One of the world's top selling drugs potentially also acts against the growth of new lymphatic vessels, with potential implications for cancer therapy. This surprising finding was brought forward by researchers at ETH Zurich with their newly developed three-dimensional cell culture system.
Researchers of the Institute of Pharmaceutical Sciences at ETH Zurich and the University of California Berkeley have made an unexpected discovery. Their search for novel pharmaceuticals that might prevent the generation of tumour metastases identified a well-known drug class: the statins. These cholesterol lowering compounds are standardly used to treat patients with cardiovascular disease to prevent the progression of atherosclerosis. Statins are among the most widely prescribed drugs worldwide.
Scientists led by Michael Detmar, Professor at the ETH Zurich Institute of Pharmaceutical Sciences of Pharmacogenomics, made this discovery with a newly developed cell culture system that allows compound screening for modulators of lymphatic vessel expansion. Lymphatic vessel growth is contributing to the dissemination of tumour cells in cancer patients and also the rejection of transplanted organs by the recipient's immune system. For their screening system, the researchers coated lymphatic endothelial cells from human skin onto microscopic micro carrier beads consisting of a natural polymer and encapsulated them in a tumour environment mimicking hydrogel. When stimulated with growth factors, the lymphatic endothelial cells started to build so-called sprouts, the first step for the formation of new lymphatic vessels.
Automated cell culture in 3D
For distinction to common cell culture methods, which consist of a two-dimensional cell layer in a plane cell culture dish, the researchers called their micro carrier bead system a three-dimensional system that enabled them to test over 1000 small chemical compounds.
"We were able to screen such a high number of substances because we succeeded in automating this process," explains Postdoc Martin Schulz, the first author of the respective study published in the Proceedings of the National Academy of Sciences. For this work, the researchers utilised an automated screening microscope at the light microscopy centre of ETH Zurich. This approach resulted in over 100'000 high-resolution images of the cell-coated micro beads that visualise the development of sprouts. The sprout number was determined by an algorithm developed especially for this study. "Manual analysis would allow a throughput of maybe ten compounds, but impossibly 1000," Schulz states.
System might allow reduction of animal experiments
By utilising known substances that inhibit lymphatic vessel growth, the researchers demonstrated that the results of their 3D-system are in closer agreement with animal experiments than commonly used cell culture test systems. "Our system thereby offers a better predictability," concludes Michael Detmar. "And in contrast to animal experiments, we are able to directly assess the response in human cells," adds Martin Schulz. The researchers are convinced that the number of animal experiments can be reduced with such a 3D-system, in particular with regard to the pharmacological testing of large numbers of chemical substances.
The so-called screening of over 1000 substances resulted in around 30 compounds that inhibit lymphatic vessel growth. Among several identified pharmaceuticals that were not known to convey this effect, two were investigated in more detail. One of the two -- as earlier mentioned -- belongs to the drug class of statins. Subsequently, the researchers confirmed the inhibitory effect of statins also in mice.
No suitable medicine available
The researchers consider it possible that statins in the future might not only be administered to patients with cardiovascular disease, but also to cancer patients. Many cancers spread over the body via lymphatic vessels, as has been known for some time -- also based on research in the group of Michael Detmar among others. Some tumours are known to secret mediators that induce the growth of lymphatic vessels towards the tumour. Therefore, clinical oncology has an interest in drugs that inhibit this growth. "So far, there are no reliable treatments available in the clinics," elaborates Detmar.
"In the future, one might imagine to prophylactically treat high risk cancer patients with statins to prevent developing tumours from metastasizing," says Detmar. Because of their extensive medical evaluation and market approval for other diseases, these drugs would require repurposing by the regulatory authorities for the application as inhibitors of lymphatic vessel growth. This process would be significantly easier than the approval of a new drug. However, according to Detmar, it is imperative to first investigate whether the commonly applied statin dosages are sufficient to reduce growth of lymphatic vessels in humans.
- Martin Michael Peter Schulz, Felix Reisen, Silvana Zgraggen, Stephanie Fischer, Don Yuen, Gyeong Jin Kang, Lu Chen, Gisbert Schneider, and Michael Detmar. Phenotype-based high-content chemical library screening identifies statins as inhibitors of in vivo lymphangiogenesis. Proceedings of the National Academy of Sciences, 2012; DOI: 10.1073/pnas.1206036109
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