Browsing by Subject "Liver cancer"
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Item A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance(Elsevier, 2024) Sun, Lei; Wan, Arabella H.; Yan, Shijia; Liu, Ruonian; Li, Jiarui; Zhou, Zhuolong; Wu, Ruirui; Chen, Dongshi; Bu, Xianzhang; Ou, Jingxing; Li, Kai; Lu, Xiongbin; Wan, Guohui; Ke, Zunfu; Medical and Molecular Genetics, School of MedicineLenvatinib, a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer, facing limitations due to drug resistance. Here, we applied a multidimensional, high-throughput screening platform comprising patient-derived resistant liver tumor cells (PDCs), organoids (PDOs), and xenografts (PDXs) to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings. Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment, expediting drug repurposing screens. Pharmacological screening identified romidepsin, YM155, apitolisib, NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models. Notably, romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway. A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models. Collectively, our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer, providing a feasible multidimensional platform for personalized medicine.Item Body Mass Index Trajectories, Weight Gain, and Risks of Liver and Biliary Tract Cancers(Oxford University Press, 2022-08-12) Yang, Wanshui; Zeng, Xufen; Petrick, Jessica L.; Danford, Christopher J.; Florio, Andrea A.; Lu, Bing; Nan, Hongmei; Ma, Jiantao; Wang, Liang; Zeng, Hongmei; Sudenga, Staci L.; Campbell, Peter T.; Giovannucci, Edward; McGlynn, Katherine A.; Zhang, Xuehong; Epidemiology, Richard M. Fairbanks School of Public HealthBackground: Little is known about the role of early obesity or weight change during adulthood in the development of liver cancer and biliary tract cancer (BTC). Methods: We investigated the associations of body mass index (BMI) and weight trajectories with the risk of liver cancer and BTC in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). BMI was self-reported at ages 20, 50, and at enrollment. BMI trajectories were determined using latent class growth models. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During a median follow-up of 15.9 years among 138,922 participants, 170 liver cancer and 143 BTC cases were identified. Compared with those whose BMI does not exceed 25 kg/m2, participants with BMI exceeding 25 kg/m2 at age 20 had increased risks of liver cancer (HR = 2.03, 95% CI: 1.26-3.28) and BTC (HR = 1.99, 95% CI: 1.16-3.39). Compared to participants maintaining normal BMI until enrollment, trajectory of normal weight at age 20 to obesity at enrollment was associated with increased risk for liver cancer (HR = 2.50, 95% CI: 1.55-4.04) and BTC (HR = 1.83, 95% CI: 1.03-3.22). Compared to adults with stable weight (+/-5kg) between age 20 to 50 years, weight gain ≥20 kg between ages 20 to 50 years had higher HRs of 2.24 (95%CI: 1.40-3.58) for liver cancer and 1.86 (95% CI: 1.12-3.09) for BTC. Conclusions: Being overweight/obese at age 20, and BMI trajectories that result in being overweight and/or obese, may increase risk for both liver cancer and BTC.Item Changes in the epidemiological trends of primary liver cancer in the Asia-Pacific region(Springer Nature, 2024-08-22) Danpanichkul, Pojsakorn; Suparan, Kanokphong; Sukphutanan, Banthoon; Kaeosri, Chuthathip; Tothanarungroj, Primrose; Sirimangklanurak, Supapitch; Kalligeros, Markos; Polpichai, Natchaya; Pang, Yanfang; Wijarnpreecha, Karn; Sripongpun, Pimsiri; Chamroonkul, Naichaya; Nguyen, Mindie H.; Liangpunsakul, Suthat; Piratvisuth, Teerha; Kaewdech, Apichat; Medicine, School of MedicinePrimary liver cancer is the third leading cause of cancer-related mortality. The increasing prevalence of metabolic syndrome and alcohol consumption, along with the existing burden of viral hepatitis, could significantly heighten the impact of primary liver cancer. However, the specific effects of these factors in the Asia-Pacific region, which comprises more than half of the global population, remain largely unexplored. This study aims to analyze the epidemiology of primary liver cancer in the Asia-Pacific region. We evaluated regional and national data from the Global Burden of Disease study spanning 2010 to 2019 to assess the age-standardized incidence, mortality, and disability-adjusted life years associated with primary liver cancer in the Asia-Pacific region. During the study period, there were an estimated 364,700 new cases of primary liver cancer and 324,100 deaths, accounting for 68 and 67% of the global totals, respectively. Upward trends were observed in the age-standardized incidence rates of primary liver cancer due to metabolic dysfunction-associated fatty liver disease (MASLD) and alcohol-associated liver disease (ALD) in the Asia-Pacific region, as well as an increase in primary liver cancer from Hepatitis B virus infection in the Western Pacific region. Notably, approximately 