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, in partnership with 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 Professor Georgios Stathopoulos, research group leader at the Institute for Lung Biology (ILBD) and Comprehensive Pneumology Center (CPC) at the Helmholtz Zentrum München. “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. 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.
Tests on active substances to treat pleural effusion
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.”
Lung cancer expert Georgios Stathopoulos joined the Helmholtz Zentrum München in 2015 (http://www.helmholtz-muenchen.de/en/press-media/press-releases/all-press-releases/press-release/article/26789/index.html). He also heads a working group at the Laboratory for Molecular Respiratory Carcinogenesis at the University of Patras in Greece. The study that has now been published was the outcome of collaboration between the two working groups.
* 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.
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.
The co-authors of the study, Malamati Vreka and Mario Pepe, are PhD students at the CPC Research School and participants in the PhD training program at the Helmholtz Graduate School of Environmental Health, in short HELENA.
Αgalioti, T. et al. (2017): Mutant KRAS promotes malignant pleural effusion formation. Nature Communications, DOI: 10.1038/ncomms15205
The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www.helmholtz-muenchen.de/en
The Comprehensive Pneumology Center (CPC) is a joint research project of the Helmholtz Zentrum München, the Ludwig-Maximilians-Universität Clinic Complex and the Asklepios Fachkliniken München-Gauting. The CPC's objective is to conduct research on chronic lung diseases in order to develop new diagnosis and therapy strategies. The CPC maintains a focus on experimental pneumology with the investigation of cellular, molecular and immunological mechanisms involved in lung diseases. The CPC is a site of the Deutsches Zentrum für Lungenforschung (DZL). http://www.helmholtz-muenchen.de/ilbd
The German Center for Lung Research (DZL) pools German expertise in the field of pulmonology research and clinical pulmonology. The association’s head office is in Giessen. The aim of the DZL is to find answers to open questions in research into lung diseases by adopting an innovative, integrated approach and thus to make a sizeable contribution to improving the prevention, diagnosis and individualized treatment of lung disease and to ensure optimum patient care. http://www.dzl.de/index.php/en
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