Carcinogenesis Advance Access originally published online on May 21, 2008
Carcinogenesis 2008 29(7):1421-1427; doi:10.1093/carcin/bgn123
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Sulindac treatment alters collagen and matrilysin expression in adenomas of ApcMin/+ mice
1 W. M. Keck Center for Transgene Research
2 Department of Chemistry and Biochemistry
3 Notre Dame Cancer Institute
4 Department of Mathematics
5 Freimann Life Science Center, University of Notre Dame, Notre Dame, IN 46556, USA
* To whom correspondence should be addressed. Tel: +1 574 631 4017; Fax: +1 574 631 4414; Email: vploplis{at}nd.edu
Non-steroidal anti-inflammatory drugs (NSAIDs) have shown potential as chemopreventive agents against cancer formation, especially colorectal cancers. However, the mechanisms by which these drugs act are not fully understood. In this study, ApcMin/+ mice, a genetic model of human familial adenomatous polyposis, were treated with sulindac, and these mice demonstrated tumor reduction of >80%, consistent with previous reports. Gene microarray analyses of RNA from adenoma-derived dysplastic epithelial cells revealed that collagen genes, viz. Col1a2, Col5a2, Col6a2 and Col6a3, were upregulated, and matrilysin matrix metalloproteases-7 (Mmp7) was downregulated, in sulindac-treated mice. Reverse transcription–polymerase chain reaction validated gene expression of the Col6a2 subunit of collagen VI and of Mmp7. Confocal microscopy and immunofluorescence showed that within the tumors of non-treated mice, collagen VI was present in low amounts, but was enhanced within the tumors of sulindac-treated mice. Collagens I and V demonstrated similar patterns, but were not as prominent as collagen VI. Mmp7 was found in ‘hot spot’ areas within the tumors of ApcMin/+ mice treated with the vehicle, but was greatly diminished in those mice treated with sulindac. Studies with ApcMin/+/Mmp7–/– double-deficient mice demonstrated the reciprocal relationships of Mmp7 expression and the levels of these three collagens in vivo. The results of this study demonstrated that sulindac was effective in increasing the expression of different collagens and decreasing the expression of Mmp7, effects that may contribute to altered tumor burden in cancer patients undergoing NSAIDs treatments.
Abbreviations: ECM, extracellular matrix; LCM, laser capture microdissection; Mmp7, matrix metalloproteases-7; NSAID, non-steroidal anti-inflammatory drug; PCR, polymerase chain reaction; PGE2, prostaglandin E2; RT, reverse transcription; WT, wild-type
Received February 19, 2008; revised May 6, 2008; accepted May 15, 2008.