Journal articles on the topic 'Human primary liver cancer'
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1
Zajkowska, Monika, and Barbara Mroczko. "Chemokines in Primary Liver Cancer." International Journal of Molecular Sciences 23, no. 16 (August 9, 2022): 8846. http://dx.doi.org/10.3390/ijms23168846.
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The liver is responsible for extremely important functions in the human body. In the liver’s structure, we distinguish between connective tissue (stroma) and parenchyma, the latter of which is formed from the basic structural and functional units of the liver—hepatocytes. There are many factors, that negatively affect the liver cells, contributing to their damage. This may lead to fibrosis, liver failure and, in consequence, primary liver cancer, which is the sixth most commonly diagnosed malignancy and the fourth leading cause of cancer death worldwide. Chemokines are a large family of secreted proteins. Their main role is to direct the recruitment and migration of cells to sites of inflammation or injury. Some authors suggest that these proteins might play a potential role in the development of many malignancies, including primary liver cancer. The aim of this study was to evaluate and summarize the knowledge regarding liver diseases, especially primary liver cancer (HCC) and the participation of chemokines in the development of this malignancy. Chemokines involved in the initiation of this type of tumor belong mainly to the CC and CXC chemokines. Their significant role in the course of hepatocellular carcinoma proves their usefulness in detecting and monitoring the course and treatment in patients with this disease.
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Takamoto, Takeshi, and Masatoshi Makuuchi. "Precision surgery for primary liver cancer." Cancer Biology & Medicine 16, no. 3 (August 1, 2019): 475–85. http://dx.doi.org/10.20892/j.issn.2095-3941.2019.0194.
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Liver resection remains the best curative option for primary liver cancer, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma. In particular, in liver resection for HCC, anatomical resection of the tumor-bearing segments is highly recommended to eradicate the intrahepatic metastases spreading through portal venous branches. Anatomical liver resection, including anatomical segmentectomy and subsegmentectomy using the dye-injection method, is technically demanding and requires experience for completion of a precise procedure. The recent development of imaging studies and new computer technologies has allowed for the preoperative design of the operative procedure, intraoperative navigation, and postoperative quality evaluation of the anatomical liver resection. Although these new technologies are related to the progress of artificial intelligence, the actual operative procedure is still performed as human-hand work. A precise anatomical liver resection still requires meticulous exposure of the boundary of hepatic venous tributaries with deep knowledge of liver anatomy and utilization of intraoperative ultrasonography.
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Christa, Laurence, Marie-Thérèse Simon, Jean-Pierre Flinois, Rolf Gebhardt, Christian Brechot, and Chantal Lasserre. "Overexpression of glutamine synthetase in human primary liver cancer." Gastroenterology 106, no. 5 (May 1994): 1312–20. http://dx.doi.org/10.1016/0016-5085(94)90024-8.
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Liu, Yewei, Shuncong Wang, Xiaohui Zhao, Yuanbo Feng, Guy Bormans, Johan Swinnen, Raymond Oyen, Gang Huang, Yicheng Ni, and Yue Li. "Predicting Clinical Efficacy of Vascular Disrupting Agents in Rodent Models of Primary and Secondary Liver Cancers: An Overview with Imaging-Histopathology Correlation." Diagnostics 10, no. 2 (January 31, 2020): 78. http://dx.doi.org/10.3390/diagnostics10020078.
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Vascular disrupting agents (VDAs) have entered clinical trials for over 15 years. As the leading VDA, combretastatin A4 phosphate (CA4P) has been evaluated in combination with chemotherapy and molecular targeting agents among patients with ovarian cancer, lung cancer and thyroid cancer, but still remains rarely explored in human liver cancers. To overcome tumor residues and regrowth after CA4P monotherapy, a novel dual targeting pan-anticancer theragnostic strategy, i.e., OncoCiDia, has been developed and shown promise previously in secondary liver tumor models. Animal model of primary liver cancer is time consuming to induce, but of value for more closely mimicking human liver cancers in terms of tumor angiogenesis, histopathological heterogeneity, cellular differentiation, tumor components, cancer progression and therapeutic response. Being increasingly adopted in VDA researches, multiparametric magnetic resonance imaging (MRI) provides imaging biomarkers to reflect in vivo tumor responses to drugs. In this article as a chapter of a doctoral thesis, we overview the construction and clinical relevance of primary and secondary liver cancer models in rodents. Target selection for CA4P therapy assisted by enhanced MRI using hepatobiliary contrast agents (CAs), and therapeutic efficacy evaluated by using MRI with a non-specific contrast agent, dynamic contrast enhanced (DCE) imaging, diffusion weighted imaging (DWI) are also described. We then summarize diverse responses among primary hepatocellular carcinomas (HCCs), secondary liver and pancreatic tumors to CA4P, which appeared to be related to tumor size, vascularity, and cellular differentiation. In general, imaging-histopathology correlation studies allow to conclude that CA4P tends to be more effective in secondary liver tumors and in more differentiated HCCs, but less effective in less differentiated HCCs and implanted pancreatic tumor. Notably, cirrhotic liver may be responsive to CA4P as well. All these could be instructive for future clinical trials of VDAs.
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Maki, Harufumi, Yoshikuni Kawaguchi, Junichi Arita, Nobuhisa Akamatsu, Junichi Kaneko, Yoshihiro Sakamoto, Kiyoshi Hasegawa, Yasushi Harihara, and Norihiro Kokudo. "Real-time confocal laser endomicroscopic evaluation of primary liver cancer based on human liver autofluorescence." Journal of Surgical Oncology 115, no. 2 (November 4, 2016): 151–57. http://dx.doi.org/10.1002/jso.24491.
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Chenivesse, Xavier, Dominique Franco, and Christian Bréchot. "MDR1 (multidrug resistance) gene expression in human primary liver cancer and cirrhosis." Journal of Hepatology 18, no. 2 (January 1993): 168–72. http://dx.doi.org/10.1016/s0168-8278(05)80243-0.
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Kung, Janet W. C., Ian S. Currie, Stuart J. Forbes, and James A. Ross. "Liver Development, Regeneration, and Carcinogenesis." Journal of Biomedicine and Biotechnology 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/984248.
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The identification of putative liver stem cells has brought closer the previously separate fields of liver development, regeneration, and carcinogenesis. Significant overlaps in the regulation of these processes are now being described. For example, studies in embryonic liver development have already provided the basis for directed differentiation of human embryonic stem cells and induced pluripotent stem cells into hepatocyte-like cells. As a result, the understanding of the cell biology of proliferation and differentiation in the liver has been improved. This knowledge can be used to improve the function of hepatocyte-like cells for drug testing, bioartificial livers, and transplantation. In parallel, the mechanisms regulating cancer cell biology are now clearer, providing fertile soil for novel therapeutic approaches. Recognition of the relationships between development, regeneration, and carcinogenesis, and the increasing evidence for the role of stem cells in all of these areas, has sparked fresh enthusiasm in understanding the underlying molecular mechanisms and has led to new targeted therapies for liver cirrhosis and primary liver cancers.
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Liu, Nian, Zhipeng Meng, Guiyu Lou, Weiping Zhou, Xiaoqiong Wang, Yunfeng Zhang, Lisheng Zhang, et al. "Hepatocarcinogenesis in FXR−/− Mice Mimics Human HCC Progression That Operates through HNF1α Regulation of FXR Expression." Molecular Endocrinology 26, no. 5 (May 1, 2012): 775–85. http://dx.doi.org/10.1210/me.2011-1383.
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Abstract Farnesoid X receptor (FXR) (nuclear receptor subfamily 1, group H, member 4) is a member of nuclear hormone receptor superfamily, which plays essential roles in metabolism of bile acids, lipid, and glucose. We previously showed spontaneously hepatocarcinogenesis in aged FXR−/− mice, but its relevance to human hepatocellular carcinoma (HCC) is unclear. Here, we report a systematical analysis of hepatocarcinogenesis in FXR−/− mice and FXR expression in human liver cancer. In this study, liver tissues obtained from FXR−/− and wild-type mice at different ages were compared by microarray gene profiling, histological staining, chemical analysis, and quantitative real-time PCR. Primary hepatic stellate cells and primary hepatocytes isolated from FXR−/− and wild-type mice were also analyzed and compared. The results showed that the altered genes in FXR−/− livers were mainly related to metabolism, inflammation, and fibrosis, which suggest that hepatocarcinogenesis in FXR−/− mice recapitulated the progression of human liver cancer. Indeed, FXR expression in human HCC was down-regulated compared with normal liver tissues. Furthermore, the proinflammatory cytokines, which were up-regulated in human HCC microenvironment, decreased FXR expression by inhibiting the transactivity of hepatic nuclear factor 1α on FXR gene promoter. Our study thereby demonstrates that the down-regulation of FXR has an important role in human hepatocarcinogenesis and FXR−/− mice provide a unique animal model for HCC study.
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Gong, Yongling. "Therapy response of Chinese herbal medicine in primary liver cancer." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 488. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.488.
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488 Background: Aiming at starting the ball rolling and contributing humble effort to promote Chinese traditional medicine, we report successful cases of Chinese herbal decoction for primary liver cancer. Methods: Conventional therapy of surgical resection and artery catheterization chemotherapy was applied in cases reported. In the meantime, we administered Chinese medicine (Gan Decoction, mixed with a variety of effective herbal components) to help them to recover from poor condition. Results: After taking the Chinese herbal decoction for months, the tumour marker (AFP, CA19-9) level dramatically decreased to the normal range. Most residual intrahepatic metastatic sites reduced according to ultrasonography/CT imaging, and the patient felt free from the complaint of abdominal discomfort. The quality of life has been greatly improved, we managed to have prolonged the PFS (Progression-Free-Survival) and TTP (Time-to-Progression) from the onset to date. Conclusions: Chinese medicine considers human body as a dynamic platform in which all organs are correlative and bind each other. Each case showed distinguished liver cancer progression and heterogeneity with individual therapy response. Our report suggested that Chinese herbs might be an additional choice with its better benefits and tolerability in the treatment of primary liver cancer.
