Altered gene expression in immunogenic poorly differentiated thyroid carcinomas from RET/PTC3p53-/- mice.
Cancers develop and progress via activation of oncogenes and loss of tumor suppressor genes, a progression that can be recapitulated through cross breeding mouse strains harboring genetic mutations. To define the role of RET/PTC3, p53 and Fhit in thyroid carcinogenesis, we intercrossed RET/PTC3 transgenics with p53-/- mice. This new strain, RET/PTC3p53-/-, succumb to rapidly growing and strikingly large multilobed thyroid tumors containing mixtures of both well and poorly differentiated, highly proliferative follicular epithelial cells. Interestingly, transplanted tumors from RET/PTC3p53-/- mice grew in SCID but not syngeneic immunocompetent mice indicating that these advanced tumors were immunogenic. RET/PTC3 protein expression was reduced to undetectable levels in tumors of older mice suggesting that the continued elevated expression of RET/PTC3 may not be necessary for tumor progression. Similarly, expression of Fhit protein was reduced in early tumors and undetected in older tumors irrespective of tumor histopathology. In contrast to RET/PTC3p53-/- mice, RET/PTC3Fhit-/- mice did not develop advanced thyroid carcinomas. These studies support a model of human thyroid cancer whereby thyroid epithelium expresses RET/PTC3 protein at early stages of tumor development, followed by the reduction of RET/PTC3 and loss of p53 function with progressive reduction of Fhit protein expression coincident with malignant progression.
Powell
D J
DJ
Department of Microbiology/Immunology and Otolaryngology-Head & Neck Surgery, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania, PA 19107, USA.
Russell
J P
JP
Li
G
G
Kuo
B A
BA
Fidanza
V
V
Huebner
K
K
Rothstein
J L
JL
D017766:Acid Anhydride Hydrolases; D000818:Animals; D000943:Antigens, Differentiation; D002277:Carcinoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D029721:Drosophila Proteins; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D008954:Models, Biological; D009363:Neoplasm Proteins; D009374:Neoplasms, Experimental; D009857:Oncogenes; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000302:isolation & purification; D054648:Protein Phosphatase 2; D000071636:Protein Phosphatase 2C; D011506:Proteins / Q000302:isolation & purification; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000302:isolation & purification; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000302:isolation & purification; D029701:Saccharomyces cerevisiae Proteins; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D000943:Antigens, Differentiation; D029721:Drosophila Proteins; D009363:Neoplasm Proteins; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D000071636:Protein Phosphatase 2C; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D029701:Saccharomyces cerevisiae Proteins; D016159:Tumor Suppressor Protein p53; D000099170:Bis(5'-adenosyl)triphosphatase; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; C087358:PTC1 protein, S cerevisiae; C000607464:PTC3 protein, S cerevisiae