Coevolution of neoplastic epithelial cells and multilineage stroma via polyploid giant cells during immortalization and transformation of mullerian epithelial cells.

Shiwu Zhang,Jinsong Liu,Robert C Bast,Imelda Mercado-Uribe,Anil Sood

doi:10.18632/genesandcancer.102

Shiwu Zhang, Jinsong Liu + Show 3 more

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https://doi.org/10.18632/genesandcancer.102

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Abstract

Stromal cells are generally considered to be derived primarily from the host's normal mesenchymal stromal cells or bone marrow. However, the origins of stromal cells have been quite controversial. To determine the role of polyploidy in tumor development, we examined the fate of normal mullerian epithelial cells during the immortalization and transformation process by tracing the expression of SV40 large T antigen. Here we show that immortalized or HRAS-transformed mullerian epithelial cells contain a subpopulation of polyploid giant cells that grow as multicellular spheroids expressing hematopoietic markers in response to treatment with CoCl2. The immortalized or transformed epithelial cells can transdifferentiate into stromal cells when transplanted into nude mice. Immunofluorescent staining revealed expression of stem cell factors OCT4, Nanog, and SOX-2 in spheroid, whereas expression of embryonic stem cell marker SSEA1 was increased in HRAS-transformed cells compared with their immortalized isogenic counterparts. These results suggest that normal mullerian epithelial cells are intrinsically highly plastic, via the formation of polyploid giant cells and activation of embryonic stem-like program, which work together to promote the coevolution of neoplastic epithelial cells and multiple lineage stromal cells.

Highlights

A carcinoma is a complex tissue composed of multiple cell types, including epithelial cancer cells as well as stromal cells that include fibroblasts, endothelial cells, and inflammatory cells [1,2,3,4]
Some studies have demonstrated that endothelial cells can be derived from cancer cells [5,6,7], and other studies have shown that stromal components of tumors may not be derived entirely from the host’s normal mesenchymal stroma or bone marrow [8, 9], suggesting that cancer cells are highly www.impactjournals.com/Genes&Cancer plastic and capable of generating stromal cells
We recently showed that Polyploid giant cancer cells (PGCCs) form via endoreplication in response to chemically induced stress; we found that these cells are capable of generating daughter cells via amitotic mechanisms such as budding, splitting, or bursting, similar to amitotic division used for asexual reproduction in yeast or protozoa [21]

Summary

Introduction

A carcinoma is a complex tissue composed of multiple cell types, including epithelial cancer cells as well as stromal cells that include fibroblasts, endothelial cells, and inflammatory cells [1,2,3,4]. It is generally believed that mutational events lead to uncontrolled proliferation of epithelial cells and that stromal components of tumors are derived from the host’s normal mesenchymal stroma or bone marrow-derived mesenchymal stem cells [1, 2]. Some studies have demonstrated that endothelial cells can be derived from cancer cells [5,6,7], and other studies have shown that stromal components of tumors may not be derived entirely from the host’s normal mesenchymal stroma or bone marrow [8, 9], suggesting that cancer cells are highly www.impactjournals.com/Genes&Cancer plastic and capable of generating stromal cells. PGCCs may be novel multipotential stem cells that are capable of generating cancer cells (and may be a previously unrecognized key player in cancer development) and stromal components

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