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Franko, Andras, Sonja Hartwig, Jörg Kotzka, Marc Ruoß, Andreas K. Nüssler, Alfred Königsrainer, Hans-Ulrich Häring, Stefan Lehr, and Andreas Peter. "Identification of the Secreted Proteins Originated from Primary Human Hepatocytes and HepG2 Cells." Nutrients 11, no. 8 (August 3, 2019): 1795. http://dx.doi.org/10.3390/nu11081795.
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The liver plays a pivotal role in whole-body carbohydrate, lipid, and protein metabolism. One of the key regulators of glucose and lipid metabolism are hepatokines, which are found among the liver secreted proteins, defined as liver secretome. To elucidate the composition of the human liver secretome and identify hepatokines in primary human hepatocytes (PHH), we conducted comprehensive protein profiling on conditioned medium (CM) of PHH. Secretome profiling using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS) identified 691 potential hepatokines in PHH. Subsequently, pathway analysis assigned these proteins to acute phase response, coagulation, and complement system pathways. The secretome of PHH was compared to the secreted proteins of the liver hepatoma cell line HepG2. Although the secretome of PHH and HepG2 cells show a high overlap, the HepG2 secretome rather mirrors the fetal liver with some cancer characteristics. Collectively, our study represents one of the most comprehensive secretome profiling approaches for PHH, allowing new insights into the composition of the secretome derived from primary human material, and points out strength and weakness of using HepG2 cell secretome as a model for the analysis of the human liver secretome.
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Leroy, Kaat, Cícero Júlio Silva Costa, Alanah Pieters, Bruna dos Santos Rodrigues, Raf Van Campenhout, Axelle Cooreman, Andrés Tabernilla, Bruno Cogliati, and Mathieu Vinken. "Expression and Functionality of Connexin-Based Channels in Human Liver Cancer Cell Lines." International Journal of Molecular Sciences 22, no. 22 (November 10, 2021): 12187. http://dx.doi.org/10.3390/ijms222212187.
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Liver cancer cell lines are frequently used in vitro tools to test candidate anti-cancer agents as well as to elucidate mechanisms of liver carcinogenesis. Among such mechanisms is cellular communication mediated by connexin-based gap junctions. The present study investigated changes in connexin expression and gap junction functionality in liver cancer in vitro. For this purpose, seven human liver cancer cell lines, as well as primary human hepatocytes, were subjected to connexin and gap junction analysis at the transcriptional, translational and activity level. Real-time quantitative reverse transcription polymerase chain reaction analysis showed enhanced expression of connexin43 in the majority of liver cancer cell lines at the expense of connexin32 and connexin26. Some of these changes were paralleled at the protein level, as evidenced by immunoblot analysis and in situ immunocytochemistry. Gap junctional intercellular communication, assessed by the scrape loading/dye transfer assay, was generally low in all liver cancer cell lines. Collectively, these results provide a full scenario of modifications in hepatocyte connexin production and gap junction activity in cultured liver cancer cell lines. The findings may be valuable for the selection of neoplastic hepatocytes for future mechanistic investigation and testing of anti-cancer drugs that target connexins and their channels.
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Adachi, Y., H. Yamamoto, F. Itoh, Y. Hinoda, Y. Okada, and K. Imai. "Contribution of matrilysin (MMP-7) to the metastatic pathway of human colorectal cancers." Gut 45, no. 2 (August 1, 1999): 252–58. http://dx.doi.org/10.1136/gut.45.2.252.
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BACKGROUND/AIMMatrilysin is one of the matrix metalloproteinases that has a critical role in tumour invasion, and is often expressed in gastrointestinal cancers. The aim of this study was to examine the role of matrilysin in metastasis of human colorectal cancers.PATIENTS (SUBJECTS)/METHODSThe relation between matrilysin expression and Dukes’s type was investigated immunohistochemically in 83 surgically resected colorectal cancers, including five with liver metastasis. Moreover, the effects of matrilysin on the in vivo invasive and metastatic potential of colon cancer cells transfected with matrilysin cDNA were examined after subcutaneous injection into SCID mice.RESULTSIn 46% of primary and all of metastatic liver tumours, over 10% of cancer cells were stained positively for matrilysin. The expression of matrilysin correlated significantly with the presence of nodal or distant metastases (p<0.05). In addition, matrilysin transfectants formed invasive tumours and multiple liver metastases in SCID mice, without producing any significant difference in the subcutaneous tumour growth from mock transfectants. Casein zymography showed that the invading and metastasised tumours showed conspicuous matrilysin activity, which correlated with the number of metastatic lesions (p<0.001).CONCLUSIONSMatrilysin showed a correlation with metastasis in a cohort of 83 colorectal cancer patients and marked metastatic potentiation in human colorectal cancer xenografts, indicating that it may play a critical role in the metastatic pathway of colorectal cancers.
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Krishnamurthy, Shivani, David Gilot, Seong Beom Ahn, Vincent Lam, Joo-Shik Shin, Gilles Jackie Guillemin, and Benjamin Heng. "Involvement of Kynurenine Pathway in Hepatocellular Carcinoma." Cancers 13, no. 20 (October 15, 2021): 5180. http://dx.doi.org/10.3390/cancers13205180.
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As the second and third leading cancer-related death in men and the world, respectively, primary liver cancer remains a major concern to human health. Despite advances in diagnostic technology, patients with primary liver cancer are often diagnosed at an advanced stage. Treatment options for patients with advanced hepatocarcinoma (HCC) are limited to systemic treatment with multikinase inhibitors and immunotherapy. Furthermore, the 5-year survival rate for these late-stage HCC patients is approximately 12% worldwide. There is an unmet need to identify novel treatment options and/or sensitive blood-based biomarker(s) to detect this cancer at an early stage. Given that the liver harbours the largest proportion of immune cells in the human body, understanding the tumour–immune microenvironment has gained increasing attention as a potential target to treat cancer. The kynurenine pathway (KP) has been proposed to be one of the key mechanisms used by the tumour cells to escape immune surveillance for proliferation and metastasis. In an inflammatory environment such as cancer, the KP is elevated, suppressing local immune cell populations and enhancing tumour growth. In this review, we collectively describe the roles of the KP in cancer and provide information on the latest research into the KP in primary liver cancer.
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Lee, Ai Qi, Yan Li, and Zhiyuan Gong. "Inducible Liver Cancer Models in Transgenic Zebrafish to Investigate Cancer Biology." Cancers 13, no. 20 (October 14, 2021): 5148. http://dx.doi.org/10.3390/cancers13205148.
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Primary liver cancer is one of the most prevalent and deadly cancers, which incidence continues to increase while treatment response remains poor; thus, in-depth understanding of tumour events is necessary to develop more effective therapies. Animal models for liver cancer are powerful tools to reach this goal. Over the past decade, our laboratory has established multiple oncogene transgenic zebrafish lines that can be robustly induced to develop liver cancer. Histological, transcriptomic and molecular analyses validate the use of these transgenic zebrafish as experimental models for liver cancer. In this review, we provide a comprehensive summary of our findings with these inducible zebrafish liver cancer models in tumour initiation, oncogene addiction, tumour microenvironment, gender disparity, cancer cachexia, drug screening and others. Induced oncogene expression causes a rapid change of the tumour microenvironment such as inflammatory responses, increased vascularisation and rapid hepatic growth. In several models, histologically-proven carcinoma can be induced within one week of chemical inducer administration. Interestingly, the induced liver tumours show the ability to regress when the transgenic oncogene is suppressed by the withdrawal of the chemical inducer. Like human liver cancer, there is a strong bias of liver cancer severity in male zebrafish. After long-term tumour progression, liver cancer-bearing zebrafish also show symptoms of cancer cachexia such as muscle-wasting. In addition, the zebrafish models have been used to screen for anti-metastasis drugs as well as to evaluate environmental toxicants in carcinogenesis. These findings demonstrated that these inducible zebrafish liver cancer models provide rapid and convenient experimental tools for further investigation of fundamental cancer biology, with the potential for the discovery of new therapeutic approaches.
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Lee, Ai Qi, Yan Li, and Zhiyuan Gong. "Inducible Liver Cancer Models in Transgenic Zebrafish to Investigate Cancer Biology." Cancers 13, no. 20 (October 14, 2021): 5148. http://dx.doi.org/10.3390/cancers13205148.
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Primary liver cancer is one of the most prevalent and deadly cancers, which incidence continues to increase while treatment response remains poor; thus, in-depth understanding of tumour events is necessary to develop more effective therapies. Animal models for liver cancer are powerful tools to reach this goal. Over the past decade, our laboratory has established multiple oncogene transgenic zebrafish lines that can be robustly induced to develop liver cancer. Histological, transcriptomic and molecular analyses validate the use of these transgenic zebrafish as experimental models for liver cancer. In this review, we provide a comprehensive summary of our findings with these inducible zebrafish liver cancer models in tumour initiation, oncogene addiction, tumour microenvironment, gender disparity, cancer cachexia, drug screening and others. Induced oncogene expression causes a rapid change of the tumour microenvironment such as inflammatory responses, increased vascularisation and rapid hepatic growth. In several models, histologically-proven carcinoma can be induced within one week of chemical inducer administration. Interestingly, the induced liver tumours show the ability to regress when the transgenic oncogene is suppressed by the withdrawal of the chemical inducer. Like human liver cancer, there is a strong bias of liver cancer severity in male zebrafish. After long-term tumour progression, liver cancer-bearing zebrafish also show symptoms of cancer cachexia such as muscle-wasting. In addition, the zebrafish models have been used to screen for anti-metastasis drugs as well as to evaluate environmental toxicants in carcinogenesis. These findings demonstrated that these inducible zebrafish liver cancer models provide rapid and convenient experimental tools for further investigation of fundamental cancer biology, with the potential for the discovery of new therapeutic approaches.
