TY - JOUR
T1 - FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer
AU - Gullotti, Lucia
AU - Czerwitzki, Jacqueline
AU - Kirfel, Jutta
AU - Propping, Peter
AU - Rahner, Nils
AU - Steinke, Verena
AU - Kahl, Philip
AU - Engel, Christoph
AU - Schüle, Roland
AU - Buettner, Reinhard
AU - Friedrichs, Nicolaus
N1 - Funding Information:
We thank Barbara Reddemann, Susanne Steiner and Christiane Esch for their expert technical assistance. Lucia Gullotti was supported as a graduate within the Graduiertenkolleg 804 of the Deutsche Forschungsgemeinschaft. This work was supported by the BONFOR grant (BonFor-Program) to NF and by a grant from the Deutsche Forschungsgemeinschaft to RB (GRK 804 and SFB 832). This work was supported by the German Cancer Aid by a grant to the German HNPCC Consortium (speaker: PP).
Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=82355181388&partnerID=8YFLogxK
U2 - 10.1038/labinvest.2011.109
DO - 10.1038/labinvest.2011.109
M3 - Journal articles
C2 - 21826055
AN - SCOPUS:82355181388
SN - 0023-6837
VL - 91
SP - 1695
EP - 1705
JO - Laboratory Investigation
JF - Laboratory Investigation
IS - 12
ER -