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


METHODS
Morphology, 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.


RESULTS
LM-234ep cells were found to be cytokeratin positive and hipertriploid, whereas LM-234mf cells were alpha-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.


CONCLUSIONS
Our 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.
Gurzov
Esteban N
EN
Department of Molecular Biology, Centro de Biología Molecular Severo Ochoa Universidad Autónoma de Madrid, Facultad de Ciencias, Madrid, Spain. egurzov@cbm.uam.es
Nabha
Sanaa M
SM
Yamamoto
Hamilto
H
Meng
Hong
H
Scharovsky
O Graciela
OG
Bonfil
R Daniel
RD
D000199:Actins / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015197:Carcinogenicity Tests; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002869:Chromosome Aberrations; D017077:Culture Media, Conditioned; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D007633:Keratins / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D019899:Paracrine Communication; D002583:Uterine Cervical Neoplasms / Q000378:metabolism
D000199:Actins; D017077:Culture Media, Conditioned; D007633:Keratins; D018093:Gelatinases