This article was written by Joan Mancuso
This year’s annual National Breast Cancer Coalition’s Leadership Summit and Lobby Day included informative sessions on metastasis research. One session about preventing breast cancer from metastasizing also holds promise for developing treatments to work against active metastatic breast cancer lesions. The session, which was titled, After 25 Years, What Do We Really Know About Preventing Metastasis? was presented in part by Dr. Cyrus Ghajar of Fred Hutchinson Cancer Center in Seattle.
Dr. Ghajar discussed how the traditional theory of the “metastatic cascade” is being replaced by new ideas that can help explain some enigmas about breast cancer. The metastatic cascade describes the natural history of metastasis as linear--going from a localized primary tumor to recruitment of blood vessels, extravasation or leaving the blood stream, and then entering new tissues. But that does not adequately explain all situations.
For example, Dr. Ghajar wanted to know why some breast cancer cells metastasize for up to 10 years or more after adjuvant chemotherapy. Why 20%-50% of those diagnosed with ductal carcinoma in situ (DCIS) have disseminated breast cancer cells in their bone marrow, even though DCIS is supposedly noninvasive. And why in mouse models, HER2 positive breast cancer cells that take as much as 6 months to form tumors have already disseminated to the bone marrow as early as one month.
In order to answer these questions, Dr. Ghajar has been looking at new models to understand metastasis and studying cellular dormancy, or why some tumor cells seem to go to sleep and then wake up at a later time. His findings showed that besides preventing breast cancer cells from metastasizing, they could also lead to treatments for metastatic breast cancer.
His research has shown that tumor cells that are not actively proliferating cluster on the outside of blood vessels. They use the vessels like highways to distant organ sites, exit the vessels, and then remain in a state of quiescence until they wake up. Furthermore, chemotherapy such as doxorubicin (Adriamycin), cyclophosphamide (Cytoxan) and paclitaxel (Taxol) do nothing to eradicate these so-called sleeping cells, even if the cells are coaxed from slumber with a growth factor. Stem cells as well as metastasis-initiating cells that can reconstitute metastases also like to reside in the same real estate.
Although a treatment to prevent the cells from waking up would seem like a good idea, Dr Ghajar noted that such a therapy would contribute to over-treating breast cancer survivors, since roughly 70% of patients never develop metastases and would not need the drug. Then add to that the long time period required by a clinical trial to test the drug and whether patients adhere to taking their pills. And what would happen if the drug were stopped? Would that result in the cancer roaring back, such as when AIDS patients stop taking the antiviral medication azidothymidine (commonly known as AZT), he said. As a result, Dr. Ghajar turned to another way of understanding and targeting the dormant cells.
From his research studies, Dr. Ghajar felt that the extravascular environment was in some way protecting the dormant cancer cells from being eradicated by chemotherapy. He discovered that several proteins are overrepresented around the vasculature. His laboratory identified the molecule alpha-v beta-3 as a potential target, and when they treated the cells with an antibody, the chemotherapy was able to destroy many of the tumor cells that were sitting on the outside of blood vessels.
Metastasis-initiating cells also cluster around blood vessels, noted Dr. Ghajar. And while the antibody works against dormant cells, it could also work toward shrinking established metastatic tumors, he said.
Dr. Ghajar is also interested in understanding how cancer cells that reside on the blood vessels go undetected by the immune system and he plans to study this phenomenon in his lab.