Abstract
Background and aims
Colorectal cancer is one of the leading causes of cancer deaths in the Western world. A better understanding of the development and progression of colorectal carcinoma is needed to define novel targets and strategies for treatment.
Patients/methods
Gene expression profiles were determined for primary tumors of 10 locally restricted (T3N0M0), 8 lymphatically metastasized (T3N+M0), 7 systemically metastasized (T3N+M1) colorectal carcinomas, and 6 specimens of normal colorectal tissue by histology-guided oligonucleotide microarray analysis.
Results
A total of 1,995 genes were differently regulated in primary tumors of colorectal carcinoma compared with normal colorectal tissue. Besides common features of dedifferentiation and different expression of genes involved in cell division, cell adhesion, angiogenesis, signal transduction and metabolism we observed a deregulation of genes with an as yet unclear function. We identified 126 genes that were subsequently up- and 204 genes down-regulated during tumor progression. Furthermore, we found a cluster of five genes exclusively up-regulated in primary tumors of systemically metastasized colorectal carcinomas. A comparison of locally restricted (T3N0M0) and systemically metastasized (T3N+M1) primary tumors showed 50 deregulated genes with a massive down-regulation of immune-modulatory genes in primary tumors of systemically metastasized carcinomas. Primary tumors of lymphatically (T3N+M0) and systemically metastasized (T3N+M1) carcinomas differed in the expression of 19 genes.
Conclusion
These results provide an additional step toward the identification of crucial genes for the progression of colorectal cancer and the identification of novel treatment targets or strategies.
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References
Pohl C, Hombach A, Kruis W (2000) Chronic inflammatory bowel disease and cancer. Hepatogastroenterology 47:57–70
Muto T, Bussey HJ, Morson BC (1975) The evolution of cancer of the colon and rectum. Cancer 36:2251–2270
Forrester K, Almoguera C, Han K, Grizzle WE, Perucho M (1987) Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature 327:298–303
Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, van Tuinen P, Ledbetter DH, Barker DF, Nakamura Y, White R, Vogelstein B (1989) Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244:217–221
Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, Koyama K, Utsunomiya J, Baba S, Hedge P (1991) Mutation of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253:665–669
Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260:816–819
Notterman DA, Alon U, Sierk AJ, Levine AJ (2001) Transcriptional gene expression profiles of colorectal adenoma, adenocarcinoma and normal tissue examined by oligonucleotide arrays. Cancer Res 61:3124–3130
Lin Y, Furukawa Y, Tsunoda T, Yue C, Yang K, Nakamura Y (2002) Molecular diagnosis of colorectal tumors by expression profiles of 50 genes expressed differentially in adenomas and carcinomas. Oncogene 21:4120–4128
Alon U, Barkai N, Notterman DA, Gish K, Ybarra S, Mack D, Levine AJ (1999) Broad patterns of gene expression revealed by clustering analysis of tumor and normal colon tissues probed by oligonucleotide arrays. Proc Natl Acad Sci 96:6745–6750
Birkenkamp-Demtroder K, Christensen LL, Olesen SH, Frederiksen CM, Laiho P, Aaltonen LA, Laurberg S, Sorensen FB, Hagemann R, Orntoft TF (2002) Gene expression in colorectal cancer. Cancer Res 62:4352–4363
Kwon HC, Kim SH, Roh MS, Kim JS, Lee HS, Choi HJ, Jeong JS, Kim HJ, Hwang TH (2004) Gene expression profiling in lymph node-positive and lymph node-negative colorectal cancer. Dis Colon Rectum 47:141–152
