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Hepatobiliary Malignancies: Tissue Microenvironment and Precision Medicine 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 22121

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Special Issue Editor

Prof. Dr. Gianluigi Giannelli

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Guest Editor

National Institute of Gastroenterology, Saverio de Bellis Research Hospital, Via Turi, 27-70013 Castellana Grotte (BA), Italy
Interests: HCC; CCA; tumor microenvironment; therapy; biomarkers; TGF-beta; notch
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Treatment for Hepatocellular carcinoma (HCC) and Cholangiocarcinoma (CCA) is still an unmet medical achievement. There are a number of reasons for the lack of response to therapy, including major side-effects caused by sorafenib and regorafenib, the only two drugs so far approved for systemic treatment of patients with HCC. In patients with CCA, survival is extremely poor and therapies are based on the use of few chemotherapics with uncertain outcome. On the other hand, there is no doubt that the molecular mechanisms responsible for tumor progression are still poorly understood, also because the underlying chronic liver disease is a heterogenic confounding factor. In the last few years, research into the tissue microenvironment has been gaining ground in view of the cross-talk between the stroma and tumor, responsible for the growth and the progression of hepatobiliary malignancies. Identification of the pathways is crucial for targeting new drugs in the scenario of a precision medicine approach. In this Special Issue, we will discuss some of the hottest topics in this area, providing new insights in the field.

The purpose of this Special Issue is to collect original research articles and reviews that concern the Hepatocellular Carcinoma and beyond as in the case of Cholangiocarcinoma. This Special Issue follows on from a past and very successful collection on “Hepatocellular Carcinoma: Tissue Microenvironment and Precision Medicine” (https://0-www-mdpi-com.brum.beds.ac.uk/journal/ijms/special_issues/HCC). Contributions from different fields of research at a molecular level are welcomed. Clinical research and survey studies are not suitable for this Special Issue of IJMS.

Prof. Gianluigi Giannelli
Guest Editor

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Keywords

microenvironment
precision medicine
stroma
epithelial mesenchimal transition
HCC
target therapy

Published Papers (4 papers)

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Research

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14 pages, 1768 KiB

Open AccessArticle

Expression of Cancer Stem Cell Markers EpCAM and CD90 Is Correlated with Anti- and Pro-Oncogenic EphA2 Signaling in Hepatocellular Carcinoma

by Nobuhiko Asakura, Naotoshi Nakamura, Atsushi Muroi, Yosui Nojima, Taro Yamashita, Shuichi Kaneko, Kazuki Ikeda, Naohiko Koshikawa and Takashi Suzuki

Int. J. Mol. Sci. 2021, 22(16), 8652; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168652 - 11 Aug 2021

Cited by 13 | Viewed by 3201

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Additionally, the efficacy of targeted molecular therapies with multiple tyrosine kinase inhibitors is limited. In this study, we focused on the cellular signaling pathways common to diverse HCC cells and used quantitative reverse phase protein array (RPPA) and statistical analyses to elucidate the molecular mechanisms determining its malignancy. We examined the heterogeneity of 17 liver cancer cell lines by performing cluster analysis of their expression of CD90 and EpCAM cancer stem cell markers. Gaussian mixture model clustering identified three dominant clusters: CD90-positive and EpCAM-negative (CD90+), EpCAM-positive and CD90-negative (EpCAM+) and EpCAM-negative and CD90-negative (Neutral). A multivariate analysis by partial least squares revealed that the former two cell populations showed distinct patterns of protein expression and phosphorylation in the EGFR and EphA2 signaling pathways. The CD90+ cells exhibited higher abundance of AKT, EphA2 and its phosphorylated form at Ser⁸⁹⁷, whereas the EpCAM+ cells exhibited higher abundance of ERK, RSK and its phosphorylated form. This demonstrates that pro-oncogenic, ligand-independent EphA2 signaling plays a dominant role in CD90+ cells with higher motility and metastatic activity than EpCAM+ cells. We also showed that an AKT inhibitor reduced the proliferation and survival of CD90+ cells but did not affect those of EpCAM+ cells. Taken together, our results suggest that AKT activation may be a key pro-oncogenic regulator in HCC. Full article