17% of new cases occurred in individuals aged 15-49 years. Despite an overall decline in the burden of primary liver cancer in the Asia-Pacific region over the past decade, increases in incidence were noted for several etiologies, including MASLD and ALD. However, viral hepatitis remains the leading cause, responsible for over 60% of the total burden. These findings underscore the urgent need for comprehensive strategies to address the rising burden of primary liver cancer in the Asia-Pacific region.Item Culture media composition influences patient-derived organoid ability to predict therapeutic responses in gastrointestinal cancers(American Society for Clinical Investigation, 2022-11-22) Hogenson, Tara L.; Xie, Hao; Phillips, William J.; Toruner, Merih D.; Li, Jenny J.; Horn, Isaac P.; Kennedy, Devin J.; Almada, Luciana L.; Marks, David L.; Carr, Ryan M.; Toruner, Murat; Sigafoos, Ashley N.; Koenig-Kappes, Amanda N.; Olson, Rachel Lo; Tolosa, Ezequiel J.; Zhang, Cheng; Li, Hu; Doles, Jason D.; Bleeker, Jonathan; Barrett, Michael T.; Boyum, James H.; Kipp, Benjamin R.; Mahipal, Amit; Hubbard, Joleen M.; Scheffler Hanson, Temperance J.; Petersen, Gloria M.; Dasari, Surendra; Oberg, Ann L.; Truty, Mark J.; Graham, Rondell P.; Levy, Michael J.; Zhu, Mojun; Billadeau, Daniel D.; Adjei, Alex A.; Dusetti, Nelson; Iovanna, Juan L.; Bekaii-Saab, Tanios S.; Ma, Wen Wee; Fernandez-Zapico, Martin E.; Anatomy, Cell Biology and Physiology, School of MedicineBACKGROUND: A patient-derived organoid (PDO) platform may serve as a promising tool for translational cancer research. In this study, we evaluated PDO’s ability to predict clinical response to gastrointestinal (GI) cancers. METHODS: We generated PDOs from primary and metastatic lesions of patients with GI cancers, including pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and cholangiocarcinoma. We compared PDO response with the observed clinical response for donor patients to the same treatments. RESULTS: We report an approximately 80% concordance rate between PDO and donor tumor response. Importantly, we found a profound influence of culture media on PDO phenotype, where we showed a significant difference in response to standard-of-care chemotherapies, distinct morphologies, and transcriptomes between media within the same PDO cultures. CONCLUSION: While we demonstrate a high concordance rate between donor tumor and PDO, these studies also showed the important role of culture media when using PDOs to inform treatment selection and predict response across a spectrum of GI cancers.Item Epigenetic aberrations of gene expression in a rat model of hepatocellular carcinoma(Taylor & Francis, 2022) Boycott, Cayla; Beetch, Megan; Yang, Tony; Lubecka, Katarzyna; Ma, Yuexi; Zhang, Jiaxi; Kurzava Kendall, Lucinda; Ullmer, Melissa; Ramsey, Benjamin S.; Torregrosa-Allen, Sandra; Elzey, Bennett D.; Cox, Abigail; Lanman, Nadia Atallah; Hui, Alisa; Villanueva, Nathaniel; de Conti, Aline; Huan, Tao; Pogribny, Igor; Stefanska, Barbara; Anatomy, Cell Biology and Physiology, School of MedicineHepatocellular carcinoma (HCC) is mostly triggered by environmental and life-style factors and may involve epigenetic aberrations. However, a comprehensive documentation of the link between the dysregulated epigenome, transcriptome, and liver carcinogenesis is lacking. In the present study, Fischer-344 rats were fed a choline-deficient (CDAA, cancer group) or choline-sufficient (CSAA, healthy group) L-amino acid-defined diet. At the end of 52 weeks, transcriptomic alterations in livers of rats with HCC tumours and healthy livers were investigated by RNA sequencing. DNA methylation and gene expression were assessed by pyrosequencing and quantitative reverse-transcription PCR (qRT-PCR), respectively. We discovered 1,848 genes that were significantly differentially expressed in livers of rats with HCC tumours (CDAA) as compared with healthy livers (CSAA). Upregulated genes in the CDAA group were associated with cancer-related functions, whereas macronutrient metabolic processes were enriched by downregulated genes. Changes of highest magnitude were detected in numerous upregulated genes that govern key oncogenic signalling pathways, including Notch, Wnt, Hedgehog, and extracellular matrix degradation. We further detected perturbations in DNA methylating and demethylating enzymes, which was reflected in decreased global DNA methylation and increased global DNA hydroxymethylation. Four selected upregulated candidates, Mmp12, Jag1, Wnt4, and Smo, demonstrated promoter hypomethylation with the most profound decrease in Mmp12. MMP12 was also strongly overexpressed and hypomethylated in human HCC HepG2 cells as compared with primary hepatocytes, which coincided with binding of Ten-eleven translocation 1 (TET1). Our findings provide comprehensive evidence for gene expression changes and dysregulated epigenome in HCC pathogenesis, potentially revealing novel targets for HCC