title: IGFBP7, a novel tumor stroma marker, with growth-promoting effects in colon cancer through a paracrine tumor-stroma interaction.
abstract: The activated tumor stroma participates in many processes that control tumorigenesis, including tumor cell growth, invasion and metastasis. Cancer-associated fibroblasts (CAFs) represent the major cellular component of the stroma and are the main source for connective tissue components of the extracellular matrix and various classes of proteolytic enzymes. The signaling pathways involved in the interactions between tumor and stromal cells and the molecular characteristics that distinguish normal 'resting' fibroblasts from cancer-associated or '-activated' fibroblasts remain poorly defined. Recent studies emphasized the prognostic and therapeutic significance of CAF-related molecular signatures and a number of those genes have been shown to serve as putative therapeutic targets. We have used immuno-laser capture microdissection and whole-genome Affymetrix GeneChip analysis to obtain transcriptional signatures from the activated tumor stroma of colon carcinomas that were compared with normal resting colonic fibroblasts. Several members of the Wnt-signaling pathway and gene sets related to hypoxia, epithelial-to-mesenchymal transition (EMT) and transforming growth factor-β (TGFβ) pathway activation were induced in CAFs. The putative TGFβ-target IGFBP7 was identified as a tumor stroma marker of epithelial cancers and as a tumor antigen in mesenchyme-derived sarcomas. We show here that in contrast to its tumor-suppressor function in epithelial cells, IGFPB7 can promote anchorage-independent growth in malignant mesenchymal cells and in epithelial cells with an EMT phenotype when IGFBP7 is expressed by the tumor cells themselves and can induce colony formation in colon cancer cells co-cultured with IGFBP7-expressing CAFs by a paracrine tumor-stroma interaction.
authors.affiliation: Clinical Institute for Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Rupp
authors.affiliation: Institute of Medical Genetics, Center of Pathobiology and Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Scherzer
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Rudisch
authors.affiliation: Institute of Medical Genetics, Center of Pathobiology and Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Unger
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Haslinger
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors.forename: N
authors.initials: N
authors.lastname: Schweifer
authors.affiliation: Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Artaker
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Nivarthi
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Moriggl
authors.affiliation: Institute of Medical Genetics, Center of Pathobiology and Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Hengstschläger
authors.affiliation: Clinical Institute for Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: D
authors.initials: D
authors.lastname: Kerjaschki
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Sommergruber
authors.affiliation: Institute of Medical Genetics, Center of Pathobiology and Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Dolznig
authors.affiliation: 1] Clinical Institute for Pathology, Medical University of Vienna, Vienna, Austria [2] Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Garin-Chesa
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D019899:Paracrine Communication; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D018969:Insulin-Like Growth Factor Binding Proteins; D009363:Neoplasm Proteins; D016212:Transforming Growth Factor beta; C102529:insulin-like growth factor binding protein-related protein 1