Research News
Key Molecule Reprograms Microenvironment to Support Tumor Growth
A team of investigators from the Ohio State University Comprehensive Cancer Center has identified two key molecules that cause normal cells in the tissue surrounding a tumor, the stroma, to produce nutrients that fuel tumor growth. The results of this study, which were published in the journal Nature Cell Biology, demonstrate what happens when normal cells called fibroblasts in mouse mammary tumors lose an important tumor-suppressor gene called Pten.
The findings suggest new strategies for controlling tumor growth by developing drugs that disrupt the communication between tumor cells and the stromal fibroblasts. They also provide insight into the mechanisms that control the co-evolution of cancer cells and stromal fibroblasts, and they demonstrate how the Pten gene normally suppresses cancer development.
According to the investigators, this study is the first to define a specific pathway in tumor-associated fibroblasts that reprograms gene activity and the behavior of multiple cell types in the tumor microenvironment, including tumor cells themselves. The team was led by Michael Ostrowski and Gustavo Leone.
In studies using mammary fibroblasts, the researchers found that the Pten gene regulates a molecule called microRNA-320 (miR-320), and that the loss of Pten leads to a dramatic drop in the level of that molecule in a tumor-associated fibroblast. With little miR-320 around, the level of a protein called ETS2 rise in the fibroblasts. As ETS2 levels increase, a number of genes become active that cause the fibroblasts to secrete more than 50 factors that stimulate the proliferation and invasiveness of nearby cancer cells. It also causes the reprogramming of other fibroblasts in the tumor and throughout the mammary gland.
These findings suggest that the development of drugs that modulate levels of miR-320 in non-cancer cells in the tumor microenvironment could provide a new approach to attacking tumor growth.
The investigators also demonstrated that the molecular signature of the miR-320 secretome – the proteins whose expression is impacted by this micro-RNA – can distinguish normal breast tissue from tumor tissue. Moreover, the molecular signature derived from tumor tissue predicted the outcome of therapy in breast cancer patients.
This work, which was supported in part by the National Cancer Institute, is detailed in a paper titled, "Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320." Investigators from McGill University also participated in this study. An abstract of this paper is available at the journal's Web site.
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