WNT-Conditioned Mechanism of Exit from Postchemotherapy Shock of Differentiated Tumour Cells

Abstract

Background: the present study aims to prove or disprove the hypothesis that the state of copy number aberration (CNA) activation of WNT signalling pathway genes accounts for the ability of differentiated tumour cells to emerge from postchemotherapy shock. Methods: In the first step, the CNA genetic landscape of breast cancer cell lines BT-474, BT-549, MDA-MB-231, MDA-MD-468, MCF7, SK-BR-3 and T47D, which were obtained from ATCC, was examined to rank cell cultures according to the degree of ectopic activation of the WNT signalling pathway. Then two lines of T47D with ectopic activation and BT-474 without activation were selected. The differentiated EpCAM+CD44-CD24-/+ cells of these lines were subjected to IL6 de-differentiation with formation of mammospheres on the background of cisplatin and WNT signalling inhibitor ICG-001. Results: it was found that T47D cells with ectopic WNT signalling activation after cisplatin exposure were dedifferentiated to form mammospheres while BT-474 cells without ectopic WNT-signalling activation did not form mammospheres. The dedifferentiation of T47D cells after cisplatin exposure was completely suppressed by the WNT signalling inhibitor ICG-001. Separately, ICG-001 reduced, but did not abolish, the ability to dedifferentiate in both cell lines. Conclusions: these data support the hypothesis that the emergence of differentiated tumour cells from postchemotherapy shock after chemotherapy is due to ectopic activation of WNT signalling pathway genes.

Prevention of Metastasis by Suppression of Stemness Genes Using a Combination of microRNAs

“…At present, mechanisms underlying the exit of tumor cells from the dormant state are being actively studied. It is well-known that systems of canonical WNT signaling and ERK/p38 pathways play a key role in the exit of micrometastatic tumor cells from the dormant state, including after chemotherapy. − Suppression of various components of WNT signaling is considered the most promising approach in terms of the development of antimetastatic drugs, and some compounds are already in phase II clinical trials . In the dormant state, tumor cells are in a fully differentiated state, not expressing stemness markers; therefore, in order to form a secondary tumor, they need to dedifferentiate into cancer stem cells (CSCs), which are capable of proliferation (giving rise to progenitor tumor cells) and of self-maintenance of their population .…”