Paradoxical antiproliferative effect by a murine mammary tumor-derived epithelial cell line

Esteban N Gurzov,R Daniel Bonfil,Sanaa M Nabha,O Graciela Scharovsky,Hamilto Yamamoto,Hong Meng

doi:10.1186/1471-2407-7-184

Abstract

BackgroundDespite significant advancement in breast cancer therapy, there is a great need for a better understanding of the mechanisms involved in breast carcinogenesis and progression, as well as of the role of epigenetic contributions from stromal cells in mammary tumorigenesis. In this study, we isolated and characterized murine mammary tumor-derived epithelial and myofibroblast cell lines, and investigated the in vitro and in vivo effect of cellular soluble factors produced by the epithelial cell line on tumor cells.MethodsMorphology, immunophenotype, cytogenetics, invasiveness, and tumorigenicity of epithelial (LM-234ep) and myofibroblast (LM-234mf) cell lines isolated from two murine mammary adenocarcinomas with common ancestor were studied. The in vitro effects of LM-234ep conditioned medium on proliferation, cell cycle distribution, and expression of cell cycle proteins, were investigated in LM-234mf cells, mouse melanoma cells (B16-F10), and human cervical adenocarcinoma cells (HeLa). The in vivo anti-tumor activity of LM-234ep conditioned media was evaluated in subcutaneous tumors formed in nude mice by B16-F10 and HeLa cells.ResultsLM-234ep cells were found to be cytokeratin positive and hipertriploid, whereas LM-234mf cells were α-smooth muscle actin positive and hypohexaploid. Chromosome aberrations were found in both cases. Only LM-234mf revealed to be invasive in vitro and to secrete active MMP-2, though neither of the cell types were able to produce progressing tumors. LM-234ep-derived factors were able to inhibit the in vitro growth of LM-234mf, B16-F10, and HeLa cells, inducing cell cycle arrest in G0/G1 phase. The administration of LM-234ep conditioned medium inhibited the growth of B16-F10 and HeLa tumors in nude mice.ConclusionOur data suggest the existence of epithelial cell variants with tumor suppressive properties within mammary tumors. To our knowledge, this is the first report showing antiproliferative and antineoplastic activities induced by tumor-derived epithelial cells.

Highlights

Despite significant advancement in breast cancer therapy, there is a great need for a better understanding of the mechanisms involved in breast carcinogenesis and progression, as well as of the role of epigenetic contributions from stromal cells in mammary tumorigenesis
Most of the earlier studies were focused exclusively on cancer cells. This concept changed over the last years, as epigenetic contributions from stromal cells in close proximity to cancer cells were found to play a crucial role in the growth, angiogenesis, invasion, and metastases of most carcinomas, including those originated in breast [2,3,4]
This is true for breast cancer, where most of the studies have focused on the luminal epithelial cells found in the ducts and alveoli, despite the presence of stromal cells including fibroblasts, myofibroblasts, leukocytes, and myoepithelial cells [4,27]

Summary

Introduction

Despite significant advancement in breast cancer therapy, there is a great need for a better understanding of the mechanisms involved in breast carcinogenesis and progression, as well as of the role of epigenetic contributions from stromal cells in mammary tumorigenesis. Despite the enormous advancement in breast cancer therapy in the last years, a better understanding of the mechanisms involved in breast carcinogenesis and progression may lead to novel therapies and increased patient survival. Most of the earlier studies were focused exclusively on cancer cells This concept changed over the last years, as epigenetic contributions from stromal cells in close proximity to cancer cells were found to play a crucial role in the growth, angiogenesis, invasion, and metastases of most carcinomas, including those originated in breast [2,3,4]. Myofibroblasts, defined as fibroblasts with α-smooth muscle actin (SMA) expression [5], constitute the most predominant carcinoma-associated stromal cells, and have been found to be involved in the production of different proteases responsible for invasion [6,7,8], as well as in the stimulation of the proliferation of cancer cells [9,10]

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Discussion

Conclusion