Study Points to Potential Target for Common Lung Cancer

Research out of University of Barcelona has characterized the role that TIMP-1—a protein unusually secreted by fibroblasts in the tumor microenvironment and often associated with poor prognosis in lung cancers—plays in the progression of lung cancer adenocarcinoma. The findings open the door to the design of new treatments for lung and other cancers associated with elevated TIMP-1 levels.

“In recent decades, cancer research has been aimed at having more specific treatments for each type of tumor and patient, improving the patients’ prognosis,” says coauthor and University of Barcelona researcher Paula Duch. “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.” 

Led by Jordi Alcaraz, lecturer at the Faculty of Medicine and Health Sciences of the University of Barcelona and researcher at the Institute for Bioengineering of Catalonia (IBEC), the team used a unique collection of fibroblasts derived from lung cancer patients at the Hospital Clínic in Spain. 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 tumor proliferation and invasion when it interacts with the CD63 receptor on cancer cells. They also found that the tumor axis formed by the interaction between TIMP-1 and CD63 occurs only in the adenocarcinoma subtype and not in squamous cell carcinoma, says Alcaraz, who is also a researcher at the Respiratory Diseases Networking Biomedical Research Centre (CIBERES).

These results may facilitate the development of new therapies directed against this pathological interaction. "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," adds Duch.

The study also shows that fibroblasts play a very important role in tumor progression, opening a way to attack this “tumor axis,” with 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 tumors," says Duch.

If the approach works, the use of these antifibrotic drugs in combination with anti-cancer therapies that attack other aspects of the tumor, such as immunotherapy, could be considered.  The results could also have implications for other cancers, as the TIMP-1 protein is also widely described as a biomarker of poor prognosis in many types of solid tumors. "Therefore, in other highly fibrotic tumors with elevated levels of TIMP-1 and its receptor, CD63, it is likely for this axis to play an important pro-tumoral role," adds Duch.

The findings were published recently in the journal Matrix Biology.