title: Human mesenchymal stem cells exploit the immune response mediating chemokines to impact the phenotype of glioblastoma.
abstract: In contrast to the application of human mesenchymal stem cells (hMSCs) in regenerative medicine, only a limited number of studies are addressing their use in anticancer therapy. As the latter may represent a new hope to improve the survival of patients with glioblastoma multiformae (GBM), the most common and malignant form of the brain tumors, we aimed to investigate the interactions of hMSCs and GBM cells under in vitro conditions. Four hMSC clones and three different GBM cell lines were used to study their mutual paracrine interactions in cocultures compared to their monocultures, where cells were grown under the same experimental conditions. The effects on cell growth, proliferation, and invasion in Matrigel were quantified. Further, bioinformatics tools were used to relate these results to the data obtained from cytokine macroarrays and cDNA microarrays that revealed proteins and genes significantly involved in cellular cross-talk. We showed that hMSCs are responsible for the impairment of GBM cell invasion and growth, possibly via induction of their senescence. On the other hand, GBM cells inversely affected some of these characteristics in hMSCs. We found CCL2/MCP-1 to be the most significantly regulated chemokine during hMSC and U87-MG paracrine signaling in addition to several chemokines that may account for changed cocultured cells' phenotype by affecting genes associated with proliferation (Pmepa-1, NF-κB, IL-6, IL-1b), invasion (EphB2, Sod2, Pcdh18, Col7A1, Gja1, Mmp1/2), and senescence (Kiaa1199, SerpinB2). As we functionally confirmed the role of CCL2/MCP-1 in GBM cell invasion we thereby propose a novel mechanism of CCL2/MCP-1 antimigratory effects on GBM cells, distinct from its immunomodulatory role. Significant alterations of GBM phenotype in the presence of hMSCs should encourage the studies on the naive hMSC use for GBM treatment.
authors.affiliation: National Institute of Biology, Department of Genetic Toxicology and Cancer Biology, Vecna pot 111, SI-1000 Ljubljana, Slovenia. helena.motaln@nib.si
authors.forename: Helena
authors.initials: H
authors.lastname: Motaln
authors.forename: Kristina
authors.initials: K
authors.lastname: Gruden
authors.forename: Matjaz
authors.initials: M
authors.lastname: Hren
authors.forename: Christian
authors.initials: C
authors.lastname: Schichor
authors.forename: Monika
authors.initials: M
authors.lastname: Primon
authors.forename: Ana
authors.initials: A
authors.lastname: Rotter
authors.forename: Tamara T
authors.initials: TT
authors.lastname: Lah
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D018920:Coculture Techniques; D003094:Collagen / Q000737:chemistry; D015536:Down-Regulation; D004338:Drug Combinations; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D056747:Immunomodulation; D007797:Laminin / Q000737:chemistry; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019899:Paracrine Communication; D010641:Phenotype; D040081:Protein Array Analysis; D011509:Proteoglycans / Q000737:chemistry; D015854:Up-Regulation
chemical_list: D018932:Chemokine CCL2; D018925:Chemokines; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen