title: Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics.
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.
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Dumont
authors.forename: Bob
authors.initials: B
authors.lastname: Liu
authors.forename: Rosa Anna
authors.initials: RA
authors.lastname: Defilippis
authors.forename: Hang
authors.initials: H
authors.lastname: Chang
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Rabban
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Karnezis
authors.forename: Judy A
authors.initials: JA
authors.lastname: Tjoe
authors.forename: James
authors.initials: J
authors.lastname: Marx
authors.forename: Bahram
authors.initials: B
authors.lastname: Parvin
authors.forename: Thea D
authors.initials: TD
authors.lastname: Tlsty
mesh_terms: D000818:Animals; D001940:Breast / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology*; D009362:Neoplasm Metastasis; D010641:Phenotype; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D016212:Transforming Growth Factor beta; D048049:Extracellular Signal-Regulated MAP Kinases; D020741:rho GTP-Binding Proteins