical research design, it is obligatory to think about how to remove the confounding effects from genetic interpatient and intratumor heterogeneity. Targeting the heterogeneity of cancer cells/cancer stem cells, angiogenesis, invasion, and immune reactions might be a promising strategy for individual personal treatment options. Aflatoxins are naturally prevailing subsidiary metabolites of the fungi Aspergillus flavus and Aspergillus parasiticus.57Kew M.C. Aflatoxins as a cause of hepatocellular carcinoma.J Gastrointest Liver Dis. 2013; 22: 305-310PubMed Google Scholar It is known to be a food contaminant and a well-known human hepatocarcinogen which is a prime agent in the pathologic process of HCC.58Magnussen A. Parsi M.A. Aflatoxins, hepatocellular carcinoma and public health.World J Gastroenterol. 2013; 19: 1508-1512Crossref PubMed Scopus (39) Google Scholar Aflatoxins may be present in a broad range of food items that include peanuts, meat, milk, oilseeds, corn, and dried fruits. There are numerous factors that influence the development of Aspergillus and the amount of aflatoxin contamination in foods. One of the factors that increase the susceptibility of plants to Aspergillus resulting in aflatoxin contamination is drought stress.58Magnussen A. Parsi M.A. Aflatoxins, hepatocellular carcinoma and public health.World J Gastroenterol. 2013; 19: 1508-1512Crossref PubMed Scopus (39) Google Scholar Once consumed, AFB1 is metabolized to a functional transitional compound, AFB1-exo-8,9-epoxide, that can attach to DNA.59El-Serag H.B. Epidemiology of viral hepatitis and hepatocellular carcinoma.Gastroenterology. 2012; 142: 1264-1273 e1Abstract Full Text Full Text PDF PubMed Scopus (1737) Google Scholar AFB1 generates a mutation at serine 249 in the tumor suppressor p53 that was diagnosed in 30–60% of HCC samples collected from people in the aflatoxin-prevalent region, most of whom were suffering from HBV disease.60Shen H.M. Ong C.N. Mutations of the p53 tumor suppressor gene and ras oncogenes in aflatoxin hepatocarcinogenesis.Mutat Res. 1996; 366: 23-44Crossref PubMed Scopus (113) Google Scholar Assays have been established to diagnose specific aflatoxin-related DNA mutations in tissues and to calculate metabolites in urine and AFB1–albumin adducts in serum.59El-Serag H.B. Epidemiology of viral hepatitis and hepatocellular carcinoma.Gastroenterology. 2012; 142: 1264-1273 e1Abstract Full Text Full Text PDF PubMed Scopus (1737) Google Scholar As compared to patients without metabolic syndrome, it is reported that those with metabolic syndrome such as obesity and diabetes have a higher incidence of HCC.1Mittal S. El-Serag H.B. Epidemiology of hepatocellular carcinoma: consider the population.J Clin Gastroenterol. 2013; 47: S2-S6Crossref PubMed Scopus (407) Google Scholar, 61Regimbeau J.M. et al.Obesity and diabetes as a risk factor for hepatocellular carcinoma.Liver Transplant. 2004; 10: S69-S73Crossref PubMed Google Scholar A study of liver cancer manifestation indicated that a body mass index (BMI) ≥25 kg/m2 is implicated with a higher risk of developing primary liver cancer.62Rui R. et al.Excess body mass index and risk of liver cancer: a nonlinear dose-response meta-analysis of prospective studies.PLoS One. 2012; 7: e44522Crossref PubMed Scopus (16) Go" @default.
• W2912201468 created "2019-02-21" @default.
• W2912201468 creator A5009001614 @default.
• W2912201468 creator A5042972608 @default.
• W2912201468 creator A5083450855 @default.
• W2912201468 date "2019-03-01" @default.
• W2912201468 modified "2023-10-14" @default.
• W2912201468 title "Hepatocellular Carcinoma: Etiology and Current and Future Drugs" @default.
• W2912201468 cites W1491779959 @default.
• W2912201468 cites W1537838684 @default.
• W2912201468 cites W1569567585 @default.
• W2912201468 cites W1600724420 @default.