prevention/treatment.Item Hepatocellular Carcinoma : A Decade of Hospitalizations and Financial Burden in the United States(Elsevier, 2017-10) Jinjuvadia, Raxitkumar; Salami, Augustine; Lenhart, Adrienne; Jinjuvadia, Kartikkumar; Liangpunsakul, Suthat; Biochemistry and Molecular Biology, School of MedicineBACKGROUND: Despite a rise in the prevalence of hepatocellular carcinoma (HCC), data on HCC-related hospitalizations and financial burden are limited. The aim of this study was to evaluate temporal trends of HCC-related hospitalizations and evaluate its financial influence. MATERIALS AND METHODS: Patients with the diagnosis of HCC, as reported by International Classification of Diseases-Ninth Revision code, were identified from the National Inpatient Sample databases from 2002-2011. The national estimates of hospitalizations were derived using appropriate sample weights. The change in total average charges per each hospitalization over the study period was calculated after adjusting for inflation. RESULTS: Hospitalizations related to HCC have increased from 24,024 in 2002 to 50,609 in 2011. Of these admissions, HCC was the principal diagnosis in 10,762 and 16,350 subjects in 2002 and 2011, respectively. Most were white males (male: 70%; white: 55%). The overall inpatient mortality was significantly decreased from 13.5% in 2002 to 9.9% in 2011 (P < 0.01). The same trend was also observed for the length of hospital stay (6.5 versus 5.6 days in 2002 and 2011, respectively). The inflation-adjusted cost per hospitalization increased by approximately 47% during the study period. CONCLUSIONS: Despite the decrease in mortality rate and length-of-stay, hospitalizations and financial burden associated with HCC continued to increase between 2002 and 2011 in the United States.Item Older Age and Disease Duration Are Highly Associated with Hepatocellular Carcinoma in Patients with Autoimmune Hepatitis(Springer, 2019-01-07) Dakhoul, Lara; Jones, Keaton R.; Gawrieh, Samer; Ghabril, Marwan; McShane, Chelsey; Vuppalanchi, Raj; Vilar-Gomez, Eduardo; Nephew, Lauren; Chalasani, Naga; Lammert, Craig; Medicine, School of MedicineBackground: Hepatocellular carcinoma (HCC) is rare in patients with autoimmune hepatitis (AIH). However, the overall burden of AIH cirrhosis in causing HCC and patients' risk factors are not well understood. Aims: To characterize the proportion of HCC linked to AIH at a large academic health center, and to identify variables associated with HCC in patients with AIH in a case-control study design. Methods: Over a 14.5-year period, medical records of all patients with HCC were reviewed. Cases are AIH patients identified from the cohort, and controls are patients with AIH without HCC. Three controls were randomly chosen from the Genetic Repository of Autoimmune Liver Disease and Coexisting Exposures database for each eligible case. Results: Out of 1250 eligible patients, 20 were linked to AIH (1.6%). Their median age was 64 years, 40% men and 100% Caucasian. Ten percent of AIH patients did not have evidence of cirrhosis at HCC diagnosis. The proportion of HCCs due to AIH decreased during the time intervals of the study. Compared to controls, cases were more likely men (40.0% vs. 18%, p = 0.049), with longer AIH duration (median 16 years vs. 5 years, p = 0.004). Prolonged AIH duration (OR 1.68, p = 0.006) and older age (OR 1.15, p = 0.049) were risk factors for HCC. Conclusions: AIH is a rare cause (1.6%) for HCC in Midwestern USA with a decreasing trend over 14.5 years. Ten percent of AIH-HCC patients did not have cirrhosis at time of HCC diagnosis. Patients with prolonged duration of the disease and older age are at high risk to develop HCC.Item Projected epidemiological trends and burden of liver cancer by 2040 based on GBD, CI5plus, and WHO data(Springer Nature, 2024-11-15) Guo, Qianqian; Zhu, Xiaorong; Beeraka, Narasimha M.; Zhao, Ruiwen; Li, Siting; Li, Fengying; Mahesh, Padukudru Anand; Nikolenko, Vladimir N.; Fan, Ruitai; Liu, Junqi; Pediatrics, School of MedicineIncidence of liver cancer as one of the most common cancers worldwide and become the significant contributor for the mortality among cancer patients. The disease burden, risk factors, and trends in incidence and mortality of liver cancer globally was described subsequently estimated the projections of liver cancer incidence or mortality by 2040. Data regarding age-standardized incidence and mortality rates for liver cancer was obtained from multiple databases, including GLOBOCAN 2020, CI5 volumes I-XI, WHO mortality database, and Global Burden of Disease (GBD)-2019. Concentrating on worldwide variations, this thorough analysis offers insights into patterns of incidence and mortality based on gender and age. Our findings encompass significant indicators, including age-standardized rates (ASRs), average annual percentage change (AAPC), and future projections extending up to the year 2040. Liver cancer holds the sixth position in terms of most