Frederiksen CM, Knudsen S, Laurberg S, Orntoft TF (2003) Classification of Dukes B and C colorectal cancers using expression arrays. J Cancer Res Clin Oncol 129:263–271
Matrisian LM, Cunha GR, Mohla S (2001) Epithelial-stromal interactions and tumor progression: meeting summary and future directions. Cancer Res 61:3844–3846
Martin-Lluesma S, Stucke VM, Nigg EA (2002) Role of Hec1 in spindle checkpoint signalling and kinetochore recruitment of MAD1/MAD2. Science 297:2267–2270
Wang X, Jin DJ, Ng RW, Feng H, Wong YC, Cheung AL, Tsao SW (2002) Significance of MAD2 expression to mitotic checkpoint control of ovarian cancer cells. Cancer Res 62:1662–1668
Behrens P, Brinkmann U, Wellmann A (2003) CSE1L/CAS: its role in proliferation and apoptosis. Apoptosis 8:39–44
O’Connell MJ, Krien MJ, Hunter T (2003) Never say never. The NIMA-related protein kinases in mitotic control. Trends Cell Biol 13:221–228
Liu ST, Hittle JC, Jablonski SA, Campbell MS, Yoda K, Yen TJ (2003) Human CENP-I specifies localization of CENP-F, MAD1 and MAD2 to kinetochores and is essential for mitosis. Nat Cell Biol 5:341–345
Saha S, Bardelli A, Buckhaults P, Velculescu VE, Rago C, St Croix B, Romans KE, Chot MA, Lengauer C, Kinzler KW, Vogelstein B (2001) A phosphatase associated with metastasis of colorectal cancer. Science 294:1343–1346
Agrawal D, Chen T, Irby R, Quackenbush J, Chanbers AF, Szabo M, Cantor A, Coppola D, Yeatman TJ (2002) Osteopontin identified as lead marker of colon cancer progression, using pooled sample expression profiling. J Natl Cancer Inst 94:513–521
Hall A (1998) Rho GTPases and the actin cytoskeleton. Science 279:509–514
Bourguignon LY, Zhu H, Shao L, Zhu D, Chen YW (1999) Rho-kinase (ROK) promotes CD44v(3,8–10)-ankyrin interaction and tumor cell migration in metastatic breast cancer cells. Cell Motil Cytoskeleton 43:269–287
Fritz G, Just I, Kaina B (1999) Rho GTPases are over-expressed in human tumors. Int J Cancer 81:682–687
Fukuda T, Kido A, Kajuno K, Tsutsumi M, Miyauchi Y, Tsujiuchi T, Konishi Y, Hino O (1999) Cloning of differentially expressed genes in highly and low metastatic rat osteosarcomas by a modified cDNA-AFLP method. Biochem Biophys Res Commun 261:35–40
Pardo J, Balkow S, Anel A, Simon MM (2002) Granzymes are essential for natural killer cell-mediated and perf-facilitated tumor control. Eur J Immunol 32:2881–2887
Mulder WM, Bloemena E, Stukart MJ, Kummer JA, Wagstaff J, Scheper RJ (1997) T cell receptor-zeta and granzyme B expression in mononuclear cell infiltrates in normal colon mucosa and colon carcinoma. Gut 40:113–119
Hippo Y, Taniguchi H, Tsutsumi S, Machida N, Chong J, Fukayama M, Kodama T, Aburatani H (2002) Global gene expression analysis of gastric cancer by oligonucleotide microarrays. Cancer Res 62:233–240
Olschwang S, Hamelin R, Laurent-Puig P, Thuille B, De Rycke Y, Li YJ, Muzeau F, Girodet J, Salmon RJ, Thomas G (1997) Alternative genetic pathways in colorectal carcinogenesis. Proc Natl Acad Sci 94:12122–12127
Ohno S, Tachibana M, Fujii T, Ueda S, Kubota H, Nagasue N (2002) Role of stromal collagen in immunomodulation and prognosis of advanced gastric carcinoma. Int J Cancer 97:770–774
Arias AM (2001) Epithelial mesenchymal interactions in cancer and development. Cell 105:425–431
Acknowledgements
The authors would like to thank Carmen Marthen and Gabriela Jusek for excellent technical assistance.
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Friederichs, J., Rosenberg, R., Mages, J. et al. Gene expression profiles of different clinical stages of colorectal carcinoma: toward a molecular genetic understanding of tumor progression. Int J Colorectal Dis 20, 391–402 (2005). https://doi.org/10.1007/s00384-004-0722-1
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DOI: https://doi.org/10.1007/s00384-004-0722-1