The extracellular matrix in hepatocellular carcinoma

The tumor microenvironment (TME) is heavily influenced by a ‘corrupt’ extracellular matrix (ECM) that sensitizes the cancer cells towards mechanical stress, growth factors, and structural alterations. However, there is a clear gap in understanding the members of this corrupt ECM that contribute to different stages of cancer.

The researchers focused the review on hepatocellular carcinoma (HCC), a highly aggressive form of liver cancer that largely remains refractory to targeted therapies possibly due to limited knowledge of new therapeutic targets residing within the corrupt hepatic ECM.

The authors discuss the contributions of various ECM components that instruct the hepatocytes and their surrounding support network towards malignant transformation. In addition, the underpinnings of ECM proteins that transduce mechanical stress signals to the liver TME are also detailed.

Finally, they shed critical insights on how targeted therapies (including immune checkpoint inhibitors) of HCC may impact hepatic ECM corruption process and offer potential tumor-restraining opportunities.

 The highlights of this review article:
• Summarizing the key extracellular matrix components that change from a healthy liver to a precancerous stage and subsequently develop HCC

• Mechanisms of a corrupt ECM that orchestrates mechanotransduction in the liver tumor microenvironment

• These will be helpful to devise a functional approach to design corrupt ECM signature as a prognostic marker for HCC

• lays a roadmap for therapeutic interventions including the impact of immunotherapies in targeting the corrupt ECM components in HCC.

In summary, this is the first extensive review manuscript that addresses the role(s) of key players promoting liver mechanotransduction and their response to targeted and current immunotherapy combinations clinically relevant to HCC patients.