title: FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer.
abstract: Four and a half LIM domain protein-2 (FHL2) is a component of the focal adhesion structures and has been suggested to have an important role in cancer progression. This study analyses the role of FHL2 in peritumoural fibroblasts of sporadic and hereditary non-polyposis colorectal cancer (HNPCC). Tissue specimens of 48 sporadic and 49 hereditary colon cancers, respectively, were stained immunohistochemically for FHL2, transforming growth factor (TGF)-β1 ligand and α-SMA. Myofibroblasts at the tumour invasion front co-expressed α-SMA and FHL2. Sporadic colon cancer but not HNPCC cases showed a correlation between TGF-β1 expression of the invading tumour cells and FHL2 staining of peritumoural myofibroblasts. Overexpression of FHL2 in peritumoural myofibroblasts correlated to lymphatic metastasis in sporadic colon cancer but not in HNPCC. In cultured mouse fibroblasts, TGF-β1 treatment induced myofibroblast differentiation, stimulated FHL2 protein expression and elevated number of migratory cells in transwell motility assays, suggesting that FHL2 is regulated downstream of TGF-β. Physical contact of colon cancer cells and myofibroblasts via FHL2-positive focal adhesions was detected in human colon carcinoma tissue and in co-culture assays using sporadic as well as HNPCC-derived tumour cell lines. Our data provide strong evidence for an important role of FHL2 in the progression of colon cancers. Tumour-secreted TGF-β1 stimulates FHL2 protein expression in peritumoural fibroblasts, probably facilitating the invasion of tumour glands into the surrounding tissue by enhanced myofibroblast migration and tight connection of fibroblasts to tumour cells via focal adhesions. These findings are absent in HNPCC-associated colon cancers in vivo and may contribute to a less invasive and more protruding tumour margin of microsatellite instable carcinomas.
authors.affiliation: Institute of Pathology, University of Bonn Medical School, Bonn, Germany.
authors.forename: Lucia
authors.initials: L
authors.lastname: Gullotti
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Czerwitzki
authors.forename: Jutta
authors.initials: J
authors.lastname: Kirfel
authors.forename: Peter
authors.initials: P
authors.lastname: Propping
authors.forename: Nils
authors.initials: N
authors.lastname: Rahner
authors.forename: Verena
authors.initials: V
authors.lastname: Steinke
authors.forename: Philip
authors.initials: P
authors.lastname: Kahl
authors.forename: Christoph
authors.initials: C
authors.lastname: Engel
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Friedrichs
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D054443:Cell Migration Assays; D003106:Colon / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D014157:Transcription Factors / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; C105987:FHL2 protein, human; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; C508960:TGFB1 protein, human; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1