title: Differential mechanical response of mesenchymal stem cells and fibroblasts to tumor-secreted soluble factors.
abstract: The progression of neoplastic malignancies is a complex process resulting not only from the accumulation of mutations within tumor cells, but also modulation of the tumor microenvironment. Recent advances have shown that the recruitment and subsequent heterotypic interactions of stromal cells--including fibroblasts and bone marrow-derived mesenchymal stem cells (MSCs)--are crucial for carcinogenesis. Though extensive work has been done analyzing the signals that recruit these cells, the governing mechanical properties have not been fully investigated. Here, we report that despite their initial similarities, MSCs respond not only faster but also more dramatically to pro-migratory tumor-secreted soluble factors. Utilizing multiple particle tracking microrheology to probe the cytoskeletal mechanical properties, we show that MSCs stiffen completely within one hour, three times faster than fibroblasts. In addition, unlike fibroblasts, MSCs exposed to tumor-secreted soluble factors display a functionally different phenotype characterized by morphological elongation, decreased actin stress fiber density, and decreased adhesion. Quantitative real-time PCR indicates these phenomena occur based on differential expression of small GTPases RhoA and Cdc42, but not Rac1. These findings demonstrate a fundamental difference in the recruitment of fibroblasts and MSCs.
authors.affiliation: School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: McGrail
authors.forename: Deepraj
authors.initials: D
authors.lastname: Ghosh
authors.forename: Nhat D
authors.initials: ND
authors.lastname: Quach
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Dawson
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D003599:Cytoskeleton / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D022001:Focal Adhesions / Q000502:physiology; D015870:Gene Expression; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D009479:Neuropeptides / Q000235:genetics; D012212:Rheology; D012995:Solubility; D041701:Swiss 3T3 Cells; D020764:cdc42 GTP-Binding Protein / Q000235:genetics; D020744:rac GTP-Binding Proteins / Q000235:genetics; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins / Q000235:genetics; D020742:rhoA GTP-Binding Protein
chemical_list: D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D009479:Neuropeptides; C484602:Rac1 protein, mouse; C526380:RhoA protein, mouse; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein