title: Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent.
abstract: Normal human and murine fibroblasts can inhibit proliferation of tumor cells when cocultured in vitro. The inhibitory capacity varies depending on the donor and the site of origin of the fibroblast. We showed previously that effective inhibition requires formation of a morphologically intact fibroblast monolayer before seeding of the tumor cells. Here we show that inhibition is extended to motility of tumor cells and we dissect the factors responsible for these inhibitory functions. We find that inhibition is due to two different sets of molecules: (i) the extracellular matrix (ECM) and other surface proteins of the fibroblasts, which are responsible for contact-dependent inhibition of tumor cell proliferation; and (ii) soluble factors secreted by fibroblasts when confronted with tumor cells (confronted conditioned media, CCM) contribute to inhibition of tumor cell proliferation and motility. However, conditioned media (CM) obtained from fibroblasts alone (nonconfronted conditioned media, NCM) did not inhibit tumor cell proliferation and motility. In addition, quantitative PCR (Q-PCR) data show up-regulation of proinflammatory genes. Moreover, comparison of CCM and NCM with an antibody array for 507 different soluble human proteins revealed differential expression of growth differentiation factor 15, dickkopf-related protein 1, endothelial-monocyte-activating polypeptide II, ectodysplasin A2, Galectin-3, chemokine (C-X-C motif) ligand 2, Nidogen1, urokinase, and matrix metalloproteinase 3.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden; Department of Biology, College of Science, Salahaddin University, 44002, Irbil, Kurdistan-Iraq;
authors.forename: Twana
authors.initials: T
authors.lastname: Alkasalias
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden;
authors.forename: Emilie
authors.initials: E
authors.lastname: Flaberg
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden; Institute of Molecular Biology and Genetics, Ukrainian National Academy of Sciences, 03680, Kiev, Ukraine; and.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kashuba
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden; Bioinformatics Infrastructure for Life Sciences, Science for Life Laboratory, 17165 Stockholm, Sweden.
authors.forename: Andrey
authors.initials: A
authors.lastname: Alexeyenko
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden;
authors.forename: Tatiana
authors.initials: T
authors.lastname: Pavlova
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden;
authors.forename: Andrii
authors.initials: A
authors.lastname: Savchenko
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden;
authors.forename: Laszlo
authors.initials: L
authors.lastname: Szekely
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden; georg.klein@ki.se.
authors.forename: George
authors.initials: G
authors.lastname: Klein
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden;
authors.forename: Hayrettin
authors.initials: H
authors.lastname: Guven
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003260:Contact Inhibition / Q000187:drug effects / Q000502:physiology*; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097573:Red Fluorescent Protein
chemical_list: D017077:Culture Media, Conditioned; D008164:Luminescent Proteins; D000097573:Red Fluorescent Protein
keywords: cancer-associated fibroblast; extracellular matrix; motility; soluble factors; tumor microenvironment