A study led by Ohio State University cancer researchers 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 (pictured top), 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 (pictured bottom), 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 principal 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.
Illustration: Ohio State University Medical Center.
Ohio State University Medical Center News Release (10/21/09)
Science Daily (10/21/09)
Abstract (Nature; 461, 1084-1091 (10/22/09))