Connective tissue growth factor inhibits metastasis and acts as an independent prognostic marker in colorectal cancer.
OBJECTIVE
Connective tissue growth factor (CTGF) has been shown to be implicated in tumor development and progression. The aim of this study was to investigate the role of CTGF in progression of colorectal cancer (CRC).


METHODS
Immunohistochemical staining of specimens from 119 patients with CRC was performed. Liposome-mediated transfection was used to introduce a CTGF expression vector into CRC cell lines. Transfectants were tested in invasive ability and experimental hepatic metastasis in BALB/c mice. Furthermore, a FOPflash/TOPflash reporter assay was performed to investigate CTGF on the beta-catenin/T-cell factor signaling pathway.


RESULTS
Patients with stage II and stage III CRC whose tumors displayed high CTGF expression had a significantly higher overall survival and a disease-free advantage over patients with CRC with low CTGF expression. Alterations in the CTGF level in CRC cell lines modulated their invasive ability with an inverse correlation. In addition, a reduction in the CTGF level of CT26 cells after stable transfection with antisense CTGF resulted in increased liver metastasis in BALB/c mice. The activity of the beta-catenin/T-cell factor signaling pathway and its downstream effector gene matrix metalloproteinase 7 in these CTGF-transfected cells was strongly attenuated. Blockage of matrix metalloproteinase 7 with its neutralizing antibodies inhibited increased invasiveness in antisense CTGF-transfected CT26 cells.


CONCLUSIONS
Our results implicate CTGF as a key regulator of CRC invasion and metastasis, and it appears to be a useful and better prognosis factor for patients with stage II and stage III CRC.
Lin
Been-Ren
BR
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Chang
Cheng-Chi
CC
Che
Ting-Fang
TF
Chen
Szu-Ta
ST
Chen
Robert Jeen-Chen
RJ
Yang
Ching-Yao
CY
Jeng
Yung-Ming
YM
Liang
Jin-Tung
JT
Lee
Po-Huang
PH
Chang
King-Jen
KJ
Chau
Yat-Pang
YP
Kuo
Min-Liang
ML
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D055513:Connective Tissue Growth Factor; D003598:Cytoskeletal Proteins / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D023421:Models, Animal; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011379:Prognosis; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D051176:beta Catenin
D014408:Biomarkers, Tumor; C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D015534:Trans-Activators; D051176:beta Catenin; D055513:Connective Tissue Growth Factor