title: Tumor fibroblast-derived epiregulin promotes growth of colitis-associated neoplasms through ERK.
abstract: Molecular mechanisms specific to colitis-associated cancers have been poorly characterized. Using comparative whole-genome expression profiling, we observed differential expression of epiregulin (EREG) in mouse models of colitis-associated, but not sporadic, colorectal cancer. Similarly, EREG expression was significantly upregulated in cohorts of patients with colitis-associated cancer. Furthermore, tumor-associated fibroblasts were identified as a major source of EREG in colitis-associated neoplasms. Functional studies showed that Ereg-deficient mice, although more prone to colitis, were strongly protected from colitis-associated tumors. Serial endoscopic studies revealed that EREG promoted tumor growth rather than initiation. Additionally, we demonstrated that fibroblast-derived EREG requires ERK activation to induce proliferation of intestinal epithelial cells (IEC) and tumor development in vivo. To demonstrate the functional relevance of EREG-producing tumor-associated fibroblasts, we developed a novel system for adoptive transfer of these cells via mini-endoscopic local injection. It was found that transfer of EREG-producing, but not Ereg-deficient, fibroblasts from tumors significantly augmented growth of colitis-associated neoplasms in vivo. In conclusion, our data indicate that EREG and tumor-associated fibroblasts play a crucial role in controlling tumor growth in colitis-associated neoplasms.
authors.affiliation: Medical Clinic 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Neufert
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Türeci
authors.forename: Maximilian J
authors.initials: MJ
authors.lastname: Waldner
authors.forename: Ingo
authors.initials: I
authors.lastname: Backert
authors.forename: Katharina
authors.initials: K
authors.lastname: Floh
authors.forename: Imke
authors.initials: I
authors.lastname: Atreya
authors.forename: Moritz
authors.initials: M
authors.lastname: Leppkes
authors.forename: Andre
authors.initials: A
authors.lastname: Jefremow
authors.forename: Michael
authors.initials: M
authors.lastname: Vieth
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
authors.forename: Patricia
authors.initials: P
authors.lastname: Klinger
authors.forename: Florian R
authors.initials: FR
authors.lastname: Greten
authors.forename: David W
authors.initials: DW
authors.lastname: Threadgill
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000150:complications*; D003106:Colon / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000473:pathology; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D066260:Epiregulin; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D059467:Transcriptome; D047368:Tumor Burden
chemical_list: C587880:EREG protein, human; D066260:Epiregulin; C587881:Ereg protein, mouse; D019394:Ki-67 Antigen; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases
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