Components of the tumour microenvironment initiate and promote cancer development. In this study, we investigated the stromal component of parathyroid neoplasia. Immuno-histochemistry for alpha-smooth muscle actin (α-SMA) showed an abundant periacinar distribution of α-SMA+ cells in normal parathyroid glands (nZ3). This pattern was progressively lost in parathyroid adenomas (PAds; nZ6) where α-SMA+ cells were found to surround new microvessels, as observed in foetal parathyroid glands (nZ2). Moreover, in atypical adenomas (nZ5) and carcinomas (nZ4), α-SMA+ cells disappeared from the parenchyma and accumulated in the capsula and fibrous bands. At variance with normal glands, parathyroid tumours (nZ37) expressed high levels of fibroblast-activation protein (FAP) transcripts, a marker of tumour-associated fibroblasts. We analysed the ability of PAd-derived cells to activate fibroblasts using human bone-marrow mesenchymal stem cells (hBM-MSCs). PAd-derived cells induced a significant increase in FAP and vascular endothelial growth factor A (VEGFA) mRNA levels in co-cultured hBM-MSCs. Furthermore, the role of the calcium-sensing receptor (CASR) and of the CXCL12/CXCR4 pathway in the PAd-induced activation of hBM-MSCs was investigated. Treatment of co-cultures of hBM-MSCs and PAd-derived cells with the CXCR4 inhibitor AMD3100 reduced the stimulated VEGFA levels, while CASR activation by the R568 agonist was ineffective. PAd-derived cells co-expressing parathyroid hormone (PTH)/CXCR4 and PTH/CXCL12 were identified by FACS, suggesting a paracrine/autocrine signalling. Finally, CXCR4 blockade by AMD3100 reduced PTH gene expression levels in PAd-derived cells. In conclusion, i) PAd-derived cells activated cells of mesenchymal origin; ii) PAd-associated fibroblasts were involved in tumuor neoangiogenesis and iii) CXCL12/CXCR4 pathway was expressed and active in PAd cells, likely contributing to parathyroid tumour neoangiogenesis and PTH synthesis modulation.

Tumour-associated fibroblasts contribute to neoangiogenesis in human parathyroid neoplasia / C. Verdelli, L. Avagliano, P. Creo, V. Guarnieri, A. Scillitani, L. Vicentini, G.B. Steffano, E. Beretta, L. Soldati, E. Costa, A. Spada, G.P. Bulfamante, S. Corbetta. - In: ENDOCRINE-RELATED CANCER. - ISSN 1351-0088. - 22:1(2015 Feb), pp. 87-98. [10.1530/ERC-14-0161]

Tumour-associated fibroblasts contribute to neoangiogenesis in human parathyroid neoplasia

C. Verdelli;L. Avagliano;E. Beretta;L. Soldati;A. Spada;G.P. Bulfamante;S. Corbetta
2015

Abstract

Components of the tumour microenvironment initiate and promote cancer development. In this study, we investigated the stromal component of parathyroid neoplasia. Immuno-histochemistry for alpha-smooth muscle actin (α-SMA) showed an abundant periacinar distribution of α-SMA+ cells in normal parathyroid glands (nZ3). This pattern was progressively lost in parathyroid adenomas (PAds; nZ6) where α-SMA+ cells were found to surround new microvessels, as observed in foetal parathyroid glands (nZ2). Moreover, in atypical adenomas (nZ5) and carcinomas (nZ4), α-SMA+ cells disappeared from the parenchyma and accumulated in the capsula and fibrous bands. At variance with normal glands, parathyroid tumours (nZ37) expressed high levels of fibroblast-activation protein (FAP) transcripts, a marker of tumour-associated fibroblasts. We analysed the ability of PAd-derived cells to activate fibroblasts using human bone-marrow mesenchymal stem cells (hBM-MSCs). PAd-derived cells induced a significant increase in FAP and vascular endothelial growth factor A (VEGFA) mRNA levels in co-cultured hBM-MSCs. Furthermore, the role of the calcium-sensing receptor (CASR) and of the CXCL12/CXCR4 pathway in the PAd-induced activation of hBM-MSCs was investigated. Treatment of co-cultures of hBM-MSCs and PAd-derived cells with the CXCR4 inhibitor AMD3100 reduced the stimulated VEGFA levels, while CASR activation by the R568 agonist was ineffective. PAd-derived cells co-expressing parathyroid hormone (PTH)/CXCR4 and PTH/CXCL12 were identified by FACS, suggesting a paracrine/autocrine signalling. Finally, CXCR4 blockade by AMD3100 reduced PTH gene expression levels in PAd-derived cells. In conclusion, i) PAd-derived cells activated cells of mesenchymal origin; ii) PAd-associated fibroblasts were involved in tumuor neoangiogenesis and iii) CXCL12/CXCR4 pathway was expressed and active in PAd cells, likely contributing to parathyroid tumour neoangiogenesis and PTH synthesis modulation.
tumour-associated fibroblasts; parathyroid; VEGFA; CXCR4; SDF1/CXCL12; PTH
Settore MED/13 - Endocrinologia
Settore MED/40 - Ginecologia e Ostetricia
feb-2015
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/272373
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