frequently diagnosed cancers and stands as the sixth leading cause of cancer-related deaths worldwide in 2020, accounting for 905,677 new cases and 782,000 fatalities. Additionally, liver cancer contributed to 12,528,421 age-standardized disability-adjusted life years (DALYs), with an age-standardized DALYs rate of 161.92 in 2019 worldwide. The age-specific incidence rates exhibited significant variations across different regions, showing a fivefold difference in males and females. A significant increase in incidence was observed in North Europe and Asia, while North African countries reported a higher mortality burden (ASR, 10 per 100,000) compared to developed countries. Since last few years, the incidence and mortality rates have increased and attained Annual Average Percentage Change (AAPC) incidence rate of 7.7 (95% CI 3.9-11.6) for men and the highest AAPC mortality rate of 12.2 (95% CI 9.5-15.0) for women. In 2019, Western Europe emerged as the high-risk region for DALYs related to smoking and alcohol consumption, while high-income North America carried a high risk for DALYs associated with a high body-mass index. The projected trend indicates a surge in new liver cancer incident cases, expected to rise from around 905,347 to an estimated 1,392,474 by 2040. This study described the evidence pertinent to higher incidence trends in liver cancer, particularly among both young and older adults, encompassing males and females, as well as those who are HIV-infected and HBsAg positive. A significant rise in the young population poses a significant public health concern that warrants attention from healthcare professionals to prioritize the promotion of health awareness and the development of effective cancer prevention strategies, particularly in many developing countries.Item Role of Non-Coding RNAs in the Progression of Liver Cancer: Evidence from Experimental Models(MDPI, 2019-10-25) O’Brien, April; Zhou, Tianhao; Tan, Christopher; Alpini, Gianfranco; Glaser, Shannon; Medicine, School of MedicineLiver cancer is a devastating cancer that ranges from relatively rare (around 2% of all cancers in the United States) to commonplace (up to 50% of cancers in underdeveloped countries). Depending upon the stage of pathogenesis, prognosis, or functional liver tissue present, transplantation or partial hepatectomy may be the only available treatment option. However, due to the rise in metabolic syndrome and the increasing demand for livers, patients often wait months or years for available organs. Due to this shortage, doctors must have other treatment options available. One promising area of cancer research lies in understanding the role of regulatory non-coding RNAs (ncRNAs) as oncogenic drivers and potential targets for prospective therapies. While the role of these ncRNAs was not initially clear, many of them have since been recognized to function as important players in the regulation of gene expression, epigenetic modification, and signal transduction in both normal and cancer cell cycles. Dysregulation of these different ncRNA subtypes has been implicated in the pathogenesis and progression of many major cancers including hepatocellular carcinoma. This review summarizes current findings on the roles noncoding RNAs play in the progression of liver cancer and the various animal models used in current research to elucidate those data.Item Systematic Survey of the Role of IGF in the Link Between Diabetes and Cancer(Indiana University, 2018) Devanathan, Nirupama; Kimble-Hill, Ann C.; Department of Medicine, Indiana University School of MedicineEpidemiological studies have proposed a link between type II diabetes and cancer via the IGF/insulin signaling pathway, which includes insulin-like peptides (IGF1, IGF2, and insulin), insulin receptors (IR-A, IR-B, IGF1R, and hybrids), and insulin substrate proteins (IRS1-6). In this study, up- and down-regulation of various components in the IGF/insulin signaling pathway are compared to clinical outcomes for cancer patients; the components include diagnosis age, overall survival, tumor invasion and vascularization, and body mass index. It was found that the up-regulation of insulin growth Factor (IGF)/insulin components was associated with overall survival and tumor invasion and vascularization, while the down-regulation of equivalent components was not associated with clinical outcomes assessed in this study. Particularly, the up-regulation of DOK5, IGF2, and IRS2 in colorectal cancer and IGF1R in liver cancer is associated with significantly decreased overall survival. Functional aberrations in either of the two proteins in co-expression pairs were identified for each cancer and correlated with overall survival and diagnosis age. Specific biomarkers proposed in this study will be further analyzed to fine-tune consistent associations that can be translated to reliable prognostic standards for the roles of IGF/insulin signaling pathway modulations that promote cancer.