Immortalized mouse mammary fibroblasts lacking dioxin receptor have impaired tumorigenicity in a subcutaneous mouse xenograft model.
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.
Mulero-Navarro
Sonia
S
Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, Avenida de Elvas s/n, 06071 Badajoz, Spain.
Pozo-Guisado
Eulalia
E
Pérez-Mancera
Pedro A
PA
Alvarez-Barrientos
Alberto
A
Catalina-Fernández
Inmaculada
I
Hernández-Nieto
Emilia
E
Sáenz-Santamaria
Javier
J
Martínez
Natalia
N
Rojas
José M
JM
Sánchez-García
Isidro
I
Fernández-Salguero
Pedro M
PM
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D002453:Cell Cycle; D002455:Cell Division; D005347:Fibroblasts / Q000166:cytology* / Q000502:physiology; D011905:Genes, ras; D007890:Leiomyosarcoma / Q000517:prevention & control*; D008321:Mammary Glands, Animal / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency* / Q000235:genetics*; D012878:Skin Neoplasms / Q000517:prevention & control*; D016038:Skin Transplantation / Q000473:pathology*; D014162:Transfection; D014183:Transplantation, Heterologous
D000952:Antigens, Polyomavirus Transforming; D018336:Receptors, Aryl Hydrocarbon