Cancer cells are able tospread from a nascent tumor much earlier than scientists long thought and are more adept than later emigrants at forming potentially lethal metastases at distant sites such asthe brain and bones, researchersreportedin two studies published Wednesday.The discoveryoffers the first molecular explanation of how that early spread occurs, hinting at why early detection and treatment often fail to prevent cancer deaths: Early is still too late.Why it mattersCancer dogma holds that after cells acquire genetic mutations that make themmalignant, theyproliferate out of control, eventually forming a tumor. Cells that make up the tumor accumulate additional mutations, some of which enable them to move into the bloodstream, reach distant organs, and set up a malignant colony. Such metastases are responsible for more than 90 percent of cancer deaths.But the two new studies of breast cancer suggest that model is wrongor, at least, that it doesnt describe all cancers. The findings challenge everything we thought we knew about how cancer spreads and forms metastases, said Dr. Julio Aguirre-Ghiso of the Icahn School of Medicine at Mount Sinai in New York, who led one of the new studies, published in Nature.The discovery might shed light on some of the most frustrating mysteries of cancer.For instance, why doesnt early detection, such as withmammography or even more advanced methodssuch asbreast MRI, save more lives' The metastases-forming, super-early departees leave when the tumor is microscopic. By the time a tumor is detectable, theyve alreadyperhaps for yearsbeen seedingpotentially fatal metastases at distant sites, said Aguirre-Ghiso.The new findings also mightexplain whytargeted drugs, whichare viewed as the greatest successes in precision medicine, dont keep most patients alive much longer than standard chemotherapy. These drugsdisable the molecular mechanisms that spur proliferation, whichdoctorsidentifyby biopsying the tumor. But if cancer cells leave before theres any tumor detectable enough to biopsy, attacking the original tumor is the proverbial locking the barn door after the horse has fled.By then, cells that left have had lots of time to evolve their own distinct mutationsto proliferate at a distant organ.Youll want to know:Earlierresearch had hintedthat some cancer cells set out for distant organs long before a tumor is detectable. A 2008 mouse study,led by Christoph Klein of Germanys University of Regensburg, who also led one of the new studies, found that cancer cellsreached the bone marrow months before breast tumors formed. A 2011 studyof 30 women with non-invasive breast cancer found that eight actually had cancer cells in the bone marrow. In about 8 percent of non-invasive breast cancers, a 2015 studyreported, metastases developeven though non-invasive means the malignant cells cant enter the bloodstream and travel to vital organs.The two new studies are the first to identify the molecular mechanisms by which cancer cells spread even before a tumor forms. They also offer a long-sought explanation for why some 5 percent of cancer patients have metastases but no original tumor, called cancer of unknown primary: Malignant cells formed metastases even before the original tumor was detectable.The nitty-grittyThe new studies were done in lab mice. The study at Regensburg found that in mice given the human breast cancer gene HER2, the hormone progesterone triggers the migration of cancer cells almost as soon as they formthat is, before a tumor is detectable. And these early migrs are better at forming metastases than cancer cells that depart the tumor later.At Mount Sinai, Aguirre-Ghiso found that a gene called p38 acts as a brake on the departure of cancer cells from still-forming breast tumors. When p38 is silenced and HER2 is activated, the combination awakensmolecules that, eventually, mobilize cancer cells into the bloodstream and on to the lungs and bones.But keep in mindIt remains to be seen whether this early departure of cancer cells to seed metastases occurs in cancers other than those of the breast. Odds are, however, that it does in at least some, especially melanoma and pancreatic cancer.What theyre saying:In a commentaryhe coauthored in Nature,cancer biologist Cyrus Ghajar of Fred Hutchinson Cancer Research Center in Seattle praised the compelling data in the studies. Oneimportant implication for women using hormone replacement therapy, he said, involves progesterones ability to trigger metastasis: This adds further evidence that post-menopausal administration of progesterone is a bad idea, as it could theoretically fuel dissemination from any breast [malignancies] that emerge later in life.Theres no question this is interesting work, said cancer biologist Tyler Jacks of the Massachusetts Institute of Technology, director of the Koch Institute for Integrative Cancer Research. By undermining the canonical view that metastasis occurs very late in carcinogenesis, he said, it raises questions about early detection and about matching targeted therapies to mutations in the original tumor. Metastases usually havesimilar but not identical mutations, he said, so the question is, how similar is similar enough'The bottom lineThe vast majority of patients [diagnosed with cancer] already have disseminated cells, said Aguirre-Ghiso. Thats a negative. But the positive is that [these] cells havent activated their proliferation programs, so there is an opportunity to intervene, by somehow attackingtheir weak spotssomething that will require whole new avenues of basic research.SEE ALSO:Yes, bacon has been linked to cancer AGAIN ' here's how bad processed meats actually are for youDON'T MISS:Coffee probably doesn't cause cancer ' but there's a catchJoin the conversation about this storyNOW WATCH: Doctors now say this type of cancer isn't actually cancer ' and the new classification is changing thousands of lives
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