A study from the Lawrence Berkeley National Laboratory, Berkeley, U.S. found that normal cells surrounding mouse blood vessels can control the growth of tumor cells which have left the primary tumor site and camped at distant organs in the body. The results, published online in this week’s issue (June 2) of the journal Nature Cell Biology, identified tumor suppressing or tumor promoting factors which will help in the design of new therapies against metastatic cancers.
When a patient is diagnosed with cancer of a late stage, removal of the tumor by surgery is a very common practice. But sometimes a few detached tumor cells are disseminated to distant places. These are just so few that are undetectable and might remain dormant for years or even decades before they establish new tumors. It is now well accepted that tumor cells have preferences in which secondary organs they will metastasize. For example, breast tumors will most likely cause metastasis in the lungs, bone marrow and brain.
What really controls the attachment and growth of the metastatic tumor cells is still a mystery, but scientists suspect that our own body’s cells, specifically the endothelium (the cells that line the arteries and veins), play a big role. In the laboratory of Mina Bissel, an award-winning scientist of the Lawrence Berkeley National Laboratory, scientists focus their studies on the tumor microenvironment, which is the healthy cells including immune system cells, blood vessels and the supporting extracellular matrix, surrounding the tumors.
In this study, Dr. Cyrus Ghahar and colleagues in Bissel laboratory have injected mice with human metastatic breast cancer cells expressing a fluorescent protein which would glow green under an ultra violet (UV) light hence distinguishing them from the normal. Few weeks later, as expected, they saw green cancer cells in many places in the mice body. Some of them were in the breast, which were proliferating. Other cells had metastasized to the lung and bone marrow and were were not proliferating. The latter were, more precisely, located around the stable, established microvascular endothelium of these organs. How come these normal, mature endothelial cells which line the surface of blood vessels could “hypnotize” the cancer cells? The researchers found that the mature endothelium released a factor which suppressed the growth of the metastatic cancer cells. This factor was thrombospondin-1 (TSP-1).
In parallel, the research team saw some cancer cells growing fast around the newly produced sprouting tips of veins and arteries (neovascular areas). When they looked for TSP-1 at the endothelium of these “neovessels”, they did not find any trace of TSP-1. More precisely, the closer to these neovessels the faster the cancer growth was, while the further from it, the slowest the growth was. This made them think that there are factors that promote the growth of cancer cells, contrary to the established, mature vessels. Indeed, they identified tumor growth factor type beta-1 (TGF-β1) and periostin (POSTN) as the factors that boost the cancer cells.
“Our study reveals that a stable microvasculature constitutes a dormant niche, whereas a sprouting neovasculature sparks micrometastatic outgrowth,” says Mina Bissell.
Previous studies have pinpointed TGF-β1 and POSTN as putative targets for therapies against metastasis. But this study “is the first study to define the dormant niche on a cellular and molecular basis, and it is interesting that the culprit is the tissue we so often assume is a passive bystander, the microvascular endothelium,” Ghajar says.
Are there other cells in addition to the endothelium or other factors in addition to TSP-1 that might stop the growth of tumors? Do other factors promote tumor growth in collaboration with TGF-β1 and periostin? If yes, then scientists could start using this information to design new therapies against metastatic cancer.
“It remains to be determined whether the mechanisms we have identified here apply also to other tumor types and in other secondary tissues.” said the authors. And if more clues regarding the interaction of tumors with the microenvironment are identified, they “will provide a vehicle by which we can design more effective therapies to keep DTCs [disseminated tumor cells] dormant — or eradicate them — in early-stage cancer patients.”
For additional information, you can watch Mina Bissell’s TED talk.