title: Cellular Adhesion Promotes Prostate Cancer Cells Escape from Dormancy.
abstract: Dissemination of prostate cancer (PCa) cells to the bone marrow is an early event in the disease process. In some patients, disseminated tumor cells (DTC) proliferate to form active metastases after a prolonged period of undetectable disease known as tumor dormancy. Identifying mechanisms of PCa dormancy and reactivation remain a challenge partly due to the lack of in vitro models. Here, we characterized in vitro PCa dormancy-reactivation by inducing cells from three patient-derived xenograft (PDX) lines to proliferate through tumor cell contact with each other and with bone marrow stroma. Proliferating PCa cells demonstrated tumor cell-cell contact and integrin clustering by immunofluorescence. Global gene expression analyses on proliferating cells cultured on bone marrow stroma revealed a downregulation of TGFB2 in all of the three proliferating PCa PDX lines when compared to their non-proliferating counterparts. Furthermore, constitutive activation of myosin light chain kinase (MLCK), a downstream effector of integrin-beta1 and TGF-beta2, in non-proliferating cells promoted cell proliferation. This cell proliferation was associated with an upregulation of CDK6 and a downregulation of E2F4. Taken together, our data provide the first clinically relevant in vitro model to support cellular adhesion and downregulation of TGFB2 as a potential mechanism by which PCa cells may escape from dormancy. Targeting the TGF-beta2-associated mechanism could provide novel opportunities to prevent lethal PCa metastasis.
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Nazanin
authors.initials: N
authors.lastname: Ruppender
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Sandy
authors.initials: S
authors.lastname: Larson
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Bryce
authors.initials: B
authors.lastname: Lakely
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Lori
authors.initials: L
authors.lastname: Kollath
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Lisha
authors.initials: L
authors.lastname: Brown
authors.affiliation: Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.affiliation: Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Roger
authors.initials: R
authors.lastname: Coleman
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Holly
authors.initials: H
authors.lastname: Nguyen
authors.affiliation: Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Eva
authors.initials: E
authors.lastname: Corey
authors.affiliation: Janssen Research and Development, LLC, Spring House, Pennsylvania, United States of America.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Snyder
authors.affiliation: Department of Veterans Affairs Medical Center, Seattle, Washington, United States of America; Department of Urology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Hung-Ming
authors.initials: HM
authors.lastname: Lam
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002450:Cell Communication; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016000:Cluster Analysis; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017154:Stromal Cells / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism
chemical_list: D019012:Integrin beta1; D053781:Transforming Growth Factor beta2; D051361:Cyclin-Dependent Kinase 6