• W2912201468 cites W1700691315 @default.
• W2912201468 cites W1709997767 @default.
• W2912201468 cites W1848738154 @default.
• W2912201468 cites W195410184 @default.
• W2912201468 cites W1965326552 @default.
• W2912201468 cites W1965855598 @default.
• W2912201468 cites W1966895191 @default.
• W2912201468 cites W1970113462 @default.
• W2912201468 cites W1970430388 @default.
• W2912201468 cites W1971837077 @default.
• W2912201468 cites W1974903851 @default.
• W2912201468 cites W1981253841 @default.
• W2912201468 cites W1982154889 @default.
• W2912201468 cites W1982160989 @default.
• W2912201468 cites W1982734162 @default.
• W2912201468 cites W1987370132 @default.
• W2912201468 cites W1988337666 @default.
• W2912201468 cites W1991148380 @default.
• W2912201468 cites W1995586054 @default.
• W2912201468 cites W1996865638 @default.
• W2912201468 cites W1997754048 @default.
• W2912201468 cites W2000307707 @default.
• W2912201468 cites W2000336618 @default.
• W2912201468 cites W2004261972 @default.
• W2912201468 cites W2008361095 @default.
• W2912201468 cites W2009519656 @default.
• W2912201468 cites W2013730096 @default.
• W2912201468 cites W2015018301 @default.
• W2912201468 cites W2015155465 @default.
• W2912201468 cites W2017477151 @default.
• W2912201468 cites W2017592190 @default.
• W2912201468 cites W2019166464 @default.
• W2912201468 cites W2022665891 @default.
• W2912201468 cites W2022851037 @default.
• W2912201468 cites W2027014617 @default.
• W2912201468 cites W2027303624 @default.
• W2912201468 cites W2029669343 @default.
• W2912201468 cites W2031472841 @default.
• W2912201468 cites W2035252444 @default.
• W2912201468 cites W2036812273 @default.
• W2912201468 cites W2042290145 @default.
• W2912201468 cites W2045031715 @default.
• W2912201468 cites W2045378539 @default.
• W2912201468 cites W2047039797 @default.
• W2912201468 cites W2052009118 @default.
• W2912201468 cites W2054850562 @default.
• W2912201468 cites W2055090900 @default.
• W2912201468 cites W2056827569 @default.
• W2912201468 cites W2057211093 @default.
• W2912201468 cites W2059671636 @default.
• W2912201468 cites W2061369977 @default.
• W2912201468 cites W2063941959 @default.
• W2912201468 cites W2065244413 @default.
• W2912201468 cites W2070902941 @default.
• W2912201468 cites W2073001877 @default.
• W2912201468 cites W2080222370 @default.
• W2912201468 cites W2083052522 @default.
• W2912201468 cites W2089353165 @default.
• W2912201468 cites W2092783623 @default.
• W2912201468 cites W2092884146 @default.
• W2912201468 cites W2092989290 @default.
• W2912201468 cites W2094338286 @default.
• W2912201468 cites W2095777941 @default.
• W2912201468 cites W2097494822 @default.
• W2912201468 cites W2101960180 @default.
• W2912201468 cites W2102397711 @default.
• W2912201468 cites W2111185880 @default.
• W2912201468 cites W2112099875 @default.
• W2912201468 cites W2114012800 @default.
• W2912201468 cites W2118471405 @default.
• W2912201468 cites W2118501663 @default.
• W2912201468 cites W2119242310 @default.
• W2912201468 cites W2120441162 @default.
• W2912201468 cites W2122438523 @default.
• W2912201468 cites W2126216210 @default.
• W2912201468 cites W2126508950 @default.
• W2912201468 cites W2130915160 @default.
• W2912201468 cites W2133775721 @default.
• W2912201468 cites W2134690686 @default.
• W2912201468 cites W2137547634 @default.
• W2912201468 cites W2141860194 @default.
• W2912201468 cites W2142676726 @default.
• W2912201468 cites W2144125868 @default.
• W2912201468 cites W2145905144 @default.
• W2912201468 cites W2147551508 @default.
• W2912201468 cites W2151600653 @default.

• next