Cancer Stem cells and fibroblast niche cross talk in an in-vitro oral dysplasia model.

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Cancer Stem cells and fibroblast niche cross talk in an in-vitro oral dysplasia model.

Mol Carcinog. 2019 Jan 15;:

Authors: Kulsum S, Raju N, Raghavan N, Dr R, Sharma A, Mehta A, Kuriakose MA, Suresh A

Abstract
Understanding the cellular interactions during oral carcinogenesis has the potential to identify novel prognostic and therapeutic targets. This study aimed at investigating the cancer stem cell (CSCs)-fibroblast niche interactions using in-vitro dysplastic cell line models developed from different stages of 4NQO-induced oral carcinogenic mice model. The spontaneously transformed epithelial cells (DysMSCTR6, 14 and 16) were developed from three time points (mild/moderate/severe), while 2 fibroblast cell lines (FibroMSCTR12, 16) were developed from moderate and severe dysplastic tissue. The epithelial (Epcam + /Ck +) and the fibroblast cell lines (Vimentin + /α-SMA + /Ck-) were authenticated and assessment of cells representing progressive grades of dysplastic severity indicated a significant increase in dysplastic marker profile (p < 0.05). Evaluation of the CSC characteristics showed that an increase in expression of Cd133, Cd44, Aldh1a1, Notch1 and Sox2 was accompanied by an increase in migratory (p > 0.05) and colony formation capacity (p > 0.005). Targeting Notch1 (GSI inhibitor PZ0187; 30µM), showed a significant reduction in cell proliferation capacity (p < 0.05) and in the dysplastic marker profile. Further, Notch1 inhibition resulted in down regulation of Cd133 and Aldh1a 1 (p < 0.05) and a complete abrogation of colony formation ability (p < 0.0001).The effect of niche interactions evaluated using FibroMSCTR12-conditioned media studies, revealed an enrichment of ALDH1A1+ cells (p < 0.05), induction of spheroid formation ability (p < 0.0001) and increased proliferation capacity (3.7fold; p < 0.005). Although PZ0187 reduced cell viability by ∼40%, was unable to abrogate the conditioned-media induced increase in proliferation capacity completely. This study reports a Notch-1 dependent enrichment of CSC properties during dysplastic progression and a Notch-1 independent dysplastic cell-fibroblast interaction during oral carcinogenesis. This article is protected by copyright. All rights reserved.

PMID: 30644602 [PubMed - as supplied by publisher]

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