(This article belongs to the Special Issue Hepatobiliary Malignancies: Tissue Microenvironment and Precision Medicine 2.0)

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Review

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32 pages, 2184 KiB

Open AccessReview

Natural Killer Cells and Type 1 Innate Lymphoid Cells in Hepatocellular Carcinoma: Current Knowledge and Future Perspectives

by Nicolas Jacquelot, Cyril Seillet, Fernando Souza-Fonseca-Guimaraes, Adrian G. Sacher, Gabrielle T. Belz and Pamela S. Ohashi

Int. J. Mol. Sci. 2021, 22(16), 9044; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22169044 - 22 Aug 2021

Cited by 7 | Viewed by 4289

Abstract

Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1) are specific innate lymphoid cell subsets that are key for the detection and elimination of pathogens and cancer cells. In liver, while they share a number of characteristics, they differ in many features. These include their developmental pathways, tissue distribution, phenotype and functions. NK cells and ILC1 contribute to organ homeostasis through the production of key cytokines and chemokines and the elimination of potential harmful bacteria and viruses. In addition, they are equipped with a wide range of receptors, allowing them to detect “stressed cells’ such as cancer cells. Our understanding of the role of innate lymphoid cells in hepatocellular carcinoma (HCC) is growing owing to the development of mouse models, the progress in immunotherapeutic treatment and the recent use of scRNA sequencing analyses. In this review, we summarize the current understanding of NK cells and ILC1 in hepatocellular carcinoma and discuss future strategies to take advantage of these innate immune cells in anti-tumor immunity. Immunotherapies hold great promise in HCC, and a better understanding of the role and function of NK cells and ILC1 in liver cancer could pave the way for new NK cell and/or ILC1-targeted treatment. Full article

(This article belongs to the Special Issue Hepatobiliary Malignancies: Tissue Microenvironment and Precision Medicine 2.0)

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Graphical abstract

29 pages, 1080 KiB

Open AccessReview

Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review

by Kyoko Oura, Asahiro Morishita, Joji Tani and Tsutomu Masaki

Int. J. Mol. Sci. 2021, 22(11), 5801; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115801 - 28 May 2021

Cited by 179 | Viewed by 11282

Abstract

Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients’ lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment. Full article

(This article belongs to the Special Issue Hepatobiliary Malignancies: Tissue Microenvironment and Precision Medicine 2.0)

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Figure 1

16 pages, 526 KiB

Open AccessReview

Molecular Landscape and Therapeutic Strategies in Cholangiocarcinoma: An Integrated Translational Approach towards Precision Medicine

by Marco Casadio, Francesca Biancaniello, Diletta Overi, Rosanna Venere, Guido Carpino, Eugenio Gaudio, Domenico Alvaro and Vincenzo Cardinale

Int. J. Mol. Sci. 2021, 22(11), 5613; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115613 - 25 May 2021

Cited by 8 | Viewed by 2504

Abstract

Cholangiocarcinomas (CCAs) are heterogeneous biliary tract malignancies with dismal prognosis, mainly due to tumor aggressiveness, late diagnosis, and poor response to current therapeutic options. High-throughput technologies have been used as a fundamental tool in unveiling CCA molecular landscape, and several molecular classifications have been proposed, leading to various targeted therapy trials. In this review, we aim to analyze the critical issues concerning the status of precision medicine in CCA, discussing molecular signatures and clusters, related to both anatomical classification and different etiopathogenesis, and the latest therapeutic strategies. Furthermore, we propose an integrated approach comprising the CCA molecular mechanism, pathobiology, clinical and histological findings, and treatment perspectives for the ultimate purpose of improving the methods of patient allocations in clinical trials and the response to personalized therapies. Full article

(This article belongs to the Special Issue Hepatobiliary Malignancies: Tissue Microenvironment and Precision Medicine 2.0)

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