Mast cells have a protumorigenic role in human thyroid cancer

Abstract

In different human carcinoma types, mast cell infiltrate increases with respect to normal tissue and mast cell density correlates with a bad prognosis. To assess the role of mast cells in human thyroid cancer, we compared the density of tryptase-positive mast cells in 96 papillary thyroid carcinomas (PTCs) versus normal thyroid tissue from 14 healthy individuals. Mast cell density was higher in 95% of PTCs (n ¼ 91) than in control tissue. Mast cell infiltrate correlated with extrathyroidal extension (P ¼ 0.0005) of PTCs. We show that thyroid cancer cell-line-derived soluble factors induce mast cell activation and chemoattraction in vitro. Different mast cell lines (HMC-1 and LAD2) and primary human lung mast cells induced thyroid cancer cell invasive ability, survival and DNA synthesis in vitro. The latter effect was mainly mediated by three mast-cell-derived mediators: histamine, and chemokines CXCL1/GROa and CXCL10/IP10. We show that xenografts of thyroid carcinoma cells (8505-C) could recruit mast cells injected into the tail vein of mice. Co-injection of human mast cells accelerated the growth of thyroid cancer cell (8505-C) xenografts in athymic mice. This effect was mediated by increased tumor vascularization and proliferation, and was reverted by treating mice with sodium cromoglycate (Cromolyn), a specific mast cell inhibitor. In conclusion, our study data suggest that mast cells are recruited into thyroid carcinomas and promote proliferation, survival and invasive ability of cancer cells, thereby contributing to thyroid carcinoma growth and invasiveness.

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

“…It has been described that the antiangiogenic effect of TIMP3 is related to its inhibition of VEGFA binding to VEGFR-2, thus attenuating downstream signaling (Qi et al, 2003), and that VEGFR inhibition is responsible for the antitumoral role of TIMP3 in several models (Ahonen et al, 2003;Mahller et al, 2008). Based on the evidence that NIM1 cells produce VEGFA (Melillo et al, 2010), the same mechanism could be responsible for the effects observed in our tumor xenograft model.…”

The immune network in thyroid cancer

“…78 In a cohort of 96 PTC patients, tumor-associated MC density was higher than in healthy thyroids and correlated with tumor extracapsular extension. 24 A higher MC density was also found in FTC compared with adenomas and correlated with extracapsular extension. 79 TC cell line CM induced in vitro MC chemotaxis through the release of VEGF-A, 24 which activated the VEGFRs on human MCs.…”

“…24 A higher MC density was also found in FTC compared with adenomas and correlated with extracapsular extension. 79 TC cell line CM induced in vitro MC chemotaxis through the release of VEGF-A, 24 which activated the VEGFRs on human MCs. 53,80 In addition, TC cells activated MCs to release cytokines (IL-6, TNF-a, GM-CSF) and chemokines (CXCL10/ IP10 and CXCL1/Gro-a).…”

“…38,41,46 In addition, MC-derived CXCL1/GRO-a and CXCL10/IP10 further increased TC cell proliferation through the engagement of CXCR2 and CXCR3 on TC cells. 24,38 CXCL12/SDF-1 and its novel receptor CXCR7 have been found in PTC patients. 47 Interestingly, CXCL12 expression was exclusively found in PTCs compared to other thyroid lesions and displayed high sensitivity, specificity, positive and negative predictive values.…”

“…23 In an in vitro model of human TC and mast cell (MC) lines, TC-derived conditioned media (CM) induced upregulation of IL-6 in human MCs. 24 Moreover, IL-6 contributed to epithelial-to-mesenchymal transition (EMT) and stemness features of TC. 25 TGF-b is overexpressed in aggressive cancers.…”