SHORT REPORTS Tumor formation in p53 mutant ovaries transplanted into wild-type female hosts Chun-Ming Chen 1,3 , Junn-Liang Chang 2 and Richard R Behringer* ,1 1 Department of Molecular Genetics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA; 2 Department of Pathology, Armed Forced Taoyuan General Hospital, Taoyuan County, Taiwan p53 gene alterations correlate highly with advanced ovarian carcinoma in women. In mice, p53 deficiency predominantly results in the formation of lymphomas and sarcomas. However, ovarian epithelial tumors have not been documented in p53 homozygous mutant (p53 / ) mice, probably because they die before other tumors can form. To determine whether p53 / ovaries can develop epithelial tumors, they were transplanted into the ovarian bursae of histocompatible wild-type recipient females. The p53 / ovarian grafts formed tumors B1 year post- transplantation. The tumor type was angiosarcoma, suggesting that vascular tissues are predisposed to tumor formation in p53 / ovaries. These findings suggest that p53 deficiency alone is not sufficient for ovarian epithelial tumorigenesis in mice. Thus, other genetic lesions are likely required to develop mouse models of human ovarian cancer. Oncogene (2004) 23, 7722–7725. doi:10.1038/sj.onc.1208037 Published online 30 August 2004 Keywords: ovarian cancer; tumor suppressor; p53; ovary transplantation; hemangiosarcoma Ovarian cancer is the second most prevalent cause of cancer-related death and the fifth leading cancer among American women (Jemal et al., 2003). Approximately 90% of human ovarian cancer is derived from the ovarian epithelium (Auersperg et al., 2001). Genetic alterations of oncogenes and tumor suppressor genes correlate with ovarian cancer formation and progression (Bast and Mills, 2000). Among these genetic alterations, p53 mutations are the most common in advanced ovarian cancer (for review, see Shelling et al., 1995; Schuijer and Berns, 2003). In contrast, p53 gene alterations are infrequent in benign ovarian tumors or the early stages of ovarian cancer. These findings suggest that p53 mutations play important roles in human ovarian cancer progression. Several strains of p53 knockout mice have been created by gene targeting in mouse embryonic stem cells (Donehower et al., 1992; Jacks et al., 1994; Purdie et al., 1994). p53 / mice spontaneously develop a spectrum of tumors that depends in part upon genetic background (Venkatachalam et al., 2002). The tumor latency for p53 / mice is generally B6–8 months of age. Lympho- mas and sarcomas are the primary tumor types on C57Bl/6  129 (B6/129) mixed and C57Bl/6 inbred genetic backgrounds (Venkatachalam et al., 2002). Carcinoma incidence in p53 / mice is relatively rare. The incidence of ovarian tumors in p53 / mice has not been reported, most likely because other types of cancer cause lethality before these tumors might arise. Given sufficient time, it seems reasonable to imagine that p53 mutant ovaries should be able to form tumors. There- fore, we used the classic technique of ovary transplanta- tion into histocompatible wild-type female hosts to avoid the lethal tumor-burden that develops in p53 / mice. The ovaries of 3- to 5-week-old p53 / mice on a C57Bl/6J (B6) congenic background (Jackson Labora- tory, Bar Harbor, ME, USA) were removed and one- half of each ovary was transplanted into the ovarian bursa of ovariectomized age-matched histocompatible C57Bl/6J (B6) inbred or B6/129F1 hybrid mice (Figure 1a). p53 þ / ovaries were transplanted, which served as controls. Subsequently, ovarian tumor forma- tion was monitored by palpating the abdomen of the recipient females twice per week. However, at 11 months post-transplantation, we were only able to identify one case of tumor formation by abdominal palpation. Therefore, we examined p53 / ovarian grafts at 7–8 and at 11–13 months post-transplantation (Table 1). p53 / ovarian grafts were grossly normal in appear- ance up to 7–8 months post-transplantation, consistent with the lack of spontaneous ovarian tumor formation in p53 / mice (Figure 1c). However, by 11–13 months post-transplantation, all successfully transplanted p53 / ovaries (five of six transplants) formed tumor masses (Figure 1e and f). The ovarian tumors were hemorrhagic (two of five), pale (one of five), or cystic (two of five) in appearance (Figure 1e and f and not shown). Histolo- gically, the hemorrhagic ovarian tumors exhibited irregular vascular channels lined by pleiomorphic neoplastic endothelial cells (Figure 2b). Focal stromal invasion, cellular atypia with bizarre nuclei, and highly Received 13 January 2004; revised 12 May 2004; accepted 20 May 2004; published online 30 August 2004 *Correspondence: RR Behringer, Department of Molecular Genetics, University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA; E-mail: rrb@notes.mdacc.tmc.edu 3 Current address: Faculty of Life Sciences, National Yang-Ming University, Taipei 112, Taiwan Oncogene (2004) 23, 7722–7725 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $30.00 www.nature.com/onc