The guanine nucleotide exchange factor Tiam1 increases colon carcinoma growth at metastatic sites in an orthotopic nude mouse model.
Alterations in migration and adhesion are critical to invasion and metastasis. To examine signaling pathways important for colon tumor metastasis, cells of increased migratory potential from the low migratory SW480 human colorectal carcinoma parental cell line were biologically selected by serial migration through modified Boyden chambers. Several sublines were obtained with statistically significantly increased migration relative to the parental cell line. One highly migratory population was single-cell cloned and characterized. The migratory clones exhibit a four- to five-fold increase in protein and mRNA expression of T-lymphoma invasion and metastasis gene 1 (Tiam1), a guanine nucleotide exchange factor. To determine directly the role of Tiam1 in the migration of these migratory sublines, the parental SW480 cell line was transfected with a plasmid encoding the Tiam1 protein, and single cell clones were established. Ectopic expression of Tiam1 in these clones led to morphologic changes identical to biologically selected clones and increased migration. Finally, the implantation of clones that overexpress Tiam1 into the cecum of athymic mice resulted in tumor growth in the spleen, liver, and lung, whereas parental cells do not form tumors by this route of injection. These results demonstrate that overexpression of Tiam1 contributes to the metastatic phenotype of colon cancer cells.
Minard
Meghan E
ME
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 173, Houston, TX 77030, USA.
Herynk
Matthew H
MH
Collard
John G
JG
Gallick
Gary E
GE
D000818:Animals; D002277:Carcinoma / Q000473:pathology* / Q000662:veterinary; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000473:pathology* / Q000662:veterinary; D020869:Gene Expression Profiling; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009374:Neoplasms, Experimental; D010641:Phenotype; D011506:Proteins / Q000494:pharmacology*; D015398:Signal Transduction; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D014407:Tumor Cells, Cultured
D020662:Guanine Nucleotide Exchange Factors; D011506:Proteins; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; C513260:Tiam1 protein, mouse