Abstract
Vitamin D and its analogs are known for their role in the development of breast cancer and in immunomodulation. Our previous studies have shown the pro-metastatic effect of calcitriol and tacalcitol (PRI-2191) in young mice bearing 4T1 breast cancer and the anti-metastatic effect in aged ovariectomized (OVX) mice. Therefore, the aim of our work was to characterize Th17 cell population in young and aged OVX mice bearing 4T1 tumors treated with calcitriol and PRI-2191. The expression of genes typical for Th17 cells was examined in splenocytes, as well as splenocytes differentiated with IL-6 and TGF-β to Th17 cells (iTh17). Expression of genes encoding vitamin D receptor (Vdr) and osteopontin (Spp1) as well as the secretion of IL-17A were evaluated in iTh17 cells. PRI-2191 treatment increased the expression of Rora and Rorc transcription factors, Il17a, Il17re and Il21 in iTh17 cells from young mice. In aged OVX mice this effect was not observed. Increased expression was observed in the case of Vdr and Spp1 genes in iTh17 cells from young mice treated with PRI-2191. What is more, in young mice treated with PRI-2191 the secretion of IL-17A to the culture media by iTh17 cells was increased, whereas in aged OVX mice a significant decrease was noted. Increased expression of Spp1 in young mice treated with PRI-2191 may enhance the differentiation of Th17 cells.
Highlights
Patients suffering from metastatic disease or those who develop metastases after successful treatment of the primary tumor have generally poor prognosis
Since the analysis of gene expression pattern in splenocytes of 4T1 tumor bearing young mice treated with calcitriol or its analogs showed increased expression of genes related to Th17 cell lineage such as: interleukin 17a (Il17a), interleukin 17 receptor E (Il17re), interleukin 1 receptor type 1 (Il1r1), Il21, RAR-related orphan receptor alpha (Rora), and RAR-related orphan receptor gamma (Rorc) [33], we focused on the role of Th17 cells population in the activity of calcitriol and its metabolite PRI-2191 in the metastasis process of 4T1 mouse mammary gland cancer in young and aged OVX mice
Rorc increased in the early stage, was still increased on day 28 in young mice treated with PRI-2191, but in old OVX mice its expression was elevated by calcitriol in the early stage and decreased (Fig. 1A and B)
Summary
Patients suffering from metastatic disease or those who develop metastases after successful treatment of the primary tumor have generally poor prognosis. The data showing promotion of tumor growth and metastasis via vitamin D deficiency are presented using xenografts of human breast cancer cell lines [22] and allografted mouse tumors [23,24,25]. Since the analysis of gene expression pattern in splenocytes of 4T1 tumor bearing young mice treated with calcitriol or its analogs showed increased expression of genes related to Th17 cell lineage such as: interleukin 17a (Il17a), interleukin 17 receptor E (Il17re), interleukin 1 receptor type 1 (Il1r1), Il21, RAR-related orphan receptor alpha (Rora), and RAR-related orphan receptor gamma (Rorc) [33], we focused on the role of Th17 cells population in the activity of calcitriol and its metabolite PRI-2191 in the metastasis process of 4T1 mouse mammary gland cancer in young and aged OVX mice
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