Breast-Cancer Model Shows Normal Cells Help Tumors Grow

COLUMBUS, Ohio – A study led by Ohio State University cancer researchers and published in the Oct. 22 issue of Nature has shown for the first time that gene changes in normal tumor cells can foster tumor growth and progression. This work provides the first animal model that accurately represents the environment found within human breast tumors, also known as the tumor microenvironment.

“Our findings demonstrate that normal cells called stromal fibroblasts play an important role in suppressing cancer development and may explain why some human breast cancer patients respond to a standard therapy while others with apparently identical disease do not,” says co-principal investigator Michael Ostrowski, professor and chair of molecular and cellular biochemistry at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

The study also identifies new biomarkers specific to these normal cells that may help guide the treatment of breast cancer patients, and new molecular targets for developing therapies aimed at gene changes in these normal cells. The findings might also improve the understanding of other pathological conditions influenced by the tissue microenvironment such as autoimmune disease, lung fibrosis and neurodegenerative diseases.

The study shows that the loss of a gene called Pten from normal-looking fibroblasts in the mammary tumor of a mouse can dramatically alter the tumor environment in ways that foster tumor growth. The gene produces a protein that is a key regulator of cell metabolism, and it is lost in many human cancers.

“Our findings reveal a new role for this gene in the tumor environment, which could lead to entirely new treatments for breast cancer and perhaps other solid tumors using agents that target cells surrounding the tumor,” says co-principal investigator Gustavo Leone, associate professor of molecular virology, immunology and medical genetics, and Ohio State cancer researcher.

This study shows that when Pten is lost in fibroblasts, a principle component of the tissue in and around tumors, it dramatically changes the structure and make-up of the tumor environment. It becomes more fibrous, inflammation worsens and tumor blood-vessel growth goes up. These changes all favor tumor growth.

Leone, Ostrowski and their colleagues learned this after removing Pten from fibroblasts in the mammary glands of mice. They were surprised to discover that Pten regulates a second gene, called Ets2, which executes the changes that occur in the tumor environment when Pten is lost.

“Remarkably, we found that this animal model mimics many of the features observed in human breast cancer, so it should help us evaluate experimental agents that might be used in combination therapies that target faulty cells in the tumor environment, as well as cancer cells” Leone says.

Funding from the National Cancer Institute, the Komen Breast Cancer Foundation, the Evelyn Simmers Charitable Trust, a Terry Fox New Frontiers Group Grant, and the Natural Science and Engineering Research Council of Canada Discovery Grants Program supported this research. Leone is the recipient of the Pew Charitable Trusts Scholar Award and the Leukemia and Lymphoma Society Scholar Award.

Other researchers involved in this study were Anthony J. Trimboli, Carmen Z. Cantemir-Stone, Fu Li, Julie A. Wallace, Anand Merchant, Nicholas Creasap, John C. Thompson, Enrico Caserta, Hui Wang, Jean-Leon Chong, Shan Naidu, Guo Wei, Sudarshana M. Sharma, Julie A. Stephens, Soledad A. Fernandez, Metin N. Gurcan, Michael B. Weinstein, Sanford H. Barsky, Lisa Yee, Thomas J. Rosol, and Paul C. Stromberg of Ohio State; Michael L. Robinson of Columbus Children’s Research Institute; and Francois Pepin, Michael Hallett and Morag Park of Rosalind and Morris Goodman Cancer Center.

The Ohio State University Comprehensive Cancer Center- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute is one of only 40 Comprehensive Cancer Centers in the United States designated by the National Cancer Institute. Ranked by U.S. News & World Report among the top 20 cancer hospitals in the nation, The James (www.jamesline.com) is the 180-bed adult patient-care component of the cancer program at The Ohio State University. The OSUCCC-James is one of only five centers in the country approved by the NCI to conduct both Phase I and Phase II clinical trials.