Tetrac Delayed the Onset of Ocular Melanoma in an Orthotopic Mouse Model.

Osnat Ashur-Fabian,Ido Didi Fabian,Aleck Hercbergs,Paul J Davis,Ofira Zloto,Martin Ellis,Ina Fabian,Galya Tsarfaty,David M Steinberg

doi:10.3389/fendo.2018.00775

Abstract

Ocular melanoma research, the most common primary intraocular malignancy in adults, is hindered by limited in vivo models. In a series of experiments using melanoma cells injected intraocularly into mouse eyes, we developed a model for ocular melanoma. Inoculation of 5 × 105 B16F10 cells led to rapid tumor growth, extensive lung metastasis, and limited animal survival, while injection of 102 cells was sufficient for intraocular tumors to grow with extended survival. In order to improve tumor visualization, 102 melanoma cells (B16F10 or B16LS9) were inoculated into Balb/C albino mouse eyes. These mice developed intraocular tumors that did not metastasize and exhibited extended survival. Next, we studied the therapeutic potential of inhibitor of the thyroid hormones-αvβ3 integrin signaling pathway in ocular melanoma. By utilizing tetraiodothyroacetic acid (tetrac), a thyroid hormone derivative, a delay in tumor onset in the B16F10 (integrin+) arm was observed, compared to the untreated group, while in the B16LS9 cells (integrin–) a similar rate of tumor onset was noticed in both experimental and control groups. In summary, following an optimization process, the mouse ocular melanoma model was developed. The models exhibited an extended therapeutic window and can be utilized as a platform for investigating various drugs and other treatment modalities.

Highlights

Ocular melanoma is the most common primary intraocular malignancy in adult patients [1, 2]
Based on these collective results, we hypothesized that natural thyroid hormone derivatives with low-potency thyromimetic activity at the integrin may be utilized for growth inhibition in ocular melanoma
Pathological processing and hematoxylin and eosin (H&E) staining of the dissected lungs demonstrated aggregates of large epithelioid melanoma cells, surrounded by typical lung tissue (Figure 1F)

Summary

INTRODUCTION

Ocular melanoma is the most common primary intraocular malignancy in adult patients [1, 2]. We have recently established that hyperthyroidism shortened survival time in a metastatic ocular melanoma mouse model, while hypothyroidism had a significant protective effect [24] Based on these collective results, we hypothesized that natural thyroid hormone derivatives with low-potency thyromimetic activity at the integrin may be utilized for growth inhibition in ocular melanoma. At the cell surface integrin receptor tetrac was shown to displace thyroid hormones binding and to block αvβ, resulting in reduced cell proliferation, anti-angiogenesis and reduced anti-apoptotic defense pathways activity in multiple cancer models, including mice and human melanoma [28, 29] and reviewed in Davis et al [11]. We report the development of novel mouse models of ocular melanomas and the effect of a specific thyroid hormoneintegrin antagonist on delaying the onset of tumor growth in such models

MATERIALS AND METHODS

RESULTS

DISCUSSION