Under the Influence

Normal cells aid tumor progression

A study led by Ohio State University cancer researchers is the first to show that gene alterations in stromal fibroblasts can foster tumor growth. This work provides the first mouse model that accurately represents the tumor microenvironment found in human breast cancer.

Co-principal investigators Michael Ostrowski, PhD, and Gustavo Leone, PhD, both of The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and their colleagues eliminated the Pten tumor suppressor gene from stromal fibroblasts present in a mouse epithelial mammary tumor.

Pten is a key regulator of cell metabolism that is lost in the malignant cells of many human cancers, this study revealed that it also influences the tumor microenvironment.

The loss of Pten led to overexpression of a second fibroblast gene, Ets2. That resulted in gene expression changes and led to extensive remodeling of the extracellular matrix, as well as increased inflammation and angiogenesis, all of which favor tumor growth.

Remarkably, altering the Pten-Ets2 alignment in the mouse model accurately mimicked histological and molecular changes that occur in human breast cancer.

The findings demonstrate that 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 don’t.

In addition, the studies identify new stromal-specific biomarkers that may help guide treatment and identify molecular targets for developing new therapies aimed at tumor stromal cells. They could also improve the understanding of other pathological conditions that are influenced by the tissue microenvironment, such as autoimmune disease, lung fibrosis and neurodegenerative diseases.

Published in the Oct. 22, 2009, issue of Nature.

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