Clínic IDIBAPS publishes a review in Cell examining the biological bases of liver cancer and how they have shaped current therapies

A team of researchers from IDIBAPS, within the context of the Clínic Barcelona Comprehensive Cancer Centre (4CB), has contributed to a special issue of the journal Cell published to mark the 25th anniversary of the “Hallmarks of Cancer”, a conceptual model that describes the fundamental biological characteristics of cancer.

In this commemorative volume, Cell includes review articles on different types of cancer, one of which is Hallmarks of liver cancer: therapeutic implications. The article is coordinated by Josep M. Llovet, Head of the Translational Research in Hepatic Oncology group at IDIBAPS, Professor of Medicine at the University of Barcelona, ICREA Research Professor, and Professor of Medicine at the Icahn School of Medicine at Mount Sinai. The review also includes contributions from Roser Pinyol, from the same group, and Silvia Affo, Head of the Tumour Microenvironment Heterogeneity and Plasticity (TMHet) group at IDIBAPS.

The article analyses the most relevant biological characteristics of liver cancer and explains how they have guided translational research and the development of new therapeutic strategies.

Liver cancer: a common and complex disease with high mortality

Liver cancer represents a major public health challenge worldwide and is one of the most common tumours with an unfavourable prognosis. Hepatocellular carcinoma (HCC) accounts for approximately 85% of cases, while intrahepatic cholangiocarcinoma (iCCA) represents around 10%. These tumours are often diagnosed at advanced stages, when therapeutic options are limited.

Over the past two decades, the treatment of liver cancer has undergone a major transformation, largely due to the introduction of targeted therapies, immunotherapy, and precision medicine.

What biological features drive liver cancer?

The review explains that the development of liver cancer does not rely on a single mechanism, but rather on a combination of biological processes that tumour cells activate in order to grow, survive and spread. These include alterations in cell proliferation, nutrient acquisition, interactions with the immune system, and the ability to adapt to inflammatory or fibrotic environments.

In hepatocellular carcinoma (HCC)

Key processes include:

Uncontrolled cell proliferation, driven by genetic alterations and by the inflammatory microenvironment typical of cirrhotic liver disease.
The formation of new blood vessels (angiogenesis), which supplies oxygen and nutrients to the tumour and has been essential for the development of drugs targeting the VEGF pathway.
The ability to evade immune surveillance, which has facilitated the introduction of immunotherapy combinations.

In intrahepatic cholangiocarcinoma (iCCA)

In addition to the above mechanisms, the review highlights:

Metabolic alterations that enable tumour cells to adapt and grow in hostile environments.
Specific genetic alterations, such as FGFR2 fusions or mutations in IDH1, ERBB2 and BRAF, which open the door to personalised treatments. Approximately 45% of iCCA cases harbour alterations that can be targeted with approved or investigational therapies.

These insights have been crucial in shaping new lines of translational research aimed at bridging laboratory discoveries with clinical practice.

How have these insights transformed liver cancer treatment?

The review describes how scientific progress based on these biological mechanisms has led to major advances in patient care.

New treatments for hepatocellular carcinoma

Therapeutic options have evolved from a very limited scenario to the availability of:

anti-angiogenic agents,
inhibitors of molecular pathways involved in tumour growth, and
immunotherapy combinations, which have become first-line treatment in advanced disease and have improved patient survival.

Precision medicine in cholangiocarcinoma

The identification of actionable mutations has marked a turning point. Today, patients with iCCA may benefit from:

FGFR2 inhibitors,
IDH1-targeted therapies,
and drugs directed at other, less frequent alterations.

In addition, the combination of chemotherapy and immunotherapy has become the standard treatment for advanced disease.

“This Cell special issue provides an opportunity to take stock of what we have learned about liver cancer. Understanding the mechanisms that tumour cells use to grow has enabled the development of more precise therapies. This review summarises 25 years of research and highlights the avenues that may further improve treatment in the future,” concludes Dr Josep M. Llovet.

Funding: This study was funded by the European Union through the THRIVE project (Grant Agreement No. 101136622).

Study reference: Llovet J, Pinyol R, Affo S, et al. Hallmarks of liver cancer: Therapeutic implications. Cell, 189, 2490-2514

Image: From left to right, Roser Pinyol, Josep M. Llovet and Sílvia Affò