Activated Hepatic Stellate Cells in Hepatocellular Carcinoma: Their Role as a Potential Target for Future Therapies

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Abstract

Hepatocellular carcinoma (HCC) is a global healthcare challenge, which affects more than 815,000 new cases every year. Activated hepatic stellate cells (aHSCs) remain the principal cells that drive HCC onset and growth. aHSCs suppress the anti-tumor immune response through interaction with different immune cells. They also increase the deposition of the extracellular matrix proteins, challenging the reversion of fibrosis and increasing HCC growth and metastasis. Therapy for HCC was reported to activate HSCs, which could explain the low efficacy of current treatments. Conversely, recent studies aimed at the deactivation of HSCs show that they have been able to inhibit HCC growth. In this review article, we discuss the role of aHSCs in HCC pathophysiology and therapy. Finally, we provide suggestions for the experimental implementation of HSCs in HCC therapies.

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A guide to cancer immunotherapy: from T cell basic science to clinical practice

Alex Waldman, Jill Fritz, Michael Lenardo (2020)

The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation. We highlight clinical trials that demonstrate therapeutic efficacy and toxicities associated with each class of drug. Finally, we summarize emerging therapies and emphasize the yet to be elucidated questions and future promise within the field of cancer immunotherapy.

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Molecular and cellular mechanisms of liver fibrosis and its regression

Tatiana Kisseleva, David Brenner (2020)

Chronic liver injury leads to liver inflammation and fibrosis, through which activated myofibroblasts in the liver secrete extracellular matrix proteins that generate the fibrous scar. The primary source of these myofibroblasts are the resident hepatic stellate cells. Clinical and experimental liver fibrosis regresses when the causative agent is removed, which is associated with the elimination of these activated myofibroblasts and resorption of the fibrous scar. Understanding the mechanisms of liver fibrosis regression could identify new therapeutic targets to treat liver fibrosis. This Review summarizes studies of the molecular mechanisms underlying the reversibility of liver fibrosis, including apoptosis and the inactivation of hepatic stellate cells, the crosstalk between the liver and the systems that orchestrate the recruitment of bone marrow-derived macrophages (and other inflammatory cells) driving fibrosis resolution, and the interactions between various cell types that lead to the intracellular signalling that induces fibrosis or its regression. We also discuss strategies to target hepatic myofibroblasts (for example, via apoptosis or inactivation) and the myeloid cells that degrade the matrix (for example, via their recruitment to fibrotic liver) to facilitate fibrosis resolution and liver regeneration.

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Holly Barker, James T-E H Paget, Aadil A Khan … (2015)

Radiotherapy plays a central part in curing cancer. For decades, most research on improving treatment outcomes has focused on modulating radiation-induced biological effects on cancer cells. Recently, we have better understood that components within the tumour microenvironment have pivotal roles in determining treatment outcomes. In this Review, we describe vascular, stromal and immunological changes that are induced in the tumour microenvironment by irradiation and discuss how these changes may promote radioresistance and tumour recurrence. We also highlight how this knowledge is guiding the development of new treatment paradigms in which biologically targeted agents will be combined with radiotherapy.