title: Metastatic growth from dormant cells induced by a col-I-enriched fibrotic environment.
abstract: Breast cancer that recurs as metastatic disease many years after primary tumor resection and adjuvant therapy seems to arise from tumor cells that disseminated early in the course of disease but did not develop into clinically apparent lesions. These long-term surviving, disseminated tumor cells maintain a state of dormancy, but may be triggered to proliferate through largely unknown factors. We now show that the induction of fibrosis, associated with deposition of type I collagen (Col-I) in the in vivo metastatic microenvironment, induces dormant D2.0R cells to form proliferative metastatic lesions through beta1-integrin signaling. In vitro studies using a three-dimensional culture system modeling dormancy showed that Col-I induces quiescent D2.0R cells to proliferate through beta1-integrin activation of SRC and focal adhesion kinase, leading to extracellular signal-regulated kinase (ERK)-dependent myosin light chain phosphorylation by myosin light chain kinase and actin stress fiber formation. Blocking beta1-integrin, Src, ERK, or myosin light chain kinase by short hairpin RNA or pharmacologic approaches inhibited Col-I-induced activation of this signaling cascade, cytoskeletal reorganization, and proliferation. These findings show that fibrosis with Col-I enrichment at the metastatic site may be a critical determinant of cytoskeletal reorganization in dormant tumor cells, leading to their transition from dormancy to metastatic growth. Thus, inhibiting Col-I production, its interaction with beta1-integrin, and downstream signaling of beta1-integrin may be important strategies for preventing or treating recurrent metastatic disease.
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Dalit
authors.initials: D
authors.lastname: Barkan
authors.forename: Lara H
authors.initials: LH
authors.lastname: El Touny
authors.forename: Aleksandra M
authors.initials: AM
authors.lastname: Michalowski
authors.forename: Jane Ann
authors.initials: JA
authors.lastname: Smith
authors.forename: Isabel
authors.initials: I
authors.lastname: Chu
authors.forename: Anne Sally
authors.initials: AS
authors.lastname: Davis
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Webster
authors.forename: Shelley
authors.initials: S
authors.lastname: Hoover
authors.forename: R Mark
authors.initials: RM
authors.lastname: Simpson
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Green
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D024042:Collagen Type I / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D010766:Phosphorylation; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D024042:Collagen Type I; D019012:Integrin beta1; D016212:Transforming Growth Factor beta; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D019061:src-Family Kinases; D009219:Myosin-Light-Chain Kinase; D048049:Extracellular Signal-Regulated MAP Kinases