title: Tumoral expression of nuclear cofactor FHL2 is associated with lymphatic metastasis in sporadic but not in HNPCC-associated colorectal cancer.
abstract: BACKGROUND
  Four and a half LIM domain protein-2 (FHL2) is part of the focal adhesion structures modulating cell motility. FHL2 may translocate into the nucleus serving as a transcriptional cofactor binding several transcription factors. Overexpression of FHL2 has been linked to cancer progression in various neoplasias. The aim of the present study was to determine, whether FHL2's function as nuclear cofactor plays a prognostic role in invading tumor cells of sporadic and HNPCC-associated colorectal cancer (CRC).
  
  
  METHODS
  Immunohistochemical staining intensity of nuclear FHL2 was quantified by Remmele score analysing 47 sporadic and 42 HNPCC-associated colorectal cancers. Analysis was restricted to carcinoma cells of the tumoral invasion front.
  
  
  RESULTS
  Confocal microscopy detected nuclear expression of FHL2 in colon cancer cells and absence of nuclear FHL2 signal in normal colon enterocytes. In colon cancer, nuclear FHL2 expression was predominantly observed in low-differentiated, often mucinous tumor areas. 42.55% of sporadic and 54.76% of HNPCC-associated CRC showed enhanced (Remmele score 6-12) nuclear FHL2 expression in the carcinoma cells of the tumoral advancing edge. Enhanced nuclear FHL2 expression was significantly linked to lymphatic metastasis in sporadic CRC (p=0.0197) and almost reached significance in HNPCC-associated CRC (p=0.0545). In contrast, nuclear FHL2 expression was neither associated with hematogenic metastasis in sporadic (p=0.7087) nor in HNPCC-associated colorectal cancer (p=0.3007).
  
  
  CONCLUSIONS
  We recently demonstrated that enhanced nuclear FHL2 expression in tumor stroma of sporadic colon cancer is associated with lymphatic metastasis. The results of the present study indicate a synergistic effect of nuclear cofactor FHL2 in tumor cells as well as in peritumoral stroma cells promoting lymphatic metastasis in sporadic CRC. As HNPCC-associated tumors did not show a significant association between tumoral nuclear FHL2 expression and lymphatic metastasis we speculate, that the intensive lymphocytic immune response in HNPCC precludes a direct contact of tumor cells and stromal cells resulting in reduced lymphatic spread.
authors.affiliation: Institute of Pathology, University of Cologne Medical School, Kerpener Str. 62, 50937 Cologne, Germany.
authors.forename: Lukman
authors.initials: L
authors.lastname: Al-Nomani
authors.affiliation: Institute of Pathology, University of Cologne Medical School, Kerpener Str. 62, 50937 Cologne, Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Friedrichs
authors.affiliation: Center for Clinical Research, University of Freiburg Medical School, Breisacherstr. 66, 79106 Freiburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
authors.affiliation: Institute of Pathology, University of Cologne Medical School, Kerpener Str. 62, 50937 Cologne, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.affiliation: Institute of Pathology, University of Cologne Medical School, Kerpener Str. 62, 50937 Cologne, Germany. Electronic address: nicolaus.friedrichs@uk-koeln.de.
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Friedrichs
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D060850:LIM-Homeodomain Proteins / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C105987:FHL2 protein, human; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors
keywords: Colon cancer; FHL2; HNPCC; Lymphatic metastasis