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Broutier, Laura, Gianmarco Mastrogiovanni, Monique MA Verstegen, Hayley E. Francies, Lena Morrill Gavarró, Charles R. Bradshaw, George E. Allen, et al. "Human primary liver cancer–derived organoid cultures for disease modeling and drug screening." Nature Medicine 23, no. 12 (November 13, 2017): 1424–35. http://dx.doi.org/10.1038/nm.4438.
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Goubran, Mariam, Weiwei Wang, Stanislav Indik, Alexander Faschinger, Shawn T. Wasilenko, Jasper Bintner, Eric J. Carpenter, et al. "Isolation of a Human Betaretrovirus from Patients with Primary Biliary Cholangitis." Viruses 14, no. 5 (April 24, 2022): 886. http://dx.doi.org/10.3390/v14050886.
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A human betaretrovirus (HBRV) has been linked with the autoimmune liver disease, primary biliary cholangitis (PBC), and various cancers, including breast cancer and lymphoma. HBRV is closely related to the mouse mammary tumor virus, and represents the only exogenous betaretrovirus characterized in humans to date. Evidence of infection in patients with PBC has been demonstrated through the identification of proviral integration sites in lymphoid tissue, the major reservoir of infection, as well as biliary epithelium, which is the site of the disease process. Accordingly, we tested the hypothesis that patients with PBC harbor a transmissible betaretrovirus by co-cultivation of PBC patients’ lymph node homogenates with the HS578T breast cancer line. Because of the low level of HBRV replication, betaretrovirus producing cells were subcloned to optimize viral isolation and production. Evidence of infection was provided by electron microscopy, RT-PCR, in situ hybridization, cloning of the HBRV proviral genome and demonstration of more than 3400 integration sites. Further evidence of viral transmissibility was demonstrated by infection of biliary epithelial cells. While HBRV did not show a preference for integration proximal to specific genomic features, analyses of common insertion sites revealed evidence of integration proximal to cancer associated genes. These studies demonstrate the isolation of HBRV with features similar to mouse mammary tumor virus and confirm that patients with PBC display evidence of a transmissible viral infection.
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Goubran, Mariam, Weiwei Wang, Stanislav Indik, Alexander Faschinger, Shawn T. Wasilenko, Jasper Bintner, Eric J. Carpenter, et al. "Isolation of a Human Betaretrovirus from Patients with Primary Biliary Cholangitis." Viruses 14, no. 5 (April 24, 2022): 886. http://dx.doi.org/10.3390/v14050886.
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A human betaretrovirus (HBRV) has been linked with the autoimmune liver disease, primary biliary cholangitis (PBC), and various cancers, including breast cancer and lymphoma. HBRV is closely related to the mouse mammary tumor virus, and represents the only exogenous betaretrovirus characterized in humans to date. Evidence of infection in patients with PBC has been demonstrated through the identification of proviral integration sites in lymphoid tissue, the major reservoir of infection, as well as biliary epithelium, which is the site of the disease process. Accordingly, we tested the hypothesis that patients with PBC harbor a transmissible betaretrovirus by co-cultivation of PBC patients’ lymph node homogenates with the HS578T breast cancer line. Because of the low level of HBRV replication, betaretrovirus producing cells were subcloned to optimize viral isolation and production. Evidence of infection was provided by electron microscopy, RT-PCR, in situ hybridization, cloning of the HBRV proviral genome and demonstration of more than 3400 integration sites. Further evidence of viral transmissibility was demonstrated by infection of biliary epithelial cells. While HBRV did not show a preference for integration proximal to specific genomic features, analyses of common insertion sites revealed evidence of integration proximal to cancer associated genes. These studies demonstrate the isolation of HBRV with features similar to mouse mammary tumor virus and confirm that patients with PBC display evidence of a transmissible viral infection.
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Rajput, Ashwani, Ekta Agarwal, Premila Leiphrakpam, Michael G. Brattain, and Sanjib Chowdhury. "Establishment and Validation of an Orthotopic Metastatic Mouse Model of Colorectal Cancer." ISRN Hepatology 2013 (April 21, 2013): 1–9. http://dx.doi.org/10.1155/2013/206875.
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Metastases are largely responsible for cancer deaths in solid tumors due to the lack of effective therapies against disseminated disease, and there is an urgent need to fill this gap. This study demonstrates an orthotopic colorectal cancer (CRC) mouse model system to develop spontaneous metastasis in vivo and compare its reproducibility against human CRC. IGF1R-dependent GEO human CRC cells were used to study metastatic colonization using orthotopic transplantation procedures and demonstrated robust liver metastasis. Cell proliferation assays were performed both in the orthotopic primary colon and liver metastatic tumors, and human CRC patient’s specimen and similar patterns in H&E and Ki67 staining were observed between the orthotopically generated primary and liver metastatic tumors and human CRC specimens. Microarray analysis was performed to generate gene signatures, compared with deposited human CRC gene expression data sets, analyzed by Oncomine, and revealed similarity in gene signatures with increased aggressive markers expression associated with CRC in orthotopically generated liver metastasis. Thus, we have developed an orthotopic mouse model that reproduces human CRC metastasis. This model system can be effective in developing new therapeutic strategies against disseminated disease and could be implemented for identifying genes that regulate the development and/or maintenance of established metastasis.
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Ágoston, Emese Irma, Balazs Acs, Zoltan Herold, Krisztina Fekete, Janina Kulka, Akos Nagy, Dorottya Mühl, et al. "Deconstructing Immune Cell Infiltration in Human Colorectal Cancer: A Systematic Spatiotemporal Evaluation." Genes 13, no. 4 (March 25, 2022): 589. http://dx.doi.org/10.3390/genes13040589.
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Cancer-related immunity has been identified as playing a key role in the outcome of colorectal cancer (CRC); however, the exact mechanisms are only partially understood. In this study, we evaluated a total of 242 surgical specimen of CRC patients using tissue microarrays and immunohistochemistry to evaluate tumor infiltrating immune cells (CD3, CD4, CD8, CD20, CD23, CD45 and CD56) and immune checkpoint markers (CTLA-4, PD-L1, PD-1) in systematically selected tumor regions and their corresponding lymph nodes, as well as in liver metastases. Additionally, an immune panel gene expression assay was performed on 12 primary tumors and 12 consecutive liver metastases. A higher number of natural killer cells and more mature B cells along with PD-1+ expressing cells were observed in the main tumor area as compared to metastases. A higher number of metastatic lymph nodes were associated with significantly lower B cell counts. With more advanced lymph node metastatic status, higher leukocyte—particularly T cell numbers—were observed. Eleven differentially expressed immune-related genes were found between primary tumors and liver metastases. Also, alterations of the innate immune response and the tumor necrosis factor superfamily pathways had been identified.
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Ringehan, Marc, Jane A. McKeating, and Ulrike Protzer. "Viral hepatitis and liver cancer." Philosophical Transactions of the Royal Society B: Biological Sciences 372, no. 1732 (September 11, 2017): 20160274. http://dx.doi.org/10.1098/rstb.2016.0274.
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Hepatitis B and C viruses are a global health problem causing acute and chronic infections that can lead to liver cirrhosis and hepatocellular carcinoma (HCC). These infections are the leading cause for HCC worldwide and are associated with significant mortality, accounting for more than 1.3 million deaths per year. Owing to its high incidence and resistance to treatment, liver cancer is the second leading cause of cancer-related death worldwide, with HCC representing approximately 90% of all primary liver cancer cases. The majority of viral-associated HCC cases develop in subjects with liver cirrhosis; however, hepatitis B virus infection can promote HCC development without prior end-stage liver disease. Thus, understanding the role of hepatitis B and C viral infections in HCC development is essential for the future design of treatments and therapies for this cancer. In this review, we summarize the current knowledge on hepatitis B and C virus hepatocarcinogenesis and highlight direct and indirect risk factors. This article is part of the themed issue ‘Human oncogenic viruses’.
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Wang, Haichuan, Diego F. Calvisi, and Xin Chen. "Organoids for the Study of Liver Cancer." Seminars in Liver Disease 41, no. 01 (January 2021): 019–27. http://dx.doi.org/10.1055/s-0040-1719176.
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AbstractLiver cancer is the second most lethal malignancy worldwide. Cell lines and murine models are the most common tools for modeling human liver carcinogenesis. Most recently, organoids with a three-dimensional structure derived from primary tissues or cells have been applied to liver cancer research. Organoids can be generated from induced pluripotent stem cells, embryonic or adult, healthy or diseased tissues. In particular, liver organoids have been widely employed in mechanistic studies aimed at delineating the molecular pathways responsible for hepatocarcinogenesis. The introduction of clustered regularly interspaced palindromic repeats (CRISPR)-associated protein 9 (Cas9) and microengineered miniorganoid technologies into liver organoids for cancer study has significantly accelerated these investigations. Translational advances have been made by utilizing liver tumor organoids for anticancer drug screening, biobanking, omics profiling, and biomarker discovery. This review summarizes the latest advances and the remaining challenges in the use of organoid models for the study of liver cancer.
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Besbes, Samaher, Shahid Shah, Iman Al-dybiat, Shahsoltan Mirshahi, Helene Helfer, Haythem Najah, Caroline Fourgeaud, et al. "Thrombopoietin Secretion by Human Ovarian Cancer Cells." International Journal of Cell Biology 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/1873834.
