The p53 suppression on tumor cells may modulate the function of macrophages for enhancing tumor progression
Department of Obstetrics and Gynecology, Kawasaki Medical School, Kurashiki, Japan
We had found that the expression of indoleamine 2,3-dioxygenase (IDO) on cervical cancer was promoted as they were progressing from carcinoma in situ (CIS) to microinvasive cancer, and that tumor-associated macrophages (TAM) were recruited at the invasive front, which were expressing IDO in cervical cancer patients (Cancer Sci 98:874-881 2007). We produced αT3 mice carrying the αA-SV40Tag transgene, developing undifferentiated lens epithelial cancer in multistep carcinogenesis (J Cancer Res Clin Oncol 135:1521-1532, 2009). In this study, αT3 mice were mated with M1 mice expressing mutant p53 in lens cells (Proc Natl Acad Sci USA, 92:6142-6146, 1995) producing αT3M1 mice, and also were mated with p53-deficient mice for producing p53-deficient αT3 (αT3p53(-/-)) mice (Cancer Lett 179:165-173, 2002, Oncol Rep 12:253-258, 2004). At 20 weeks of age, a proportion of progression from CIS to invasive cancer was analyzed pathologically and the number of recruited, IDO-expressing TAM was determined by immunohistochemical staining and FACS analysis. Both αT3M1 and αT3p53(-/-) tumors significantly progressed from CIS to invasive cancer more than αT3 tumors did. There were a few macrophages in wild-type lens, but there were more TAM in each tumors of αT3, αT3M1 and αT3p53(-/-). However, there was no significant difference of the number of IDO-expressing macrophages in peritoneal cavity among wild-type, αT3, αT3M1 and αT3p53(-/-) mice. Moreover, we established tumor cell lines from each αT3, αT3M1 and αT3p53(-/-) tumors to analyze peritoneal macrophages in wild-type mice after i.p. injection of these cells. IDO-expressing peritoneal macrophages were significantly more detected in 4 days after each i.p. injection of αT3M1 and αT3p53(-/-) cells than i.p. injection of αT3 cells. These results suggested that the amount of p53 suppression on tumor cells would be related to the number of IDO-expressing TAM which may suppress an innate immunity and may enhance tumor progression.
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