Lung cancer patients are particularly susceptible to malignant pleural effusion, when fluid collects in the space between the lungs and the chest wall. Researchers at the Helmholtz Zentrum München, member of the German Center for Lung Research (DZL), have discovered a novel mechanism that causes this to happen. Their study, published in ‘Nature Communications’, also shows that various active substances could potentially be used to treat this condition.
Malignant pulmonary effusion (MPE) frequently occurs in patients with metastatic breast or lung cancer. It involves a build-up of excess fluid in the pleural cavity, the area between the lungs and the chest wall, with accompanying malignant cells. The lung is surrounded by fluid, which can cause shortness of breath and chest pain, for example, and may even prove fatal.
“There is still no effective treatment for this,” explains DZL Scientist Professor Georgios Stathopoulos, research group leader at the Institute for Lung Biology and Comprehensive Pneumology Center at the Helmholtz Zentrum München (DZL Site CPC-M). “In the case of larger pulmonary effusions with volumes exceeding one liter, treatment usually involves aspiration in order to relieve pressure on the lung.”
Cancer cells trigger mechanism
Stathopoulos and his team are working to understand the causes of pleural effusion, which remain unclear, in an effort to advance the treatment of this condition in the future. In the current study, the scientists examined cancer cells they had obtained from pleural effusions with a malignant mutation in the KRAS gene ((Kirsten rat sarcoma viral oncogene homolog). KRAS is known to play a key role in the growth of various malignant tumors.
“We were able to show that these cells release a messenger substance into the bloodstream, which in turn attracts immune cells.* These cells then wander via the spleen to the pleural cavity, where they cause the effusion,” Stathopoulos says, explaining the mechanism. In addition, the scientists found the KRAS-mutant cancer cells in the MPE material of lung cancer patients as well as in the cell lines derived from them.
In order to verify whether their newly acquired knowledge could be applied in clinical practice, the researchers tested two active substances that interrupt the mechanism at two different points. In an experimental model they were able to demonstrate that both the KRAS inhibitor Deltarasin** and an antibody against the messenger substance released by the cancer cells prevented pleural effusion.
“Nearly two thirds of all MPEs are the result of lung cancer. In view of the still large numbers of smokers, appropriate treatments are urgently needed,” Stathopoulos stresses. “Our results lead us to assume that drugs that target the mechanism we have discovered could be a potential treatment option. Further studies are now needed to confirm that.”
Prof. Dr. Georgios Stathopoulos,
Helmholtz Zentrum München - German Research Center for Environmental Health, Comprehensive Pneumology Center (DZL Site CPC-M),
Max-Lebsche-Platz 31,
81377 München, Germany
Tel.: +49 89 3187 4846
E-mail: stathopoulos@helmholtz-muenchen.de
* The messenger substance in question is CCL2 (CC-Chemokinligand 2), which is often released when inflammation occurs.
** Deltarasin prevents the transport of the cancer-causing protein KRAS to the cell membrane.
Αgalioti, T. et al. (2017): Mutant KRAS promotes malignant pleural effusion formation. Nature Communications, DOI: 10.1038/ncomms15205
Source: Helmholtz Zentrum München
In 2015 a team headed by Professor Stathopoulos discovered that in lung cancer patients mast cells collect in the pleural cavity, where they cause a pleural effusion. In a preclinical model, initial experiments with Imatinib, a tyrosine kinase inhibitor, revealed a smaller pleural effusion and fewer mast cells.
