Study finds colorectal cancer cells and bacteria to be fellow travelers during metastasis
Like nomads who carry tokens of home on their travels, colorectal cancer cells that spread to other parts of the body appear to bring several of the species of bacteria that were their companions in the colon, Dana-Farber Cancer Institute scientists report in a new study in the journal Science. The findings are the latest evidence that the microbiome — the menagerie of microorganisms in the body — may play a role in colon cancer growth and could offer a new avenue for treatment of the disease, researchers say.
As part of the study, investigators implanted colorectal tumor tissue from a patient into mouse models. Not only did the implanted tissue retain the same bacterium as the original tumor, but when researchers treated the animals with an antibiotic that targets the bacterium, tumor cell proliferation and overall tumor growth declined.
“This represents one of the first times that the microbiome of colorectal cancers is maintained when the cancer metastasizes to other organs,” says the study’s senior author, Matthew Meyerson, MD, PhD, director of Cancer Genomics at Dana-Farber, as well as a member of the Broad Institute of Massachusetts Institute of Technology and Harvard, and a faculty member at Brigham and Women’s Hospital. “The fact that tumor cell growth and proliferation slowed in mice treated with a targeted antibiotic may indicate that the bacteria help drive tumor cell growth, but that is very much an open question.”
Colorectal cancers are conglomerations of malignant cells, normal colon cells, and microorganisms. In 2011, Meyerson and his colleagues discovered that colorectal cancer tissue contain high levels of several types of bacteria, most notably Fusobacterium nucleatum. The discovery was intriguing, in part, because Fusobacterium usually isn’t found in the colon: It’s normally present in the mouth, where excess amounts are associated with periodontal disease.
Subsequent studies by Meyerson’s lab and others linked high Fusobacterium levels in the large intestine to increased susceptibility to colorectal cancers and to a dampened immune system response to cancer. The new study sought to determine if the Fusobacterium-laced nature of colorectal cancers is preserved when the tumor cells metastasize to the liver.
Researchers analyzed paired primary and metastatic colon cancers, and found that in the vast majority of case, both the primary and metastatic tumors tested positive for Fusobacterium and co-occurring bacteria types. They then grew Fusobacteriumfrom both the primary and metastatic colorectal cancer tissue from two patients, and, by whole genome sequencing of these bacteria, found the same strain of Fusobacterium in the metastasized tissue as in the original tumor. Together, these findings are strong evidence of a similar or identical bacterial strain for each of the pairs.
“Our findings suggest that the microbiome is a consistent feature of colorectal cancers, regardless of whether it is a primary cancer or a metastasis of that cancer,” says the study’s lead author, Susan Bullman, PhD, of Dana-Farber and the Broad Institute. “It underscores the importance of the microbiome within the tumor microenvironment [the cells, blood vessels, and supportive tissue around a tumor].”
The researchers next showed that the Fusobacterium in human colorectal tumors remained when samples of the tumors were implanted in mice. Moreover, when investigators treated the animals with the antibiotic metronidazole, which kills Fusobacterium, the animals’ overall load of the bacterium dropped, as did the rate of cancer cell proliferation and tumor growth.
Though these results may seem to point to a mutually beneficial relationship between colorectal cancer and Fusobacterium – in which the bacterium helps the cancer cells grow and spread while the cancer helps the bacterium survive – it is far from certain, researchers say. Nor is it clear how Fusobacterium makes the journey from the colon to the liver or other organs. These and other questions will be the subject of future research.
The co-authors of the study are: Chandra S. Pedamallu, PhD, Xiaoyang Zhang, PhD, Diana Cai, Aruna Ramachandran, MS, Fatima Guevara and Begoña Diosdado, MD, PhD, of Dana-Farber and the Broad Institute; Ewa Sicinska, MD, Donna Neuberg, ScD, Fatima Guevara, Timothy Nelson, Otari Chipashvili, Timothy Hagan, and Kimmie Ng, MD, of Dana-Farber; Andrew J. Aguirre, MD, PhD, and William C. Hahn, MD, PhD, of Dana-Farber, the Broad Institute, and Brigham and Women’s Hospital (BWH); Thomas E. Clancy, MD, of BWH; Katherine Huang, and Mark Walker, PhD, of the Broad Institute; Stefania Landolfi, Santiago Ramon y Cajal, Elena Élez, Josep Tabernero, MD, PhD, and Paolo Nuciforo, of Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Spain; Shuji Ogino, MD, PhD, of Dana-Farber, BWH, and Harvard T.H. Chan School of Public Health; and Charles S. Fuchs, MD, MPH, of Yale Cancer Center.
The research was supported by US National Institutes of Health (NIH) grants (R35CA197568, R35 CA197735, K07 CA148894, R01 CA118553, R01 CA169141) and the DF/HCC GI SPORE (P50 CA 127003); an American Cancer Society Research Professorship; the Hale Family Center for Pancreatic Cancer; the Project P Fund for Colorectal Cancer Research; Stand-up-to-Cancer;the Chambers Family Fund for Colorectal Cancer Research; the Team Perry Fund; the Clark Family Fund for GI Cancer Research; Prevent Cancer Foundation Figdor Family Fellowship; the Cellex Private Foundation; and the Banco Bilbao Vizcaya Argentaria Foundation.