Pleural mesothelioma is a relatively rare but very aggressive malignancy of the linings of the chest wall. The main risk factor for development of pleural mesothelioma is the inhalation of asbestos fibers. While many cancer types depend on activating mutations of growth promoting genes called oncogenes, pleural mesothelioma is mainly characterized by inactivating mutations in growth limiting genes called tumor suppressor genes. The high aggressiveness of pleural mesothelioma in the absence of activated oncogenes could result from growth stimulation of cancer cells by other cells in the vicinity of the tumor, the so called tumor microenvironment. Especially fibroblasts, which are themselves activated by signals from the tumor cells and are then called cancer-associated fibroblasts or CAFs, could play an important role in this process.
In a paper recently published in the “Journal of Experimental & Clinical Cancer Research“, a group of researchers from the Medical University of Vienna and the University of Vienna headed by Michael Grusch from the Center for Cancer Research isolated and characterized fibroblasts from the tumor tissue of mesothelioma patients. The research team was able to show that Meso-CAFs, as these mesothelioma-associated fibroblasts were termed, and the growth factors they produce strongly influence the aggressive behavior of pleural mesothelioma cells as well as their response to therapeutic drugs.
Meso-CAFs are clearly distinct from mesothelioma cells regarding their morphology as well as on the DNA, RNA and protein level. The set of proteins secreted by Meso-CAFs also particularly differs from that of normal fibroblasts. In cell culture experiments performed with 2 dimensional (2D) and 3 dimensional (3D) culture models, the researchers could demonstrate that the presence of Meso-CAFs strongly enhanced the growth and migration of pleural mesothelioma cells. By using conditioned media, it was proven that the secreted proteins are responsible for this effect. Conditioned media from normal fibroblasts, in contrast, could not induce the same effects. The research team used a panel of inhibitors to identify the specific pathways (c-Met/PI3K or WNT) required for growth stimulation by Meso-CAFs. This information will be highly important when considering novel inhibitors as potential cancer therapeutics.
The scientists could also show that Meso-CAFs influence the response of mesothelioma cells to existing cancer therapeutics. While the efficacy of the widely used chemotherapeutic cisplatin was not reduced but rather even enhanced by the presence of Meso-CAFs, treatment with the EGFR inhibitor erlotinib was ineffective in their presence. This could help to explain the lack of response to EGFR inhibitors seen in clinical trials with pleural mesothelioma patients.
Overall, the results of the study demonstrate that Meso-CAFs have a substantial stimulating influence on growth and migration of pleural mesothelioma cells and thereby may act as important drivers of mesothelioma aggressiveness. Moreover, their presence also highly impacts the response to therapeutic agents. These results could be important for developing novel therapeutic approaches for pleural mesothelioma patients and ultimately improving disease prognosis.
Publication: Journal of Experimental & Clinical Cancer Research
"Mesothelioma‑associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c‑Met/PI3K and WNT signaling but do not protect against cisplatin"
Alexander Ries, Daniela Flehberger, Astrid Slany, Christine Pirker, Johanna C. Mader, Thomas Mohr, Karin Schelch, Katharina Sinn, Berta Mosleh, Mir Alireza Hoda, Balazs Dome, Helmut Dolznig, Georg Krupitza, Leonhard Müllauer, Christopher Gerner, Walter Berger & Michael Grusch