Breast Fibroblasts Modulate Early Dissemination, Tumorigenesis, and Metastasis through Alteration of Extracellular Matrix Characteristics

• Published in: Neoplasia (New York, N.Y.) Vol. 15; no. 3; pp. 249 - IN7
• Main Authors: Dumont, Nancy, Liu, Bob, DeFilippis, Rosa Anna, Chang, Hang, Rabban, Joseph T, Karnezis, Anthony N, Tjoe, Judy A, Marx, James, Parvin, Bahram, Tlsty, Thea D
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2013; Elsevier
• Subjects: Animals; Breast - metabolism; Breast - pathology; Cell Line, Tumor; Cell Transformation, Neoplastic - metabolism; Coculture Techniques; Epithelial Cells - metabolism; Epithelial Cells - pathology; Extracellular Matrix - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Fibroblasts - metabolism; Humans; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Neoplasm Metastasis; Oncology; Phenotype; Proto-Oncogene Proteins c-jun - metabolism; rho GTP-Binding Proteins - metabolism; Signal Transduction; Transforming Growth Factor beta - metabolism; invasive ductal carcinoma; carcinoma-associated fibroblasts; ROCK; EpCAM; stromal-derived factor-1; SDF-1; TNC; IDC; fluorescence-activated cell sorting; FACS; RMFs; cleaved caspase 3; GFP; CC3; reduction mammoplasty fibroblasts; human mammary epithelial cells; CAFs; variant HMEC with repressed p16 INK4A; tenascin C; CTCs; TGFβ receptor kinase inhibitor; Fn; HMECs; circulating tumor cells; lysyl oxidase; green fluorescent protein; ECM; Lux; Rho-associated kinase; ductal carcinoma in situ; fibronectin; LOX; transforming growth factor-β; DCIS; luciferase; TGFβ; vHMEC; TβRKi; extracellular matrix; epithelial cell adhesion molecule
• ISSN: 1476-5586; 1476-5586; 1522-8002
• DOI: 10.1593/neo.121950

Abstract A wealth of evidence has now demonstrated that the microenvironment in which a tumorigenic cell evolves is as critical to its evolution as the genetic mutations it accrues. However, there is still relatively little known about how signals from the microenvironment contribute to the early events in the progression to malignancy. To address this question, we used a premalignant mammary model to examine how fibroblasts, and the extracellular matrix (ECM) proteins they secrete, influence progression to malignancy. Their effect on metastatic malignant cells was also assessed for comparison. We found that carcinoma-associated fibroblasts, and the distinct aligned ECM they deposit, can cause both premalignant and malignant mammary epithelial cells to assume a mesenchymal morphology that is associated with increased dissemination and metastasis, while benign reduction mammoplasty fibroblasts favor the maintenance of an epithelial morphology and constrain early dissemination, tumor growth, and metastasis. Our results suggest that normalizing the organization of the ECM could be effective in limiting systemic dissemination and tumor growth.