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The thrombopoietin (TPO) gene expression in human ovary and cancer cells from patients with ovarian carcinomatosis, as well as several cancer cell lines including MDA-MB231 (breast cancer), K562 and HL60 (Leukemic cells), OVCAR-3NIH and SKOV-3 (ovarian cancer), was performed using RT PCR, real-time PCR, and gene sequencing. Human liver tissues are used as controls. The presence of TPO in the cells and its regulation by activated protein C were explored by flow cytometry. TPO content of cell extract as well as plasma of a patient with ovarian cancer was evaluated by ELISA. The functionality of TPO was performed in coculture on the basis of the viability of a TPO-dependent cell line (Ba/F3), MTT assay, and Annexin-V labeling. As in liver, ovarian tissues and all cancer cells lines except the MDA-MB231 express the three TPO-1 (full length TPO), TPO-2 (12 bp deletion), and TPO-3 (116 pb deletion) variants. Primary ovarian cancer cells as well as cancer cell lines produce TPO. The thrombopoietin production by OVCAR-3 increased when cells are stimulated by aPC. OVCAR-3 cell’s supernatant can replace exogenous TPO and inhibited TPO-dependent cell line (Ba/F3) apoptosis. The thrombopoietin produced by tumor may have a direct effect on thrombocytosis/thrombosis occurrence in patients with ovarian cancer.
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Zhang, Guangzhi, Kiandokht Bashiri, Mark Kneteman, Kevan Cave, Youngkee Hong, John R. Mackey, Harvey J. Alter, and Andrew L. Mason. "Seroprevalence of Human Betaretrovirus Surface Protein Antibodies in Patients with Breast Cancer and Liver Disease." Journal of Oncology 2020 (January 27, 2020): 1–9. http://dx.doi.org/10.1155/2020/8958192.
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Mouse mammary tumor virus (MMTV) is a betaretrovirus that plays a causal role in the development of breast cancer and lymphoma in mice. Closely related sequences that share 91–99% nucleotide identity with MMTV have been repeatedly found in humans with neoplastic and inflammatory diseases. Evidence for infection with a betaretrovirus has been found in patients with breast cancer and primary biliary cholangitis and referred to as the human mammary tumor virus and the human betaretrovirus (HBRV), respectively. Using the gold standard technique of demonstrating retroviral infection, HBRV proviral integrations have been detected in cholangiocytes, lymph nodes, and liver of patients with primary biliary cholangitis. However, the scientific biomedical community has not embraced the hypothesis that MMTV like betaretroviruses may infect humans because reports of viral detection have been inconsistent and robust diagnostic assays are lacking. Specifically, prior serological assays using MMTV proteins have produced divergent results in human disease. Accordingly, a partial HBRV surface (Su) construct was transfected into HEK293 to create an ELISA. The secreted HBRV gp52 Su protein was then used to screen for serological responses in patients with breast cancer and liver disease. A greater proportion of breast cancer patients (n = 98) were found to have serological reactivity to HBRV Su as compared to age- and sex-matched control subjects (10.2% versus 2.0%, P=0.017, OR = 5.6 [1.25–26.3]). Similarly, the frequency of HBRV Su reactivity was higher in patients with primary biliary cholangitis (n = 156) as compared to blood donors (11.5% vs. 3.1%, P=0.0024, OR = 4.09 [1.66–10.1]). While the sensitivity of the HBRV Su ELISA was limited, the assay was highly specific for serologic detection in patients with breast cancer or primary biliary cholangitis, respectively (98.0% [93.1%–99.7%] and 97.0% [93.4%–98.6%]). Additional assays will be required to link immune response to betaretrovirus infection and either breast cancer or primary biliary cholangitis.
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Wadkin, James C. R., Daniel A. Patten, Sivesh K. Kamarajah, Emma L. Shepherd, Vera Novitskaya, Fedor Berditchevski, David H. Adams, Chris J. Weston, and Shishir Shetty. "CD151 supports VCAM-1-mediated lymphocyte adhesion to liver endothelium and is upregulated in chronic liver disease and hepatocellular carcinoma." American Journal of Physiology-Gastrointestinal and Liver Physiology 313, no. 2 (August 1, 2017): G138—G149. http://dx.doi.org/10.1152/ajpgi.00411.2016.
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CD151, a member of the tetraspanin family of receptors, is a lateral organizer and modulator of activity of several families of transmembrane proteins. It has been implicated in the development and progression of several cancers, but its role in chronic inflammatory disease is less well understood. Here we show that CD151 is upregulated by distinct microenvironmental signals in a range of chronic inflammatory liver diseases and in primary liver cancer, in which it supports lymphocyte recruitment. CD151 was highly expressed in endothelial cells of the hepatic sinusoids and neovessels developing in fibrotic septa and tumor margins. Primary cultures of human hepatic sinusoidal endothelial cells (HSECs) expressed CD151 at the cell membrane and in intracellular vesicles. CD151 was upregulated by VEGF and HepG2 conditioned media but not by proinflammatory cytokines. Confocal microscopy confirmed that CD151 colocalized with the endothelial adhesion molecule/immunoglobulin superfamily member, VCAM-1. Functional flow-based adhesion assays with primary human lymphocytes and HSECs demonstrated a 40% reduction of lymphocyte adhesion with CD151 blockade. Inhibition of lymphocyte adhesion was similar between VCAM-1 blockade and a combination of CD151/VCAM-1 blockade, suggesting a collaborative role between the two receptors. These studies demonstrate that CD151 is upregulated within the liver during chronic inflammation, where it supports lymphocyte recruitment via liver endothelium. We propose that CD151 regulates the activity of VCAM-1 during lymphocyte recruitment to the human liver and could be a novel anti-inflammatory target in chronic liver disease and hepatocellular cancer prevention. NEW & NOTEWORTHY Chronic hepatitis is characterized by lymphocyte accumulation in liver tissue, which drives fibrosis and carcinogenesis. Here, we demonstrate for the first time that the tetraspanin CD151 supports lymphocyte adhesion to liver endothelium. We show that CD151 is upregulated in chronic liver disease and hepatocellular carcinoma (HCC) and is regulated on endothelium by tissue remodeling and procarcinogenic factors. These regulatory and functional studies identify CD151 as a potential therapeutic target to treat liver fibrosis and HCC.
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Grossman, Julie G., Timothy M. Nywening, Brian Belt, Elizabeth Pittman, Andrew Giorgi, Ahlers Michael, William G. Hawkins, et al. "The role of inflammatory monocytes in human metastatic colorectal cancer." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 624. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.624.
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624 Background: Colorectal cancer (CRC) is the most common gastrointestinal malignancy. 60% of CRC patients are diagnosed with metastatic (m) CRC and the 5-year survival is <20%. Myeloid cells, particularly inflammatory monocytes (IM), are recruited from the bone marrow to the tumor microenvironment where they become tumor associated macrophages and play a crucial role in tumor progression, metastasis, and chemoresistance. While the importance of IM have been shown in other malignancies, little is known about their role in human CRC. Methods: Human tissue was collected under an IRB approved protocol at Washington University. Flow cytometry was performed on PBMCs and single cell suspensions of normal tissue and tumor samples. Qualitative RT-PCR and confocal microscopy were performed for CCL2. T-cell suppression assays were performed using CD14+ IM isolated from patient peripheral blood and tumor samples. Results: Analysis of pre-operative blood revealed that monocyte levels correlate with the extent of disease burden. Monocytes were elevated in CRC patients compared with controls (p<0.0001), additionally patients with liver metastasis had further elevation in monocytes compared with patient’s with primary disease (p=0.01). In metastatic patients, monocyte levels also correlate with survival following resection of hepatic metastasis (p=0.0002). FACS analysis confirmed these findings and demonstrated that the circulating CD11b+/CD14+/CCR2+ subset of IM was responsible for the increase. Both primary CRC and liver mCRC had increased expression of CCL2 compared to uninvolved tissue (p=0.008 and p=0.03, respectively). Production of CCL2 was localized to CRC cells. FACS analysis showed CCR2+ tumor infiltrating macrophages were elevated in CRC liver metastasis compared to adjacent normal liver and a paucity of effector T-cells. CD14+ TAMs isolated from mCRC inhibited T-cell proliferation, illustrating the immune suppressive phenotype of these cells. Conclusions: Inflammatory monocytes correlate to prognosis in mCRC. Therefore, targeting CCR2+ myeloid cells may improve anti-tumor immunity and patient survival in metastatic disease.
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Yang, Hai-Yan, Hao-Ling Liu, Lan-Tian Tian, Rui-Peng Song, Xuan Song, Da-Long Yin, Ying-Jian Liang, et al. "Expression and prognostic value of ING3 in human primary hepatocellular carcinoma." Experimental Biology and Medicine 237, no. 4 (April 2012): 352–61. http://dx.doi.org/10.1258/ebm.2011.011346.
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The tumor-suppressor ING3 has been shown to be involved in tumor transcriptional regulation, apoptosis and the cell cycle. Some studies have demonstrated that ING3 is dysregulated in several types of cancers. However, the expression and function of ING3 in human hepatocellular carcinoma (HCC) remains unclear. The aim of this study is to investigate ING3 expression in hepatic tumors and its clinical relevance in hepatic cancer. The expression of ING3 protein was examined in 120 dissected HCC tissues and 47 liver tissues adjacent to the tumor by immunohistochemical assays and confirmed by Western blot analysis in 20 paired frozen tumor and non-tumor liver tissues. The relationship between ING3 staining and clinico-pathological characteristics of HCC was further analyzed. The mRNA expression of ING3 in the dissected tissues was also analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) and realtime PCR. Both mRNA and protein concentrations of ING3 were found to be downregulated in the majority of HCC tumors in comparison with matched non-tumor hepatic tissues. Analysis of the relationship between ING3 staining and clinico-pathological characteristics of HCC showed that the low expression of ING3 protein is correlated with more aggressive behavior of the tumor. Kaplan–Meier curves demonstrated that patients with a low expression of ING3 have a significantly increased risk of shortened survival time. In addition, multivariate analysis suggested that the level of ING3 expression may be an independent prognostic factor. Our findings indicate that ING3 may be an important marker for human hepatocellular carcinoma progression and prognosis, as well as a potential therapeutic target.
