Thyroid targeting of the N-ras(Gln61Lys) oncogene in transgenic mice results in follicular tumors that progress to poorly differentiated carcinomas

Vitagliano, Donata; Portella, Giuseppe; Troncone, Giancarlo; Francione, A; Rossi, Cosmo; Bruno, Alain; Giorgini, Andrea; Coluzzi, Sabrina; Nappi, Tito Claudio; Rothstein, Jay L.; Pasquinelli, Rosa; Chiappetta, Gennaro; Terracciano, Daniela; Macchia, Vincenzo; Melillo, Rosa Marina; Fusco, Alfredo; Santoro, Massimo

doi:10.1038/sj.onc.1209527

Cited by 67 publications

(44 citation statements)

References 34 publications

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“…NRAS transgene expression results in follicular tumors that progress to poorly differentiated carcinomas (TGNRAS; ref. 29). Finally, animals expressing the SV40 large T antigen (TGSV) present aggressive thyroid cancer with features similar to human ATC (30).…”

Section: Resultsmentioning

confidence: 99%

Biological Role and Potential Therapeutic Targeting of the Chemokine Receptor CXCR4 in Undifferentiated Thyroid Cancer

et al. 2007

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Anaplastic thyroid carcinoma (ATC) is a rare thyroid cancer type with an extremely poor prognosis. Despite appropriate treatment, which includes surgery, radiotherapy, and chemotherapy, this cancer is invariably fatal. CXCR4 is the receptor for the stromal cell-derived factor-1 (SDF-1)/CXCL12 chemokine and it is expressed in a variety of solid tumors, including papillary thyroid carcinoma. Here, we show that ATC cell lines overexpress CXCR4, both at the level of mRNA and protein. Furthermore, we found that CXCR4 was overexpressed in ATC clinical samples, with respect to normal thyroid tissues by real-time PCR and immunohistochemistry. Treatment of ATC cells with SDF-1 induced proliferation and increase in phosphorylation of extracellular signal-regulated kinases and protein kinase B/AKT. These effects were blocked by the specific CXCR4 antagonist AMD3100 and by CXCR4 RNA interference. Moreover, AMD3100 effectively reduced tumor growth in nude mice inoculated with different ATC cells. Thus, we suggest that CXCR4 targeting is a novel potential strategy in the treatment of human ATC. [Cancer Res 2007;67(24):11821-9]

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Section: Resultsmentioning

confidence: 99%

Biological Role and Potential Therapeutic Targeting of the Chemokine Receptor CXCR4 in Undifferentiated Thyroid Cancer

et al. 2007

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“…Among 88 mice examined, 26 (30%) developed carcinomas that were follicular or had mixed papillary-follicular features and 9 (10%) had invasive carcinomas with large poorly differentiated areas closely resembling those observed in human patients. Distant metastases were observed in the liver of three mice, lung of two mice, and the right femur of one mouse (76). Although occurrence of metastasis requires long latency, the mice are potentially useful for studies of thyroid carcinogenesis.…”

Section: Rasmentioning

confidence: 97%

“…Another mouse model was created by targeting a human NRAS with a mutation at codon 61 (N-Ras Gln61Lys ) to thyroid follicular cells (76). Comparison of thyroid histopathology between these transgenic mice and wild-type littermates up to 18 months of age indicated progressive changes from hyperplasia to adenoma and carcinoma in some transgenic mice.…”

Section: Rasmentioning

confidence: 99%

Lessons from Mouse Models of Thyroid Cancer

Kim

Zhu

2009

Thyroid

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Background: Thyroid cancer is the most common endocrine tumor and is increasing in incidence. The aim of this study was to review mouse models of differentiated thyroid cancer and how they elucidate human thyroid cancer biology. Summary: Differentiated thyroid cancer, primarily papillary and follicular, comprises the majority of thyroid cancers. There has been tremendous growth in the cross-talk between basic science and clinical practice for thyroid cancer management. Insight into the framework of genes responsible for differentiated thyroid cancer has been gained through the use of mouse models. Common genetic alterations found in human papillary thyroid cancer such as RET=PTC rearrangements or the BRAF V600E mutation have genetically modified mouse counterparts. These and other preclinical mouse models have validated the importance of the cyclic adenosine monophosphate (cAMP)=protein kinase A and mitogen-activated protein kinase (MAPK) signaling pathways in papillary thyroid cancer (PTC). RAS mutations have a role in both papillary and follicular thyroid cancer development. Mice with overactivation of the phosphatidylinol-3-kinase (PI3K)-AKT and=or thyrotropinregulated signaling pathways have been found to develop follicular thyroid cancer. Additional mouse models of thyroid cancer that utilize inducible expression systems are in development or are being characterized and will better reflect the majority of human thyroid cancers which are non-hereditary. Advances in in vivo imaging of mice allow for earlier detection of metastasis and the ability to follow tumor growth or regression which may be used in evaluation of pharmaceutical agents. Conclusions: Mouse models have expanded our understanding of the altered signaling pathways that contribute to thyroid cancer tumorigenesis and provide a powerful tool to develop novel diagnostic approaches and therapies.

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“…Interestingly, transgenic mice expressing N-RAS in thyroid follicular cells developed 11% FAs and approximately 40% developed invasive follicular carcinomas, in some cases with a mixed papillary/follicular morphology. About 25% of the Tg-N-RAS carcinomas displayed large, poorly differentiated areas, featuring vascular invasion and forming distant metastases in lung, bone or liver [42].…”

Section: The Intriguing Role Of Ras Oncogenes In Both Ptc and Ftcmentioning

confidence: 99%