Src transformation of colonic epithelial cells: enhanced anchorage-independent growth in an Apc(+/min) background.
Colon cancer arises through a multistep process involving inactivation of tumor suppressor proteins and activation of oncogene-encoded proteins. Development of colon cancer frequently involves mutation of the adenomatous polyposis coli (APC) tumor suppressor. The activity of the proto-oncogene-encoded Src tyrosine kinase is commonly elevated in colon cancer, with higher activity observed as tumors progress and metastasize. Both APC and Src are multifunctional proteins that have been implicated in the control of cell proliferation, but also as regulators of cytoskeletal changes associated with cell motility and invasion. To investigate the potential for biological cooperativity between APC partial loss-of-function and Src gain-of-function, oncogenic Src was stably expressed in mouse colon epithelial cell lines IMCE (APC(+/min)) and YAMC (APC(+/+)). Under permissive growth conditions, these lines are conditionally immortalized through inactivation of p53. Irrespective of the APC genotype or p53 status, oncogenic Src expression led to morphologic transformation associated with loss of cell-cell junctions, cytoskeletal disorganization, and acquisition of invasive properties. However IMCE cells that carry one copy of the mutant APC(min) allele exhibited increased capacity for Src-mediated anchorage-independent proliferation as compared to the YAMC cells, and this property was enhanced under permissive growth conditions. beta-catenin levels and transcriptional activity were also elevated in the Src-transformed IMCE cells. The selective Src inhibitor, AZD0530, was found to be effective in blocking both cell invasion and anchorage-independent proliferation. These findings suggest that the combined effects of elevated Src activity and APC partial loss-of-function may contribute to the growth of colon tumors.
Constancio-Lund
Sabata S
SS
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN-37232-8240, USA.
Brabek
Jan
J
Hanks
Steven K
SK
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003106:Colon / Q000473:pathology*; D004847:Epithelial Cells / Q000473:pathology; D017491:Genes, APC; D016391:Genes, src; D051379:Mice