Abstract 3973: Role of thyroid tumor microenvironment secretome in cancer initiation and progression

Abstract

Abstract The incidence of thyroid cancer in the United States is on a rise with an appreciably high disease recurrence rate of 20-30%. Tumor associated macrophages (TAMs) release cytokines, chemokines and other secretory components like exosomes which aid in thyroid tumor progression and metastasis. In our previous study on thyroid tumor microenvironment, we established that M1 polarized pro-inflammatory macrophages modulate thyroid cancer phenotype. TAMs secretome, consisting of pro-inflammatory cytokines such as TGF-β, IL6, TNF-α, IL-1β, amongst others, induce epithelial to mesechymal transition (EMT) in thyroid cancer cells promoting tumor metastasis and propagation. In our present study, we used an in vitro model system to assess the effects of secretory molecules called exosomes, in the thyroid tumor microenvironment. We used thyroid cancer cell lines: BCPAP (papillary), 8505C (anaplastic) and CGTHW-1 (follicular) to represent the spectrum of clinically observed thyroid cancers. THP-1 monocyte/macrophage cell line was used to denote the inflammatory component. Thyroid cancer cells treated with activated M1 polarized THP-1 macrophage exosomes showed halt in proliferation, transformation to mesenchymal phenotype as well as modulation in expression of EMT markers, such as vimentin and NFk-B, indicative of induction of EMT in thyroid cancer cells. Interestingly, secretory exosomes from anaplastic thyroid cancer cells led to activation of THP-1 monocytes. Since the exosomal cargo is the reflection and fingerprint of its originating parental cells, we profiled exosomal miRNA derived from thyroid cancer cells and THP1 cells. Modulation of various miRNA in follicular and anaplastic thyroid cancer exosomes was observed, when compared to papillary thyroid cancer exosomes. We detected a down regulation of miR-138-5p, miR-146a-5p, miR-26a-5p, miR-26b-5p, miR-34a-5p and miR-31-5p in anaplastic and follicular cancer exosomes, which may play a role in promoting cancer invasion and metastasis. In comparison to papillary thyroid cancer exosomes, an upregulation of miR-214-3p, miR-200a-3p, miR-298, miR-299-3p, and miR-302a-3p was ascertained in follicular thyroid cancer exosomes. Conversely, we noted a down regulation of these miRNAs in anaplastic thyroid cancer exosomes. These distinct miRNA expressions in cancer secretome will provide new insights into the tumor development and dissemination. Our findings suggest an important crosstalk between the secretome of thyroid cancer cells and inflammatory cells in tumor microenvironment, defining thyroid cancer phenotype. These exosomal miRNA serve as early diagnostic markers of thyroid cancer differentiation as well as targets for novel therapies specifically for anaplastic thyroid cancer. Citation Format: Neha Yashpal Tuli, Ameet Kamat, Rachana Maniyar, Ghada Ben Rahoma, Sanjukta Chakraborty, Sarnath Singh, Augustine Moscatello, Jan Geliebter, Raj K. Tiwari. Role of thyroid tumor microenvironment secretome in cancer initiation and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3973. doi:10.1158/1538-7445.AM2017-3973