Cell competition between anaplastic thyroid cancer and normal thyroid follicular cells exerts reciprocal stress response defining tumor suppressive effects of normal epithelial tissue.

Aidana Amrenova,Keiji Suzuki,Shunichi Yamashita,Norisato Mitsutake,Vladimir Saenko,Salvatore V Pizzo

doi:10.1371/journal.pone.0249059

Abstract

The microenvironment of an early-stage tumor, in which a small number of cancer cells is surrounded by a normal counterpart milieu, plays a crucial role in determining the fate of initiated cells. Here, we examined cell competition between anaplastic thyroid cancer cells and normal thyroid follicular cells using co-culture method. Cancer cells were grown until they formed small clusters, to which normal cells were added to create high-density co-culture condition. We found that co-culture with normal cells significantly suppressed the growth of cancer cell clusters through the activation of Akt-Skp2 pathway. In turn, cancer cells triggered apoptosis in the neighboring normal cells through local activation of ERK1/2. A bi-directional cell competition provides a suppressive mechanism of anaplastic thyroid cancer progression. Since the competitive effect was negated by terminal growth arrest caused by radiation exposure to normal cells, modulation of reciprocal stress response in vivo could be an intrinsic mechanism associated with tumor initiation, propagation, and metastasis.

Highlights

At earlier stages of carcinogenesis, malignant transformation starts from a single cell that grows within an epithelial monolayer
Cell competition was reproduced by establishing a co-culture system between anaplastic thyroid cancer cell line, ACT1, and normal thyroid follicular epithelial cells (NTECs)
ACT1 cells plated at a low density grow clonally and form densely packed cell clusters by Day 5 (Fig 1A), and NTECs were added to the culture

Summary

Introduction

At earlier stages of carcinogenesis, malignant transformation starts from a single cell that grows within an epithelial monolayer. The initiated cell continues to proliferate and accumulates genetic alterations, which give rise to malignant cancer cells. Tissue microenvironment, in which multiple types of cells coexist, affects malignant propagation of initiated cells [1,2,3,4,5,6,7]. In a tissue microenvironment, the initiated cells are likely to interact with normal counterparts in a dynamic fashion over time. Such interactions may lead to a balance.

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Results

Conclusion