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Yu, Jianing, Yuanyuan Hong, Pei Zhihua, Tiancheng Han, Song Xiaofeng, Xue Song, Wang Xiaoqing, Zhang Zhuo, Weizhi Chen, and Ji He. "DNA methylation profile in unknown cancer origin identification: A multi-class classification model." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e13554-e13554. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e13554.
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e13554 Background: Approximately 3-5% of human cancers are cancer of unknown primary (CUP). Treatment of a cancer patient is largely dependent on the tumor origin. Therefore, identification of the tumor origin can improve the survival of patients with CUP. We developed a multi-class classification model using DNA methylation profile as biomarker to determine the primary site of CUP. Methods: We split 7,082 primary tumor samples of 19 cancers and 679 normal samples of 15 tissues from TCGA into a 75% training set and a 25% testing set to develop the classification model. We started with multiple support vector machine (SVM) models, and then combined them into an optimal multi-class ensemble model. Predictors included tumor-specific markers and tissue-specific markers, which were filtered by comparing between groups. Only the training samples were used for feature selection and model development. A validation dataset consisting of 150 primary tissues, 54 metastasis tissues, 105 plasma samples with known cancer site origins from 12 classes was generated in house by a self-designed panel. Performance was measured by area under the curve (AUC) using the one-vs-all approach. Results: 7,453 tumor-specific and 1,533 tissue-specific markers were selected for model construction. AUCs of all cancer types were high in TCGA training and testing set (AUC≥0.96 for all classes). In our validation tissues, esophageal cancer, pancreatic cancer, colorectal cancer, lung adenocarcinoma, breast cancer and liver cancer achieved high AUC in both primary (0.83, 0.83, 0.82, 0.82, 0.80 and 0.79 respectively) and metastasis (0.74, 0.92, 0.86, 0.61, 0.92 and 0.65 respectively). Lung adenocarcinoma, colorectal cancer, liver cancer, breast cancer and esophageal cancer even achieved high AUC in the plasmas. Conclusions: Performance of our model in tissue and plasma samples indicated the potential clinical application of DNA methylation profile in unknown cancer origin identification.
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Sharma, Rajesh. "Descriptive epidemiology of incidence and mortality of primary liver cancer in 185 countries: evidence from GLOBOCAN 2018." Japanese Journal of Clinical Oncology 50, no. 12 (July 28, 2020): 1370–79. http://dx.doi.org/10.1093/jjco/hyaa130.
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Abstract Purpose This study aims to examine the burden of primary liver cancer in 185 countries in 2018. Methods The estimates of incidence, mortality and prevalence of primary liver cancer were procured from GLOBOCAN 2018. The development status of a country was measured using the human development index—a composite indicator of income per capita, education and life expectancy. Results Globally, primary liver cancer resulted in an estimated 781 631 deaths at age-standardized mortality rate of 8.5/100 000, and 841 080 cases were estimated to be diagnosed in 2018. Males accounted for 596 574 cases and 548 375 deaths, which is more than twice the burden of primary liver cancer in females (cases: 244 506; deaths: 233 456). The global age-standardized incidence rate was 9.3/100 000 in 2018, varying from Morocco (1.1/100 000) to Mongolia (93.7/100 000). There were remarkable variations in terms of age-standardized mortality rate, too, which ranged from 1/100 000 in Nepal to 75.4/100 000 in Mongolia. East Asia was the top region contributing 55.6% of global cases and 54.7% of global deaths. Conclusions Since majority of the primary liver cancer burden pertains to hepatocellular carcinoma and screening approaches are yet to be fully proven, the policy focus must be on prevention approaches through the hepatitis-B vaccine, early detection of hepatitis-C infection, reduced alcohol consumption, obesity control, reduced aflatoxin exposure and containment of other modifiable risk factors.
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Ullman, Nicholas A., Luis I. Ruffolo, Katherine M. Jackson, Alexander Chacon, Rachel Jewell, Mary Georger, Brian A. Belt, and David Linehan. "Association of CXCR2+ granulocytic myeloid derived suppressor cells with the development of cholangiocarcinoma: A possible target for intervention." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): 565. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.565.
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565 Background: Cholangiocarcinoma (CCA) is the second most common primary liver malignancy, with increasing incidence. Currently, surgical resection offers the only chance for cure, however the prognosis remains poor in part due to high rates of unresectability, recurrence, and poor response to conventional therapy. Thus, new systemic therapies represent an unmet medical need. Few preclinical models exist for identifying and testing new targeted or immune based therapies. Here we present our findings of the immune infiltrate in human CCA tumor microenvironment (TME) and a spontaneous murine model that faithfully recapitulates human disease. Methods: Histology and immunohistochemistry (IHC) staining was performed on human CCA and adjacent normal liver. Mice with targeted hepatic Kras activation and loss of p53 (KPPC) spontaneously develop CCA. KPPC hepatic tumors and normal livers from littermate controls underwent histological and gene expression studies. Flow cytometric analysis was performed on bone marrow, spleen, peripheral blood, CCA tumors and normal littermate livers. Results: Digital IHC quantification of archival human CCA specimens demonstrated elevated levels of CD15+CXCR2+ granulocytic myeloid derived suppressor cells (G-MDSC) compared to adjacent normal liver (p = < 0.05). In addition, the CXCR2 ligand, CXCL5, was significantly elevated in CCA tumors compared to adjacent normal liver. In KPPC mice, flow cytometric analysis of hepatic tumors showed an abundance of CD45+ leukocytes comprised of immunosuppressive G-MDSC vs normal littermate controls (p = 0.0007) which recapitulates human disease. qRT-PCR demonstrated significantly increased expression of G-csf, Csf1, Cxcl1, Cxcl2, and Cxcl5 (p = < 0.0001) in CCA KPPC tumors compared to normal livers. Accordingly, granulocytes in KPPC mice were elevated in both the bone marrow and blood compared to normal littermate controls. Conclusions: These data suggest CCA co-opts the ELR+ cytokine/CXCR2 axes to mobilize and recruit immunosuppressive G-MDSC to the TME. Targeted therapy against tumor infiltrating neutrophils can be tested in this pre-clinical model to inform clinical translation.
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Duchamp, Olivier, Gael Krysa, Loic Morgand, Hugo Quillery, Robin Artus, Maxime Ramelet, Jeremy Odillard, et al. "Abstract 1654: Mouse models of hepatocellular carcinoma: A comprehensive and functional preclinical platform for immunotherapy research." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1654. http://dx.doi.org/10.1158/1538-7445.am2022-1654.
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Abstract Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death and accounts for over 80% of primary liver cancer worldwide. Early stage HCC can be treated by local ablation, surgical resection or liver transplantation. Systemic pharmacological options are limited (kinase and immune-checkpoint inhibitors). Most cases of liver cancer occur in the setting of chronic liver diseases. Risk factors include chronic Hepatitis B and C, alcohol addiction and metabolic diseases. HCC is a multistep process comprising chronic liver injury, inflammation, fibrosis/cirrhosis and cancer formation. Therefore, providing palliative and curative options remains a high medical need. And with the recent success of immunotherapies in HCC, mouse models that better recapitulate the human disease and antitumor immune response are needed. In order to better evaluate new preventive and curative treatments of liver cancers we developed complementary and integrated strategies to mimic the liver cancer initiation and progression steps in mouse models. These models involve chemotoxic agents, diet-induced disorders and syngeneic or xenogeneic tumor implantation strategies. We established an orthotopic syngeneic model using Hepa1.6 mouse liver hepatoma cells, characterized through liver index, alpha-fetoprotein measurement in serum and liver, and MRI. The response to chemotherapy (sorafenib) and immunotherapy (anti PD-1, anti-TLR) was also assessed and show moderate to high efficiency. Moreover, a panel of xenograft models including Patient-Derived Xenograft models (PDXs) are available to assess new treatment options in human HCC with regards of the genetic mutations and the variety of etiologies seen in human. But as xenograft models are not completely mimicking the human situation of both immune and liver microenvironment, we have recently initiated the development of a double humanized (immune and liver) transgenic mouse as a better host for human tumor engraftment. During the course of HCC formation, the liver undergoes cycles of inflammation, necrosis with regeneration, fibrosis, cell dysplasia and ultimately HCC. Thus, we developed a model induced by a low dose of streptozotocin and high fat diet regimen. In this model, mice develop metabolic syndrome NASH and fibrosis within 12 weeks and HCC within 16 weeks. Of interest, 100% of male mice develop HCC within 16 weeks, in accordance with studies showing that men had a 2-to 7-fold higher risk of developing HCC in human. Treatment of mice with lenvatinib alone or in combination with anti-PD1 increases survival and reduces tumor burden as shown with reduced liver weight/body weight ratio at 16 weeks. Altogether, these results demonstrate the usefulness of this comprehensive platform of preclinical in vivo HCC models to discover and identify novel therapeutic strategies that could circumvent the progression of liver cancers. Citation Format: Olivier Duchamp, Gael Krysa, Loic Morgand, Hugo Quillery, Robin Artus, Maxime Ramelet, Jeremy Odillard, Peggy Provent, Sylvie Maubant, Caroline Mignard, Fabrice Viviani, Samira Benhamouche-Trouillet. Mouse models of hepatocellular carcinoma: A comprehensive and functional preclinical platform for immunotherapy research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1654.
