Growth and invasion of sporadic colorectal adenocarcinomas in terms of genetic change.
Integrative genetic changes were examined in relation to tumor growth and progression of sporadic colorectal cancers. Ninety-two sporadic colorectal cancer patients and 12 human colorectal cancer cell lines were evaluated. Genetic changes in representative steps of colorectal tumorigenesis were determined. Biological characteristics, i.e., clinicopathologic parameters, expression of invasion-associated molecules, and in vitro invasion and migration, in association with these changes were further analyzed. Adenomatous polyposis coli (APC) and/or Wnt-activated alterations occurred in 66% patients, whereas mismatch repair (MMR) defects and/or RAF-mediated alterations were identified in 47% patients. The crossover rate between these two alterations was 26%. Differential mRNA expression of ARK5 was closely associated with that of MMP2, MMP9, and S100A4 (P< or =0.044-0.001). Additionally, enhanced ARK5 mRNA expression was more frequent in tumors displaying RAF-mediated alterations and crossover pathways (P=0.01 and 0.03, respectively). Upregulation of CEA mRNA was more common in the advanced stages (P=0.034), while VEGF expression was greater in poorly differentiated or mucinous tumors (P=0.042). The high expressions of MMP2 and MMP9 were closely associated with invasion and migration of colorectal tumors and cell lines. Our results conclusively show that specific pathways of colorectal tumorigenesis are closely associated with characteristic tumor growth and invasion.
Roh
Seon Ae
SA
Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea.
Choi
Eun Young
EY
Cho
Dong Hyung
DH
Jang
Se Jin
SJ
Kim
Seon Young
SY
Kim
Yong Sung
YS
Kim
Jin Cheon
JC
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D002272:Carcinoembryonic Antigen; D012097:Repressor Proteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C077591:S100A4 protein, human; D011494:Protein Kinases; C470845:NUAK1 protein, human; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9