期刊
NEOPLASIA
卷 22, 期 11, 页码 576-589出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neo.2020.09.003
关键词
DCIS; Inflammatory microenvironment; HER2; HIF1-alpha
类别
资金
- Polish National Science Centre grant: OPUS [UMO-2013/09/NZ4/02512]
- Polish National Science Centre grant: PRELUDIUM [UMO-2018/29/N/NZ3/02407]
There are data to suggest that some ductal carcinoma in situ (DCIS) may evolve through an evolutionary bottleneck, where minor clones susceptible to the imposed selective pressure drive disease progression. Here, we tested the hypothesis that an impact of the inflammatory environment on DCIS evolution is HER2-dependent, conferring proliferative dominance of HER2-negative cells. In tissue samples, density of tumour-infiltrating immune cells (TIICs) was associated only with high tumour nuclear grade, but in 9% of predominantly HER2-negative cases, the presence of tumoral foci ('hot-spots') of basal-like cells with HIF1-alpha activity adjacent to the areas of dense stromal infiltration was noted. Results of in vitro analyses further demonstrated that IL-1 beta and TNF-alpha as well as macrophage-conditioned medium triggered phosphorylation of NF-kappa B and subsequent upregulation of COX2 and HIF1-alpha, exclusively in HER2-negative cells. Treatment with both IL-1 beta and TNF-alpha resulted in growth stimulation and inhibition of HER2-negative and HER2-positive cells, respectively. Moreover, ectopic overexpression of HIF1-alpha rescued HER2-positive cells from the negative effect of IL-1 beta and TNF-alpha on cell growth. Our data provide novel insight into the molecular basis of HER2-dependent proliferation of DCIS cells and indicate the NF-kappa B/COX2 -> HIF1-alpha signalling axis as a dominant mechanism of DCIS evolution induced by inflammatory microenvironment. Presented findings also highlight the clinical significance of heterogeneity of DCIS tumours and suggest that HIF1-alpha might be considered as a predictive marker of disease progression.
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