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Hlady, Ryan, and Keith Robertson. "Genetic and Epigenetic Heterogeneity in Normal Liver Homeostasis and Its Implications for Liver Disease and Hepatocellular Cancer." Seminars in Liver Disease 38, no. 01 (February 2018): 041–50. http://dx.doi.org/10.1055/s-0037-1621712.
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AbstractHepatocellular carcinoma (HCC) is the most prevalent primary tumor of the liver, and is steadily becoming one of the most lethal cancers worldwide. Liver resection, which is the recommended procedure for early localized HCC, results in frequent recurrence (50–70%), while the standard of care for late-stage HCC, multikinase inhibitors, only improves survival by a few months. The lack of success for these treatment modalities is attributable, at least in part, to marked phenotypic heterogeneity within the tumor. Intratumoral heterogeneity (ITH) has emerged as a defining characteristic of human tumors, with individual cancer cells displaying distinct differences in properties including growth rate, metastatic capacity, and response to treatment. This heterogeneity, which is unlikely to be captured from a biopsy, impacts outcome because a single treatment targeting one cancer-specific pathway would spare tumor cells having distinct characteristics. Development of effective biomarkers remains a major challenge for similar reasons. Understanding, interpreting, and circumventing the impact of ITH is therefore paramount for developing reliable biomarkers and designing effective individualized treatment strategies for HCC.
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Li, Shipeng, Wenfeng Han, Qichen He, Wei Zhang, and Youcheng Zhang. "Relationship between Intestinal Microflora and Hepatocellular Cancer Based on Gut-Liver Axis Theory." Contrast Media & Molecular Imaging 2022 (August 1, 2022): 1–8. http://dx.doi.org/10.1155/2022/6533628.
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The intestinal microflora is a bacterial group that lives in the human digestive tract and has a long-term interdependence with the host. Due to the close anatomical and functional relationship between the liver and the intestine, the intestinal flora affects liver metabolism via the intestinal-hepatic circulation, thereby playing an extremely important role in the pathological process of liver inflammation, chronic fibrosis, and liver cancer. In recent years, the rapid development of technologies in high-throughput sequencing and genomics has opened up possibilities for a broader and deeper understanding of the crosstalk between the intestinal flora and the occurrence and development of liver cancer. This review aims to summarize the mechanisms by which the gut microbiota changes the body’s metabolism, through the gut-liver axis, thereby affecting the occurrence and development of primary liver cancer. In addition, the potential regulation of intestinal microflora in the treatment of liver cancer is discussed.
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Kamaraju, Sailaja, Jill Depke, Janice Povletich, Adam Currey, and Elizabeth Weil. "Cutaneous Metastasis due to Breast Cancer in a Patient with Primary Biliary Cirrhosis: A Case Report." Case Reports in Oncology 9, no. 3 (November 8, 2016): 718–25. http://dx.doi.org/10.1159/000452145.
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Background: Breast cancer is the most common solid tumor to cause cutaneous metastases. These are incurable and the treatment goal is geared toward local control with surgical excision, radiation, and chemotherapy. However, treatment can be challenging in subjects with end-stage liver disease and a multidisciplinary approach is warranted. Case Report: In this case report, we present a 61-year-old female with primary biliary cirrhosis and human epidermal growth factor-2 (HER-2)-positive breast cancer, who subsequently developed cutaneous metastases. We briefly describe the treatment challenges due to underlying end-stage liver disease, and an exceptional response to trastuzumab and nab-paclitaxel. Conclusion: A multidisciplinary approach to local control and attenuated doses of nab-paclitaxel and trastuzumab suggest a durable response to HER-2-positive breast cancer with cutaneous metastasis. Subjects with end-stage liver disease pose unique challenges and toxicities, warranting additional research and drug development for less hepatotoxic antineoplastic agents.
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Sahu, Biswajyoti, Päivi Pihlajamaa, Kaiyang Zhang, Kimmo Palin, Saija Ahonen, Alejandra Cervera, Ari Ristimäki, Lauri A. Aaltonen, Sampsa Hautaniemi, and Jussi Taipale. "Human cell transformation by combined lineage conversion and oncogene expression." Oncogene 40, no. 36 (July 23, 2021): 5533–47. http://dx.doi.org/10.1038/s41388-021-01940-0.
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AbstractCancer is the most complex genetic disease known, with mutations implicated in more than 250 genes. However, it is still elusive which specific mutations found in human patients lead to tumorigenesis. Here we show that a combination of oncogenes that is characteristic of liver cancer (CTNNB1, TERT, MYC) induces senescence in human fibroblasts and primary hepatocytes. However, reprogramming fibroblasts to a liver progenitor fate, induced hepatocytes (iHeps), makes them sensitive to transformation by the same oncogenes. The transformed iHeps are highly proliferative, tumorigenic in nude mice, and bear gene expression signatures of liver cancer. These results show that tumorigenesis is triggered by a combination of three elements: the set of driver mutations, the cellular lineage, and the state of differentiation of the cells along the lineage. Our results provide direct support for the role of cell identity as a key determinant in transformation and establish a paradigm for studying the dynamic role of oncogenic drivers in human tumorigenesis.
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Kukla, David A., and Salman R. Khetani. "Bioengineered Liver Models for Investigating Disease Pathogenesis and Regenerative Medicine." Seminars in Liver Disease 41, no. 03 (June 17, 2021): 368–92. http://dx.doi.org/10.1055/s-0041-1731016.
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AbstractOwing to species-specific differences in liver pathways, in vitro human liver models are utilized for elucidating mechanisms underlying disease pathogenesis, drug development, and regenerative medicine. To mitigate limitations with de-differentiated cultures, bioengineers have developed advanced techniques/platforms, including micropatterned cocultures, spheroids/organoids, bioprinting, and microfluidic devices, for perfusing cell cultures and liver slices. Such techniques improve mature functions and culture lifetime of primary and stem-cell human liver cells. Furthermore, bioengineered liver models display several features of liver diseases including infections with pathogens (e.g., malaria, hepatitis C/B viruses, Zika, dengue, yellow fever), alcoholic/nonalcoholic fatty liver disease, and cancer. Here, we discuss features of bioengineered human liver models, their uses for modeling aforementioned diseases, and how such models are being augmented/adapted for fabricating implantable human liver tissues for clinical therapy. Ultimately, continued advances in bioengineered human liver models have the potential to aid the development of novel, safe, and efficacious therapies for liver disease.
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Neal, Gordon E. "Further circumstantial evidence for the involvement of aflatoxin in primary liver cancer?" Human & Experimental Toxicology 13, no. 9 (September 1994): 603–4. http://dx.doi.org/10.1177/096032719401300904.
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Fifty-eight percent of hepatocellular carcinomas (HCCs) from Qidong, China, contain an AGG to AGT mutation at codon 249 of the p53 tumour suppressor gene, a mutation that is rarely seen in HCCs from Western countries. The population of Qidong is exposed to high levels of aflatoxin B1(AFB1), a fungal toxin that has been shown to induce the same mutation in cultured human HCC cells. To investigate the role of AFB1 and of these p53 mutations in hepatocarcinogenesis, normal liver samples from the United States, Thailand and Qidong (where AFB1 exposures are negligible, low and high, respectively) were examined for p53 mutations. The frequency of the AGG to AGT mutation at codon 249 paralleled the level of AFB 1 exposure, which supports the hypothesis that this toxin has a causative-and probably early-role in hepatocarcinogenesis.
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Lin, Longfei, Lei Yan, Yuling Liu, Changhai Qu, Jian Ni, and Hui Li. "The Burden and Trends of Primary Liver Cancer Caused by Specific Etiologies from 1990 to 2017 at the Global, Regional, National, Age, and Sex Level Results from the Global Burden of Disease Study 2017." Liver Cancer 9, no. 5 (2020): 563–82. http://dx.doi.org/10.1159/000508568.
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Background: Liver cancer is one of the leading causes of cancer-related deaths worldwide. The primary causes of liver cancer include hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol consumption, nonalcoholic fatty liver disease, and other factors. Aims: The objective of this study was to evaluate the global and sex-, age-, region-, country-, and etiology-related liver cancer burden, as well as the trends in liver cancer caused by different etiologies. Methods: The causes of liver cancer from 1990 to 2017, including global, regional, and national liver cancer incidence, mortality, and etiology, were collected from the Global Burden of Disease study 2017, and the time-dependent change in the trends of liver cancer burden was evaluated by annual percentage change. Results: The global liver cancer incidence and mortality have been increasing. There were 950,000 newly-diagnosed liver cancer cases and over 800,000 deaths in 2017, which is more than twice the numbers recorded in 1990. HBV and HCV are the major causes of liver cancer. HBV is the major risk factor of liver cancer in Asia, while HCV and alcohol abuse are the major risk factors in the high sociodemographic index and high human development index regions. The mean onset age and incidence of liver cancer with different etiologies have gradually increased in the past 30 years. Conclusions: The global incidence is still rising and the causes have national, regional, or population specificities. More targeted prevention strategies must be developed for the different etiologic types in order to reduce liver cancer burden.
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Kim, Tae Suk, Minjong Lee, Minji Park, Sae Yun Kim, Min Suk Shim, Chea Yeon Lee, Dae Hee Choi, and Yuri Cho. "Metformin and Dichloroacetate Suppress Proliferation of Liver Cancer Cells by Inhibiting mTOR Complex 1." International Journal of Molecular Sciences 22, no. 18 (September 17, 2021): 10027. http://dx.doi.org/10.3390/ijms221810027.
