Tumour-asssociated myofibroblasts in parathyroid tumours
C. Verdelli1, L. Avagliano2, M. Meregalli3, V. Guarnieri4, A. Scillitani4, L. Vicentini5, G. Steffano6, E. Costa1, Y. Torrente2, A. Spada5, G. Bulfamante2 & S. Corbetta7
Tumour-associated myofibroblasts are activated fibroblasts known to influence many aspects of tumour development. Parathyroid tumours show increased microvessels and atypical/malignant tumours are characterized by fibrous bands suggesting activation of the stromal cells. The aim of the present study was to investigate the role of myofibroblasts in parathyroid tumorigenesis. Human parathyroid tissues were analysed by specific immunostaining for the myofibroblast marker alpha-smooth muscle actin (alpha-SMA). Alpha-SMA+ cells were well represented in the parenchyma of normal parathyroid glands (n=3) lining the acinar cellular structures. In typical adenomas (PA, n=5) intraparenchymal alpha-SMA+ cells were variably reduced, though they surrounded new microvessels suggesting a role in neoangiogenesis. In atypical adenomas (n=3) and carcinomas (n=3), the parathyroid chief cells proliferating in sheets were not sustained by myofibroblasts, which were highly represented in the stroma of fibrous bands and capsula. Interestingly, in human fetal parathyroids (n=2; 19 and 24 weeks of gestation), myofibroblasts were exclusively found lining blood vessels. By RT-PCR activated fibroblasts markers such as vimentin, stromal derived factor-1 (SDF-1) and fibroblast activated protein (FAP) were detected in PA samples. To characterize alpha-SMA+ cells, tumor explants (n=5) were cultured on fibronectin in 10% FBS for 9 days. Large spindle-shaped alpha-SMA+ cells outgrew from explants. By immunofluorescence (IF), a subset of alpha-SMA+ cells co-expressed the specific parathyroid marker GCM2, and TBX1, an embryonic nuclear transcription factor involved in endodermic pharynx development. Moreover, by FACS and IF, cells expressing the SDF-1 receptor CXCR4 were detected in PAs. In conclusions, we identified cells showing features of tumour-associated myofibroblasts in parathyroid tumours. Data suggested that: 1) they might be involved in fetal as well as in tumoral neoangiogenesis; 2) they might contribute to matrix deposition in fibrous bands; 3) they might cross-talk with parathyroid cells by the SDF-1/CXCR4 signalling; 4) they might derived their origin from epithelial-to-mesenchymal transition.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.