title: SCCOHT tumors acquire chemoresistance and protection by interacting mesenchymal stroma/stem cells within the tumor microenvironment.
abstract: Chemotherapeutic drug testing of SCCOHT-1 and BIN-67 tumor cells revealed synergistic growth-inhibition of >95% in vitro with a combination of foretinib and FK228. Application of this drug combination in vivo in NODscid mice-induced SCCOHT-1GFP tumors was associated with ~6-fold reduction in tumor mass within 10 days, whereby synergistic effects of the two compounds remained undetectable compared to previous results with foretinib treatment alone. Histopathologic evaluation revealed a reduced vascularization and a lower amount of proliferating cells in the treated tumors. Surprisingly, a simultaneous significant accumulation of extracellular matrix structures with positive elastin-van Gieson staining was observed following foretinib/FK228 exposure. Expression analysis of treated animal tumors exhibited various changes including increased mouse transcript levels of elastin, laminin, and fibronectin. In parallel, markers for mesenchymal stroma/stem cells (MSC) including CD73 and CD90 were detectable in all mouse tumors suggesting a possible involvement of these cells in extracellular matrix restructure. Indeed, incubation of MSC with FK228 or foretinib/FK228 demonstrated morphologic alterations and enhanced expression of laminin and fibronectin. Moreover, a co-culture of MSC with lentiviral-labeled SCCOHT-1GFP cells contributed to protection of the tumor cells against FK228-mediated cytotoxicity. Furthermore, explant cultures of SCCOHT-1GFP-induced tumors acquired an increased resistance to FK228 and a combination of foretinib/FK228 in contrast to foretinib alone. Together, these data suggested that FK228-mediated extracellular matrix protein expression by MSC contributes to increased protection and enhanced resistance of SCCOHT tumors which could represent a more general mechanism of MSC during drug-induced alterations of a tumor microenvironment.
authors.affiliation: Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Otte
authors.affiliation: Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: von der Ohe
authors.affiliation: Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Catharina
authors.initials: C
authors.lastname: Melzer
authors.affiliation: Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hillemanns
authors.affiliation: Institute for Pathology, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Feuerhake
authors.affiliation: Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Hass
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004549:Elastin / Q000378:metabolism; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011804:Quinolines / Q000494:pharmacology*; D018800:Thy-1 Antigens / Q000378:metabolism; D059016:Tumor Microenvironment / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D047630:Depsipeptides; D005353:Fibronectins; C544831:GSK 1363089; D007797:Laminin; D011804:Quinolines; D018800:Thy-1 Antigens; D004549:Elastin; C087123:romidepsin; D015720:5'-Nucleotidase