New therapeutic target against common lung cancer

TIMP-1 protein levels in both tissues and blood have been repeatedly associated with a poor prognosis in lung cancers, but its role in this cancer process was, to date, unknown. Now, Spanish and US researchers have determined that this protein is not only a good biomarker, but it is also involved in the progression of lung adenocarcinoma. Their results, published in the journal Matrix Biology, open the door to the design of new treatments against this disease.

“In recent decades, cancer research has been aimed at having more specific treatments for each type of tumour and patient, improving the patients’ prognosis,” said Paula Duch, a researcher at the University of Barcelona (UB) and first author on the paper. “In this line, this study is relevant because it identifies a therapeutic target for those patients with adenocarcinoma subtype non-small cell lung cancer, the most common lung cancer.”

TIMP-1 is a protein unusually secreted by fibroblasts, a type of non-malignant cell that accompanies cancer cells and the main component of what is called the tumour microenvironment. To understand the role of TIMP-1 in this process, the researchers used a unique collection of fibroblasts derived from lung cancer patients at the Hospital Clínic de Barcelona. Specifically, they performed cell culture assays in vitro and in vivo on non-small cell lung cancer, which accounts for up to 85% of lung cancers and is subdivided into two subtypes: adenocarcinoma and squamous cell carcinoma.

The results first showed that elevated levels of TIMP-1 in lung cancer are due to fibroblasts secreting ‘pathological levels’ of this protein. Next, they found that TIMP-1 from fibroblasts causes increased tumour proliferation and invasion when it interacts with the CD63 receptor on cancer cells. Finally, they found that “this tumour axis formed by the interaction between TIMP-1 and CD63 occurs only in the adenocarcinoma subtype and not in squamous cell carcinoma”, said study leader and UB lecturer Jordi Alcaraz.

These results may facilitate the development of new therapies directed against this pathological interaction. According to Duch, “Knowing that patients with adenocarcinoma have hyperactive fibroblasts that secrete TIMP-1 excessively allows us to consider the use of therapies that prevent its secretion.”

The study, in addition to showing that fibroblasts play a very important role in tumour progression, thus opens up a way to attack the tumour axis using antifibrotic drugs, developed to inhibit the pathological functions of these cells.

“The idea is to examine whether antifibrotic drugs are capable of inhibiting the abnormal secretion of TIMP-1 and whether this inhibition reduces the progression of adenocarcinoma tumours,” Duch said. “In the long term, if this approach works, the use of these antifibrotic drugs in combination with anticancer therapies that attack other aspects of the tumour, such as immunotherapy, could be considered.”

These results could work for other cancers, as the TIMP-1 protein is also widely described as a biomarker of poor prognosis in many types of solid tumours. “Therefore,” Duch concluded, “in other highly fibrotic tumours with elevated levels of TIMP-1 and its receptor, CD63, it is likely for this axis to play an important pro-tumoural role.”

Image credit: iStock.com/utah778

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