Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor.
Mutations in the gene encoding the retinoblastoma tumor suppressor predispose humans and mice to tumor development. Here we have assessed the effect of Nras loss on tumor development in Rb1 heterozygous mice. Loss of one or two Nras alleles is shown to significantly reduce the severity of pituitary tumors arising in Rb1(+/-) animals by enhancing their differentiation. By contrast, C-cell thyroid adenomas occurring in Rb1(+/-) mice progress to metastatic medullary carcinomas after loss of Nras. In Rb1(+/-)Nras(+/-) animals, distant medullary thyroid carcinoma metastases are associated with loss of the remaining wild-type Nras allele. Loss of Nras in Rb1-deficient C cells results in elevated Ras homolog family A (RhoA) activity, and this is causally linked to the invasiveness and metastatic behavior of these cells. These findings suggest that the loss of the proto-oncogene Nras in certain cellular contexts can promote malignant tumor progression.
Takahashi
Chiaki
C
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. chtakaha@virus.kyoto-u.ac.jp
Contreras
Bernardo
B
Iwanaga
Tsuyoshi
T
Takegami
Yujiro
Y
Bakker
Anke
A
Bronson
Roderick T
RT
Noda
Makoto
M
Loda
Massimo
M
Hunt
Jennifer L
JL
Ewen
Mark E
ME
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D018276:Carcinoma, Medullary / Q000235:genetics / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011905:Genes, ras / Q000235:genetics*; D006579:Heterozygote; D051379:Mice; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000473:pathology*; D000090063:Proto-Oncogene Mas; D011725:Pyridines / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology* / Q000556:secondary; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D000577:Amides; D004791:Enzyme Inhibitors; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011725:Pyridines; D016160:Retinoblastoma Protein; C108830:Y 27632; D000324:Adrenocorticotropic Hormone; D020742:rhoA GTP-Binding Protein