title: Deletion of Ptp4a3 reduces clonogenicity and tumor-initiation ability of colitis-associated cancer cells in mice.
abstract: The PTP4A3 gene is highly expressed in human colon cancer and often associates with enhanced metastatic potential. Genetic disruption of the mouse Ptp4a3 gene reduces the frequency of colon tumor formation in mice treated in a colitis-associated cancer model. In the current study, we have examined the role of Ptp4a3 in the tumor-initiating cell population of mouse colon tumors using an in vitro culture system. Tumors generated in vivo following AOM/DSS treatment were isolated, dissociated, and expanded on a feeder layer resulting in a CD133(+) cell population, which expressed high levels of Ptp4a3. Tumor cells deficient for Ptp4a3 exhibited reduced clonogenicity and growth potential relative to WT cells as determined by limiting dilution analysis. Importantly, expanded tumor cells from WT mice readily formed secondary tumors when transplanted into nude mice, while tumor cells without Ptp4a3 expression failed to form secondary tumors and thus were not tumorigenic. These results demonstrate that Ptp4a3 contributes to the malignant phenotype of tumor-initiating cells and supports its role as a potential therapeutic target to inhibit tumor self-renewal and metastasis.
authors.affiliation: Department of Pathology, 200 Lothrop Street, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261.|McGowan Institute for Regenerative Medicine, 450 Technology Drive, Suite 300, University of Pittsburgh, Pittsburgh, PA, 15219.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cramer
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, 203 Lothrop Street, Pittsburgh, PA, 15260.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Zimmerman
authors.affiliation: Department of Bioengineering, 3700 O'Hara St, University of Pittsburgh, Pittsburgh, PA, 15261.
authors.forename: Tim
authors.initials: T
authors.lastname: Thompson
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, 203 Lothrop Street, Pittsburgh, PA, 15260.|Department of Anesthesiology, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261.
authors.forename: Gregg E
authors.initials: GE
authors.lastname: Homanics
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, 203 Lothrop Street, Pittsburgh, PA, 15260.
authors.forename: John S
authors.initials: JS
authors.lastname: Lazo
authors.affiliation: Department of Pathology, 200 Lothrop Street, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261.|McGowan Institute for Regenerative Medicine, 450 Technology Drive, Suite 300, University of Pittsburgh, Pittsburgh, PA, 15219.
authors.forename: Eric
authors.initials: E
authors.lastname: Lagasse
mesh_terms: D000818:Animals; D003092:Colitis / Q000201:enzymology* / Q000473:pathology*; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D004195:Disease Models, Animal; D017874:Immediate-Early Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*
chemical_list: D017874:Immediate-Early Proteins; C111534:Ptp4a3 protein, mouse; D017027:Protein Tyrosine Phosphatases