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Targeted therapy of VEGFR2 and EGFR significantly inhibits growth of anaplastic thyroid cancer in an orthotopic murine model.

ABSTRACT: Anaplastic thyroid carcinoma (ATC) is one of the most lethal human cancers with a median survival of 6 months. The inhibition of epidermal growth factor receptor (EGFR) alone, or with VEGF receptor 2 (VEGFR2), represents an attractive approach for treatment of ATC. Several reports have examined agents that target these receptors. However, with the misidentification of as many as 60% of all commonly used ATC cell lines, the significance of these past findings is unclear.Cell lines authenticated by short tandem repeat profiling were selected to establish xenograft tumors in an orthotopic murine model of ATC. These mice were then treated with vandetanib to evaluate its effects on ATC tumor growth. Dynamic contrast-enhanced (DCE) MRI was utilized to measure the impact of vandetanib on tumor vasculature.Vandetanib inhibited tumor growth of the ATC cell lines Hth83 and 8505C in vivo by 69.3% (P < 0.001) and 66.6% (P < 0.05), respectively, when compared with control. Significant decreases in vascular permeability (P < 0.01) and vascular volume fraction (P < 0.05) were detected by DCE-MRI in the orthotopic xenograft tumors after 1 week of treatment with vandetanib as compared with control.The inhibition of EGFR and VEGFR2 by vandetanib and its tremendous in vivo antitumor activity against ATC make it an attractive candidate for further preclinical and clinical development for the treatment of this particularly virulent cancer, which remains effectively untreatable. Vandetanib disrupts angiogenesis and DCE-MRI is an effective method to quantify changes in vascular function in vivo.

SUBMITTER: Gule MK

PROVIDER: S-EPMC3079006 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Targeted therapy of VEGFR2 and EGFR significantly inhibits growth of anaplastic thyroid cancer in an orthotopic murine model.

Gule Maria K MK Chen Yunyun Y Sano Daisuke D Frederick Mitchell J MJ Zhou Ge G Zhao Mei M Milas Zvonimir L ZL Galer Chad E CE Henderson Ying C YC Jasser Samar A SA Schwartz David L DL Bankson James A JA Myers Jeffrey N JN Lai Stephen Y SY

Clinical cancer research : an official journal of the American Association for Cancer Research 20110110 8

<h4>Purpose</h4>Anaplastic thyroid carcinoma (ATC) is one of the most lethal human cancers with a median survival of 6 months. The inhibition of epidermal growth factor receptor (EGFR) alone, or with VEGF receptor 2 (VEGFR2), represents an attractive approach for treatment of ATC. Several reports have examined agents that target these receptors. However, with the misidentification of as many as 60% of all commonly used ATC cell lines, the significance of these past findings is unclear.<h4>Experi ...[more]

PMID: 21220477

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Project description:IntroductionSecuring a well-established mouse model is important in identifying and validating new therapeutic targets for immuno-oncology. The C57BL/6 mouse is one of the most fully characterised immune system of any animal and provides powerful platform for immuno-oncology discovery. An orthotopic tumor model has been established using TBP3743 (murine anaplastic thyroid cancer [ATC]) cells in B6129SF1 hybrid mice, this model has limited data on tumor immunology than C57BL/6 inbred mice. This study aimed to establish a novel orthotopic ATC model in C57BL/6 mice and characterize the tumor microenvironment focusing immunity in the model.MethodsAdapted TBP3743 cells were generated via in vivo serial passaging in C57BL/6 mice. Subsequently, the following orthotopic tumor models were established via intrathyroidal injection: B6129SF1 mice injected with original TBP3743 cells (original/129), B6129SF1 mice injected with adapted cells (adapted/129), and C57BL/6 mice injected with adapted cells (adapted/B6).ResultsThe adapted TBP3743 cells de-differentiated but exhibited cell morphology, viability, and migration/invasion potential comparable with those of original cells in vitro. The adapted/129 contained a higher Ki-67+ cell fraction than the original/129. RNA sequencing data of orthotopic tumors revealed enhanced oncogenic properties in the adapted/129 compared with those in the original/129. In contrast, the orthotopic tumors grown in the adapted/B6 were smaller, with a lower Ki-67+ cell fraction than those in the adapted/129. However, the oncogenic properties of the tumors within the adapted/B6 and adapted/129 were similar. Immune-related pathways were enriched in the adapted/B6 compared with those in the adapted/129. Flow cytometric analysis of the orthotopic tumors revealed higher cytotoxic CD8+ T cell and monocytic-myeloid-derived suppressor cell fractions in the adapted/B6 compared with the adapted/129. The estimated CD8+ and CD4+ cell fractions in the adapted/B6 were similar to those in human ATCs but negligible in the original/B6.ConclusionA novel orthotopic tumor model of ATC was established in C57BL/6 mice. Compared with the original B6129SF1 murine model, the novel model exhibited more aggressive tumor cell behaviours and strong immune responses. We expect that this novel model contributes to the understanding tumor microenvironment and provides the platform for drug development.

Dataset Information

Targeted therapy of VEGFR2 and EGFR significantly inhibits growth of anaplastic thyroid cancer in an orthotopic murine model.

Publications

Targeted therapy of VEGFR2 and EGFR significantly inhibits growth of anaplastic thyroid cancer in an orthotopic murine model.

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