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Título : Immortalized mouse mammary fibroblasts lacking dioxin receptor have impaired tumorigenicity in a subcutaneous mouse xenograft model
Autor : Pérez-Mancera, P. A.; Sánchez García, Isidro
Fecha de publicación : 9-jun-2005
Editor: American Society for Biochemistry and Molecular Biology
Citación : Journal of Biological Chemistry 280(31): 28731-42871 (2005)
Resumen: Although the dioxin receptor, the aryl hydrocarbon receptor (AhR), is considered a major regulator of xenobiotic-induced carcinogenesis, its role in tumor formation in the absence of xenobiotics is still largely unknown. Trying to address this question, we have produced immortalized cell lines from wild-type (T-FGM-AhR+/+) and mutant (T-FGM-AhR-/-) mouse mammary fibroblasts by stable co-transfection with the simian virus 40 (SV-40) large T antigen and proto-oncogenic c-H-Ras. Both cell lines had a myofibroblast phenotype and similar proliferation, doubling time, SV-40 and c-H-Ras expression and activity, and cell cycle distribution. AhR+/+ and AhR-/- cells were also equally able to support growth factor- and anchorage-independent proliferation. However, the ability of T-FGM-AhR-/- to induce subcutaneous tumors (leimyosarcomas) in NOD/SCID-immunodeficient mice was close to 4-fold lower than T-FGM-AhR+/+. In culture, T-FGM-AhR-/- had diminished migration in collagen-I and decreased lamellipodia formation. VEGFR-1/Flt-1, a VEGF receptor that regulates cell migration and blood vessel formation, was also down-regulated in AhR-/- cells. Signaling through the ERK-FAK-PKB/AKT-Rac-1 pathway, which contributes to cell motility and invasion, was also significantly inhibited in T-FGM-AhR-/-. Thus, the lower tumorigenic potential of T-FGM-AhR-/- could result from a compromised adaptability of these cells to the in vivo microenvironment, possibly because of an impaired ability to migrate and to respond to angiogenesis.
Descripción : 11 páginas, 9 figuras.-- PMID: 15946950 [PubMed].-- et al.
Versión del editor: http://dx.doi.org/10.1074/jbc.M504538200
URI : http://hdl.handle.net/10261/6262
DOI: 10.1074/jbc.M504538200
ISSN: 0021-9258
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