ZIA BC 011191 (ZIA) | |||
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Title | Preclinical Mouse Models of Thyroid Cancer | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Cheng, Sheue-yann | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $501,602 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2016 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) |
Head and Neck (40.0%) Thyroid (60.0%) |
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Research Type | |||
Cancer Initiation: Oncogenes & Tumor Suppressor Genes Endogenous Factors in the Origin and Cause of Cancer |
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Abstract | |||
Inhibition of STAT3 activity delays obesity-induced thyroid carcinogenesis in a mouse model. Compelling epidemiologic studies indicate that obesity is a risk factor for many human cancers, including thyroid cancer. In recent decades, the incidence of thyroid cancer has dramatically increased along with a marked rise in obesity prevalence. We previously demonstrated that a high fat diet (HFD) effectively induced the obese phenotype in a mouse model of thyroid cancer (TRbetaPV/PVPten+/- mice). Moreover, HFD activates the STAT3 signal pathway to promote more aggressive tumor phenotypes. The aim of the present study was to evaluate the effect of S3I-201, a specific inhibitor of STAT3 activity, on HFD-induced aggressive cancer progression in the mouse model of thyroid cancer. Wild type and TRbetaPV/PVPten+/- mice were treated with HFD together with S3I-201 or vehicle-only as controls. We assessed the effects of S3I-201 on HFD-induced thyroid cancer progression, the leptin-JAK2-STAT3 signaling pathway, and key regulators of epithelial-mesenchymal transition. S3I-201 effectively inhibited HFD-induced aberrant activation of STAT3 and its downstream targets to markedly inhibit thyroid tumor growth and to prolong survival. Decreased protein levels of cyclins D1 and B1, cyclin dependent kinase (CDK) 4, CDK 6, and phosphorylated retinoblastoma TRbetaPV/PVPten+/- mice. Reduced occurrence of vascular invasion and blocking of anaplasia and lung metastasis in thyroid tumors of S3I-201-treated TRbetaPV/PVPten+/- mice were mediated via decreased expression of vimentin and matrix metalloproteinases, two key effectors of epithelial-mesenchymal transition. The present findings suggest that inhibition of the STAT3 activity would be a novel treatment strategy for obesity-induced thyroid cancer. Metformin blocks progression of obesity-activated thyroid cancer in a mouse model. We previously demonstrated that a high fat diet (HFD) effectively induces the obese phenotype in a mouse model of aggressive follicular thyroid cancer (TRbetaPV/PVPten+/- mice). We showed that HFD promotes cancer progression through aberrant activation of the leptin-JAK2-STAT3 signaling pathway. HFD-promoted thyroid cancer progression allowed us to test other molecular targets for therapeutic opportunity for obesity-induced thyroid cancer. Metformin is a widely used drug to treat patients with type II diabetes. It has been shown to reduce incidences of neoplastic diseases and cancer mortality in type II diabetes patients. The present study aimed to test whether metformin could be a therapeutic for obesity-activated thyroid cancer. TRbetaPV/PVPten+/- mice were fed HFD together with metformin or vehicle-only, as controls, for 20 weeks. While HFD- TRbetaPV/PVPten+/- mice had shorter survival than LFD-treated mice, metformin had no effects on the survival of HFD- TRbetaPV/PVPten+/- mice. Remarkably, metformin markedly decreased occurrence of capsular invasion and completely blocked vascular invasion and anaplasia in HFD- TRbetaPV/PVPten+/- mice without affecting thyroid tumor growth. The impeded cancer progression was due to the inhibitory effect of metformin on STAT3-ERK-vimentin and fibronectin-integrin signaling to decrease tumor cell invasion and de-differentiation. The present studies provide additional molecular evidence to support the link between obesity and thyroid cancer risk. Importantly, our findings suggest that metformin could be used as an adjuvant in combination with antiproliferative modalities to improve the outcome of patients with obesity-activated thyroid cancer. SAHA-induced loss of the tumor suppressor Pten gene promotes thyroid carcinogenesis in a mouse model. Thyroid cancer is on the rise. Novel approaches are needed to improve the outcome of patients with recurrent and advanced metastatic thyroid cancers. FDA approval of suberoylanilide hydroxamic acid (SAHA; vorinostat), an inhibitor of histone deacetylase, for the treatment of hematologic malignancies le |