Tumour-associated fibroblasts contribute to neoangiogenesis in human parathyroid neoplasia

Endocr Relat Cancer. 2015 Feb;22(1):87-98. doi: 10.1530/ERC-14-0161. Epub 2014 Dec 16.

Abstract

Components of the tumour microenvironment initiate and promote cancer development. In this study, we investigated the stromal component of parathyroid neoplasia. Immunohistochemistry for alpha-smooth muscle actin (α-SMA) showed an abundant periacinar distribution of α-SMA(+) cells in normal parathyroid glands (n=3). This pattern was progressively lost in parathyroid adenomas (PAds; n=6) where α-SMA(+)cells were found to surround new microvessels, as observed in foetal parathyroid glands (n=2). Moreover, in atypical adenomas (n=5) and carcinomas (n=4), α-SMA(+) cells disappeared from the parenchyma and accumulated in the capsula and fibrous bands. At variance with normal glands, parathyroid tumours (n=37) 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.

Keywords: CXCR4; PTH; SDF1/CXCL12; VEGFA; parathyroid; tumour-associated fibroblasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / blood supply*
  • Adenoma / metabolism
  • Adenoma / pathology*
  • Benzylamines
  • Coculture Techniques
  • Cyclams
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Immunohistochemistry
  • Mesenchymal Stem Cells / pathology
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Parathyroid Neoplasms / blood supply*
  • Parathyroid Neoplasms / metabolism
  • Parathyroid Neoplasms / pathology*
  • Signal Transduction
  • Stromal Cells / pathology
  • Tumor Cells, Cultured
  • Tumor Microenvironment

Substances

  • Benzylamines
  • Cyclams
  • Heterocyclic Compounds
  • plerixafor