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The Warburg effect is important for cancer cell proliferation. This phenomenon can be flexible by interaction between glycolysis and mitochondrial oxidation for energy production. We aimed to investigate the anticancer effects of the pyruvate dehydrogenase kinase inhibitor, dichloroacetate (DCA) and the mitochondrial respiratory complex I inhibitor metformin in liver cancer cells. The anticancer effect of DCA and/or metformin on HepG2, PLC/PRF5 human liver cancer cell lines, MH-134 murine hepatoma cell lines, and primary normal hepatocytes using MTT assay. Inhibition of lactate/ATP production and intracellular reactive oxygen species generation by DCA and metformin was investigated. Inhibition of PI3K/Akt/mTOR complex I was evaluated to see whether it occurred through AMPK signaling. Anticancer effects of a combination treatment of DCA and metformin were evaluated in HCC murine model. The results showed that metformin and DCA effectively induced apoptosis in liver cancer cells. A combination treatment of metformin and DCA did not affect viability of primary normal hepatocytes. Metformin upregulated glycolysis in liver cancer cells, thereby increasing sensitivity to the DCA treatment. Metformin and DCA inhibited mTOR complex I signaling through upregulated AMPK-independent REDD1. In addition, metformin and DCA increased reactive oxygen species levels in liver cancer cells, which induced apoptosis. A combination treatment of metformin and DCA significantly suppressed the tumor growth of liver cancer cells using in vivo xenograft model. Taken together, the combined treatment of metformin and DCA suppressed the growth of liver cancer cells. This strategy may be effective for patients with advanced liver cancer.
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Laes, Jean-François, Luis Antonio Parada, Bertil Johansson, Göran Levan, Claude Szpirer, and Josiane Szpirer. "Alterations of P19ARF in Rodent Hepatoma Cell Lines but not in Human Primary Liver Cancer." Cancer Genetics and Cytogenetics 117, no. 2 (March 2000): 118–24. http://dx.doi.org/10.1016/s0165-4608(99)00157-0.
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Yuzhalin, Arseniy E., Su Yin Lim, Alex N. Gordon-Weeks, Roman Fischer, Benedikt M. Kessler, Dihua Yu, and Ruth J. Muschel. "Proteomics analysis of the matrisome from MC38 experimental mouse liver metastases." American Journal of Physiology-Gastrointestinal and Liver Physiology 317, no. 5 (November 1, 2019): G625—G639. http://dx.doi.org/10.1152/ajpgi.00014.2019.
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Dissemination of primary tumors to distant anatomical sites has a substantial negative impact on patient prognosis. The liver is a common site for metastases from colorectal cancer, and patients with hepatic metastases have generally much shorter survival, raising a need to develop and implement novel strategies for targeting metastatic disease. The extracellular matrix (ECM) is a meshwork of highly crosslinked, insoluble high-molecular-mass proteins maintaining tissue integrity and establishing cell–cell interactions. Emerging evidence identifies the importance of the ECM in cancer cell migration, invasion, intravasation, and metastasis. Here, we isolated the ECM from MC38 mouse liver metastases using our optimized method of mild detergent solubilization followed by biochemical enrichment. The matrices were subjected to label-free quantitative mass spectrometry analysis, revealing proteins highly abundant in the metastatic matrisome. The resulting list of proteins upregulated in the ECM significantly predicted survival in patients with colorectal cancer but not other cancers with strong involvement of the ECM component. One of the proteins upregulated in liver metastatic ECM, annexin A1, was not previously studied in the context of cancer-associated matrisome. Here, we show that annexin A1 was markedly upregulated in colon cancer cell lines compared with cancer cells of other origin and also over-represented in human primary colorectal lesions, as well as hepatic metastases, compared with their adjacent healthy tissue counterparts. In conclusion, our study provides a comprehensive ECM characterization of MC38 experimental liver metastases and proposes annexin A1 as a putative target for this disease. NEW & NOTEWORTHY Here, the authors provide an extensive proteomics characterization of murine colorectal cancer liver metastasis matrisome (the ensemble of all extracellular matrix molecules). The findings presented in this study may enable identification of therapeutic targets or biomarkers of hepatic metastases.
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Liu, Yuchen, Xiaohui Wang, and Yingzi Yang. "Hepatic Hippo signaling inhibits development of hepatocellular carcinoma." Clinical and Molecular Hepatology 26, no. 4 (October 1, 2020): 742–50. http://dx.doi.org/10.3350/cmh.2020.0178.
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Primary liver cancer is one of the most common cancer worldwide. Hepatocellular carcinoma (HCC) in particular, is the second leading cause of cancer deaths in the world. The Hippo signaling pathway has emerged as a major oncosuppressive pathway that plays critical roles inhibiting hepatocyte proliferation, survival, and HCC formation. A key component of the Hippo pathway is the inhibition of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) transcription factors by the Hippo kinase cascade. Aberrant activation of YAP or TAZ has been found in several human cancers including HCC. It is also well established that YAP/TAZ activation in hepatocytes causes HCC in mouse models, indicating that YAP/TAZ are potential therapeutic targets for human liver cancer. In this review, we summarize the recent findings regarding the multifarious roles of Hippo/YAP/TAZ in HCC development, and focus on their cell autonomous roles in controlling hepatocyte proliferation, differentiation, survival and metabolism as well as their non-cell autonomous in shaping the tumor microenvironment.
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Fang, Xingbao, Yongping Xu, Kezhi Li, Peiwan Liu, Hong Zhang, Yang Jiang, Jianwei Tang, and Yuehong Li. "Exosomal lncRNA PCAT1 Promotes Tumor Circulating Cell-Mediated Colorectal Cancer Liver Metastasis by Regulating the Activity of the miR-329-3p/Netrin-1-CD146 Complex." Journal of Immunology Research 2022 (August 31, 2022): 1–13. http://dx.doi.org/10.1155/2022/9916228.
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Objective. This study explored the colorectal cancer exosome lncRNA prostate cancer associated transcript 1– (PCAT1) mediated circulating tumors and the mechanism of cell colorectal cancer liver metastasis. Methods. Exosomes were extracted from the primary colorectal cancer (CRC) cell lines HCT116 and SW480 and cultured with T84 and human umbilical vein endothelial (HUVE) cells. The expression of PCAT1 and miR-329-3p was detected by real-time quantitative polymerase chain reaction (RT-qPCR), the expression of Netrin-1, CD146, and epithelial mesenchymal transition (EMT) related proteins was detected by Western blot, the proliferation activity of T84 cells was detected by cell counting kit 8 (CCK-8), and cell migration was detected by Transwell. The expression of the F-actin signal was detected by immunofluorescence after coculture of exosomes with human umbilical vein endothelial cells (HUVECs). Changes in subcutaneous tumor and liver nodule size after PCAT1 deletion were observed in a mouse model of liver metastasis from rectal cancer. Results. PCAT1 expression was upregulated in primary cell lines and their exosomes. After exosomes were cocultured with colorectal cancer tumor circulating T84 cells, the expression of Netrin-1 and CD146 was upregulated, the expression of miR-329-3p was downregulated, the proliferation and migration ability of T84 cells were enhanced, and EMT occurred. After knocking down PCAT1, the above phenomenon was reversed. Similarly, after exosomes were cocultured with HUVECs, the expression of the F-actin signal increased, and after PCAT1 was knocked down, the F-actin signal also decreased. PCAT1 regulates miR-329-3p/Netrin-1 and affects the biological behavior of T84 and F-actin signal expression in HUVECs. In a mouse model of colorectal cancer liver metastasis, knocking down PCAT1 significantly reduced the nodules formed by liver metastasis in mice. Conclusions. LncRNA PCAT1 derived from colorectal cancer exosomes regulates the activity of the Netrin-1-CD146 complex in circulating tumor cells (CTCs) to promote the occurrence of colorectal cancer EMT and liver metastasis and provides new molecular targets for the treatment of colorectal cancer liver metastasis.
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Chen, Ivy X., Vikash P. Chauhan, Jessica Posada, Mei R. Ng, Michelle W. Wu, Pichet Adstamongkonkul, Peigen Huang, Neal Lindeman, Robert Langer, and Rakesh K. Jain. "Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer." Proceedings of the National Academy of Sciences 116, no. 10 (January 30, 2019): 4558–66. http://dx.doi.org/10.1073/pnas.1815515116.
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Metastatic breast cancers (mBCs) are largely resistant to immune checkpoint blockade, but the mechanisms remain unclear. Primary breast cancers are characterized by a dense fibrotic stroma, which is considered immunosuppressive in multiple malignancies, but the stromal composition of breast cancer metastases and its role in immunosuppression are largely unknown. Here we show that liver and lung metastases of human breast cancers tend to be highly fibrotic, and unlike primary breast tumors, they exclude cytotoxic T lymphocytes (CTLs). Unbiased analysis of the The Cancer Genome Atlas database of human breast tumors revealed a set of genes that are associated with stromal T-lymphocyte exclusion. Among these, we focused onCXCL12as a relevant target based on its known roles in immunosuppression in other cancer types. We found that the CXCL12 receptor CXCR4 is highly expressed in both human primary tumors and metastases. To gain insight into the role of the CXCL12/CXCR4 axis, we inhibited CXCR4 signaling pharmacologically and found that plerixafor decreases fibrosis, alleviates solid stress, decompresses blood vessels, increases CTL infiltration, and decreases immunosuppression in murine mBC models. By deletingCXCR4in αSMA+cells, we confirmed that these immunosuppressive effects are dependent on CXCR4 signaling in αSMA+cells, which include cancer-associated fibroblasts as well as other cells such as pericytes. Accordingly, CXCR4 inhibition more than doubles the response to immune checkpoint blockers in mice bearing mBCs. These findings demonstrate that CXCL12/CXCR4-mediated desmoplasia in mBC promotes immunosuppression and is a potential target for overcoming therapeutic resistance to immune checkpoint blockade in mBC patients.
