Inhibition of epidermal growth factor receptor (EGFR) impairs the growth of liver tumor cells and makes them sensitive to the suppressive action of the cytokine TGF-beta, by activating mechanisms of programmed death (apoptosis). This is the result of research conducted by researchers from the Biological clues of the invasive and metastatic phenotype group at IDIBELL, led by Isabel Fabregat.

The results could lead to the development of new targeted therapies for liver cancer. The work has been published in the online edition of the Journal of Hepatology.

Hepatocellular carcinoma is the fifth most common cancer in the world wide and the third cause of cancer-related death globally. The origin of this tumor is associated with several molecular alterations; the most obvious is alteration of the mechanisms that regulate the balance between proliferation and cell death

Dual role of TGF–beta
The aim of this study is to dissect the response of tumor cells to TGF-beta when we eliminate the EGFR pathway. The TGF-beta is involved in various regulation cellular processes. With regard to tumors, it has been shown to have a contradictory dual function. On the one hand, at initial states it induces programmed cell death, so that has a suppressive function of tumor cell growth, but in more advanced states it promotes cell migration and invasion and thus metastasis.

The cancellation of the EGFR pathway was realized pharmacologically and by silencing its expression using RNA interference with the same results. EGF receptor inhibition not only reduces cell proliferation but also increases the suppressive function of TGF-beta, so it could be a therapeutic target for liver cancer. However, this slowdown in the growth of tumor cells does not occur in all cases. The cell lines that have certain genetic alterations (in the operation of TGF-beta or in proteins involved in the EGFR signaling pathway but at later steps to the receiver) do not respond to EGFR inhibition and tumor cells continue to grow.

The study coordinator, Isabel Fabregat, stressed that for develope “a good personalized medicine is necessary to analyze the molecular biology of patient’s tumor cells, its phenotype and its genetic and epigenetic background, so we can predict which patients are likely to respond effectively to the treatment and which not.” The study was conducted in hepatocarcinoma cell lines and in the coming months it will begin a study with an experimental model in mice.

Article reference

Caja L., Sancho P., Bertran E., Fabregat I. Dissecting the effect of targeting the epidermal growth factor receptor on TGF-B-induced-apoptosis in human hepatocellular carcinoma cells, Journal of Hepatology 2011: 55, 351–358.