Current perspectives on the tumor microenvironment in hepatocellular carcinoma
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REVIEW ARTICLE
Current perspectives on the tumor microenvironment in hepatocellular carcinoma Cositha Santhakumar1,2 · Edward J. Gane1 · Ken Liu2,3 · Geoffrey W. McCaughan2,3 Received: 10 August 2020 / Accepted: 22 October 2020 © Asian Pacific Association for the Study of the Liver 2020
Abstract Hepatocellular carcinoma (HCC) is a heterogeneous inflammation-driven malignancy, which, despite significant advances in management, continues to portend a poor prognosis. Recent advances in basic and translational research have increasingly defined the role of the tumor microenvironment in the development and progression of HCC and facilitated the development of novel molecular targets. The hepatoma microenvironment is characterised by an immunosuppressive milieu of immune cells and tumor vasculature that is both structurally and functionally abnormal. Normalising the tumor microenvironment by adopting a multipronged approach that targets both carcinogenic processes and the immunosuppressive milieu has been supported by pre-clinical and clinical data. In this review, we summarise the current understanding of the hepatoma microenvironment, its influences and dynamic interactions with tumor cells, the vasculature and the gut. Finally, we discuss how manipulating the tumor microenvironment continues to shape the evolving landscape of HCC therapy. Keywords Hepatocellular carcinoma · Carcinogenesis · Microenvironment · Vasculature · Inflammation · immunotherapy · Prognosis · Microbiome · Vessel normalisation · Single cell sequencing
Introduction Hepatocellular carcinoma (HCC) is the sixth most frequent cancer and the fourth leading cause of cancer-related death [1], representing a major global health problem. Despite recent improvements in therapeutic options, outcomes in advanced HCC remain poor with a median survival * Cositha Santhakumar [email protected] Edward J. Gane [email protected] Ken Liu [email protected] Geoffrey W. McCaughan [email protected] 1
New Zealand Liver Transplant Unit, Level 15, Support Building, Auckland City Hospital, Private Bag 92024, Auckland 1023, New Zealand
2
Centenary Institute, The University of Sydney, Sydney, Locked Bag 6, Newtown, NSW 2042, Australia
3
AW Morrow Gastroenterology and Liver Centre, 9 East, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia
following diagnosis ranging from 4 to 20 months [2, 3]. The poor prognosis results from delayed diagnosis, when tumor stage is advanced with high rates of lymphovascular invasion and intra- and extrahepatic metastases. The phenotypic and genetic heterogeneity of this cancer may also contribute to high rates of recurrence and metachronous HCCs following curative interventions such as resection and ablation [4]. HCC almost always develops within a diseased liver, most often secondary to chronic viral infection (hepatitis B and hepatitis C virus infection) and rarely due to inherited and metabolic disorders [5]. Whatever the etiology, hepatocarcinogenesis is invariably rela
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