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Oyama, Astushi, Hidenori Shiraha, Daisuke Uchida, Masaya Iwamuro, Hironari Kato, Akinobu Takaki, Fusao Ikeda, et al. "A Phase I/Ib trial of Ad-REIC in liver cancer: study protocol." Future Oncology 15, no. 31 (November 2019): 3547–54. http://dx.doi.org/10.2217/fon-2019-0115.
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This study will assess the safety and efficacy of the administration of adenoviral vector expressing the human-reduced expression in immortalized cells (Ad-REIC) to a liver tumor in patients with hepatocellular carcinoma (HCC) or liver metastasis of pancreatic cancer. A Phase I clinical study of Ad-REIC administration to a liver tumor in a patient with HCC or liver metastasis of pancreatic cancer will be conducted. The study is a single-arm, prospective, nonrandomized, noncomparative, open-label, single-center trial performed in Okayama University Hospital, Okayama, Japan. Ad-REIC will be injected into the liver tumor under ultrasound guidance. Ad-REIC administration will be repeated a total of three-times every 2 weeks. The primary end point is the dose-limiting toxicity and incidence of adverse events. The secondary end points are the objective response rate and disease control rate. This study aims to expand the indication of Ad-REIC by assessing its safety and efficacy in patients with HCC or liver metastasis of pancreatic cancer.
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Bortolami, Marina, Daniela Molè, Chiara Carlotto, Andromachi Kotsafti, Milena Minotto, Romilda Cardin, and Fabio Farinati. "Sa1717 mTOR and LC3 Gene and Protein Expression in Chronic Liver Disease and in Primary and Secondary Human Liver Cancer." Gastroenterology 148, no. 4 (April 2015): S—1019. http://dx.doi.org/10.1016/s0016-5085(15)33485-5.
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Ibrahim, Nisreen S., Anthoula Lazaris, Miran Rada, Stephanie K. Petrillo, Laurent Huck, Sabah Hussain, Shaida Ouladan, et al. "Angiopoietin1 Deficiency in Hepatocytes Affects the Growth of Colorectal Cancer Liver Metastases (CRCLM)." Cancers 12, no. 1 (December 20, 2019): 35. http://dx.doi.org/10.3390/cancers12010035.
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Colorectal cancer liver metastases (CRCLM) that receive their blood supply via vessel co-option are associated with a poor response to anti-angiogenic therapy. Angiopoietins (Ang1 and Ang2) with their Tyrosine-protein kinase receptor (Tie2) have been shown to support vessel co-option. We demonstrate significantly higher expression of Ang1 in hepatocytes adjacent to the tumor region of human chemonaïve and treated co-opting (replacement histopathological growth patterns: RHGP) tumors. To investigate the role of the host Ang1 expression, Ang1 knockout (KO) mice were injected intra-splenically with metastatic MC-38 colon cancer cells that develop co-opting liver metastases. We observed a reduction in the number of liver metastases and interestingly, for the first time, the development of angiogenic driven desmoplastic (DHGP) liver metastases. In addition, in-vitro, knockout of Ang1 in primary hepatocytes inhibited viability, migration and invasion ability of MC-38 cells. We also demonstrate that Ang 1 alone promotes the migration and growth of both human and mouse colon cancer cell lines These results provide evidence that high expression of Ang1 in the host liver is important to support vessel co-option (RHGP lesions) and when inhibited, favours the formation of angiogenic driven liver metastases (DHGP lesions).
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Hu, Kaiweng. "Recombinant adenoviral human p53 gene infusion in treatment of malignant pleural effusions and malignant ascites." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 3027. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3027.
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3027 Background: Malignant pleural or peritoneal effusions are frequently developed in the late-stage malignant tumors in chest or abdominal cavity. Various drainage methods and intra-cavity chemotherapy have transient and limited benefits. Here we evaluated the role of recombinant adenoviral human p53 gene (rAd-p53) infusion for patients with malignant pleural or peritoneal effusions. Methods: Thirty-two patients with historically diagnosed malignant pleural (18 cases) or peritoneal (14 cases) effusions, 19 males and 13 females with an average age of 61 years old (37–80 years), were included this study. The malignant pleural effusions were caused by primary lung cancers (8 cases), lung metastatic tumors (4 cases), breast cancers (3 cases), pleural mesothelioma (2 cases), lymphoma (1 cases), and the peritoneal effusions were caused by ovarian cancers (5 cases), primary liver cancers (4 cases), liver metastatic tumors (2 cases), colon cancer (1 case), gastric cancer (1 case), and prostate cancer (1 case). After draining most of the fluids, 4×1012 viral particles (VP) of rAd-p53 diluted into 1,000 ml of saline solution for intra-abdominal cavity infusion and 2×1012VP of rAd-p53 diluted into 500 ml of saline solution for intra-chest cavity infusion, were given weekly for 4 weeks. The response rate was evaluated. The complete response is defined as the complete disappearance of pleural or peritoneal fluid and negative cytologic findings for >4 weeks, and the partial response is defined as a decrease over 50% of the fluid without the need of drainage and negative cytologic findings for >4 weeks. Results: The pleural effusion showed a complete response in 6 patients (33.3%) and a partial response in 6 patients (33.3%). The peritoneal effusion had a complete response in 3 patients (21.4%) and a partial response in 7 patients (50.0%). The overall response rate was 68.8% (22/32). The symptoms associated with the malignant effusion relieved in 27 patients (84.4%). There were no serious side effects observed except for self-limited fever found in all the cases. Conclusions: Intra-abdominal or chest cavity infusion of rAd-p53 is a safe and effective treatment for some malignant pleural or peritoneal effusions.
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Sanghvi, Viraj, Aleksander Rust, Josef Leibold, Scott Lowe, Agnes Viale, John Chodera, Ronald C. Hendrickson, Elisa de Stanchina, and Hans-Guido Wendel. "Abstract PO029: Targeting non-canonical Hippo pathway in NRF2-mutant liver cancer." Clinical Cancer Research 28, no. 17_Supplement (September 1, 2022): PO029. http://dx.doi.org/10.1158/1557-3265.liverca22-po029.
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Abstract NRF2 is an “undruggable” oncogenic transcription factor recurrently mutated in solid tumors such as liver and lung cancers. Our recent study demonstrates that NRF2 acts by coordinating the redox and metabolic stress responses as well as drug resistance programs in liver and other cancers. Developing an NRF2 inhibitor is a major goal of cancer drug discovery. Here, we identify the non-canonical Hippo pathway protein serine/threonine kinase 38 (STK38/NDR1) as a new NRF2 kinase that is a requirement for its stability and function. STK38 directly phosphorylates NRF2 at two sites (S33 and T559), and both sites contribute to full NRF2 activation. Loss of STK38 disables the redox response in NRF2 driven cancers and leads to tumor regression in vivo. Conversely, STK38 can also activate NRF2 and promote de novo liver cancer development in mice. This oncogenic effect is reflected in low frequency (3%) genomic amplifications in human liver cancers. Importantly, inhibition of the upstream STK38-activating mammalian Hippo kinases STK3/4 (MST2/1) by XMU-MP-1 inactivates STK38-NRF2 regulatory axis in vitroand in vivo. More importantly, XMU-MP-1 produces single agent activity against NRF2-driven liver and lung cancers in vivo in primary and patient derived xenograft (PDX)-based mouse models. In addition, we performed an in-silicoscreen and identified TAE-684 as an STK38 inhibitor that was subsequently confirmed to block STK38 activity in an in vitro kinase assay. TAE-684 treatment resulted in significant growth impairment of NRF2-mutant PDXs in vivo but no activity was observed in NRF2 wildtype counterparts. Together, these results uncover a surprising role of Hippo-related kinase STK38 in NRF2 activation and point to a paradoxical vulnerability in NRF2-driven cancers. Citation Format: Viraj Sanghvi, Aleksander Rust, Josef Leibold, Scott Lowe, Agnes Viale, John Chodera, Ronald C. Hendrickson, Elisa de Stanchina, Hans-Guido Wendel. Targeting non-canonical Hippo pathway in NRF2-mutant liver cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO029.
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Selvaggi, Federico, Teresa Catalano, Roberto Cotellese, and Gitana Maria Aceto. "Targeting Wnt/β-Catenin Pathways in Primary Liver Tumours: From Microenvironment Signaling to Therapeutic Agents." Cancers 14, no. 8 (April 10, 2022): 1912. http://dx.doi.org/10.3390/cancers14081912.
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Primary liver cancers (PLCs) are steadily increasing in incidence and mortality in the world. They have a poor prognosis due to their silent nature, late discovery and resistance to common chemotherapy. At present, there are limited treatment alternatives, and the understanding of PLC molecular aspects is essential to develop more efficient drugs and therapeutic surgical and loco-regional strategies. A clear causal link with liver damage, inflammation, and regeneration has been found in the occurrence of PLC over the last few decades. Physiologically, Wingless/It (Wnt)-β-catenin signaling plays a key role in liver development, metabolic zonation and regeneration. Loss of functional homeostasis of this pathway appears to be a major driver of carcinogenesis in the liver parenchyma. In the hepatic microenvironment, molecular deregulations that exceed the Wnt signaling biological capacity can induce tumor initiation and progression. Indeed, somatic mutations are identified in key components of canonical and non-canonical Wnt signaling and in PLCs and precancerous lesions. In this review, the altered functions of Wnt/β-catenin signaling are considered in human PLCs, with emphasis on hepatocellular carcinomas (HCC), cholangiocarcinomas (CCA) and hepatoblastomas (HB). Based on recent literature, we also focused on liver cancerogenesis through Wnt deregulation. An overview of preclinical and clinical studies on approved and experimental drugs, targeting the Wnt/β-catenin cascade in PLCs, is proposed. In addition, the clinical implication of molecule inhibitors that have been shown to possess activity against the Wnt pathway in association with conventional surgical and loco-regional therapies are reviewed.