Breast Cancers Activate Stromal Fibroblast-Induced Suppression of Progenitors in Adjacent Normal Tissue

• Published in: Stem cell reports Vol. 10; no. 1; pp. 196 - 211
• Main Authors: Chatterjee, Sumanta, Basak, Pratima, Buchel, Edward, Safneck, Janice, Murphy, Leigh C., Mowat, Michael, Kung, Sam K., Eirew, Peter, Eaves, Connie J., Raouf, Afshin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09-01-2018; Elsevier
• Subjects: activated stromal fibroblasts; Animals; breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Female; Fibroblasts - metabolism; Fibroblasts - pathology; Humans; Mice; Mice, Inbred BALB C; Mice, Knockout; Neoplasm Proteins - metabolism; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Stromal Cells - metabolism; Stromal Cells - pathology; suppression of normal breast tissue progenitors; TGF-β; Transforming Growth Factor beta - metabolism; tumor-adjacent tissue; suppression of normal breast tissue progenitors; activated stromal fibroblasts; tumor-adjacent tissue; breast cancer; TGF-β
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2017.11.002

Human breast cancer cells are known to activate adjacent “normal-like” cells to enhance their own growth, but the cellular and molecular mechanisms involved are poorly understood. We now show by both phenotypic and functional measurements that normal human mammary progenitor cells are significantly under-represented in the mammary epithelium of patients' tumor-adjacent tissue (TAT). Interestingly, fibroblasts isolated from TAT samples showed a reduced ability to support normal EGF-stimulated mammary progenitor cell proliferation in vitro via their increased secretion of transforming growth factor β. In contrast, TAT fibroblasts promoted the proliferation of human breast cancer cells when these were co-transplanted in immunodeficient mice. The discovery of a common stromal cell-mediated mechanism that has opposing growth-suppressive and promoting effects on normal and malignant human breast cells and also extends well beyond currently examined surgical margins has important implications for disease recurrence and its prevention.
[Display omitted]
•Alterations to the breast tissue extend as far as 6 cm away from the primary tumors•The matching contralateral non-tumor-bearing breast tissue remains unaltered•Tumor-adjacent breast tissue contained significantly diminished progenitor pool•Extending surgical margins may not be effective in reducing risk of tumor recurrence
Because breast-conserving surgeries are popular among breast cancer patients, studying the “normal” tissue remaining after the surgery is important for understanding how this tissue is primed to promote the growth of residual tumor cells. In this article, Raouf and colleagues show that tumor-adjacent breast tissue contains altered fibroblasts that diminish normal progenitor proliferation while augmenting breast cancer cell growth.