Germline Stem Cell Protein Piwil2-Deficiency Alters Tumor Spectrum in p53-Deficient Mice
G He, QT Yan, L Chen, Y Ye, RL Shen, SH Barsky, HF Lin, JX Gao. Ohio State University, Columbus, OH; Yale University School of Medicine, New Haven, CT
Background: Piwil2 (alias mili in mouse) is a member of Ago/Piwi family of proteins containing Piwi and PAZ domains (PPD). The PPD proteins participate in RNA interference (RNAi) at transcriptional and posttranscriptional levels. Recently, we have found that piwil2 is stably expressed in pCSCs and regulates their proliferation in vitro, suggesting that piwil2 plays an important role for tumor development. Therefore, we investigated whether piwil2-decificiency effects tumor development.
Design: Since p53-deficienct mice spontaneously develop tumors with lymphoma being dominant, we crossed p53-/- mice with mili-/- mice to generate p53-/-mili-/-, p53-/-mili+/-, and p53-/-mili+/+ mice. The tumor incidence was monitored and the tumor spectrum was examined by histopathology. To investigate the mechanisms underlying the tumor type changes, precancerous stem cells (pCSCs) were established from lymphoma or sarcoma and transplanted subcutaneously into Scid mice.
Results: Most mice (80%) with p53-/- phenotype were male [80% of p53-/-milli-/- mice (12/15), 78.5% of p53-/-mili+/- mice (11/14) and 100% p53-/-mili+/+ mice (3/3)]. All p53-/-mili-/-, p53-/-mili+/-, and p53-/-mili+/+ mice developed tumors. In p53-/-milli-/- mice, 80% of the mice developed high grade malignant fibrohistiocytoma-like spindle cell sarcoma and high grade angiosarcoma (12/15), and only 20% of the mice developed lymphoma (3/15). In contrast, 64.28% of p53-/-milli+/- mice developed sarcoma and angiosarcoma (9/14), and 38.7% of them developed lymphoma or leukemia (5/14). P53-/-milli+/+ mice were dominant with lymphoma (2/2). The lifespan between p53-/-mili-/-, p53-/-mili+/- and p53-/-mili+/+ mice was not statistically significantly different, although p53-/-mili-/- mice appeared to die earlier than p53-/-mili+/- and p53-/-mili+/+ mice. Interestingly, stromal pCSC lines were established from lymphoma with p53-/-mili-/- or p53-/-mili+/- genotypes, and vice versa. The stromal pCSCs could develop both high grade lymphoma and sarcoma after transplanted into Scid mice.
Conclusions: Our studies demonstrate that Piwil2-deficiency may alter tumor spectrum in p53-/- mice in a gene dose-dependent manner and implicate that lymphoma and sarcoma may originate from the same pCSCs. The outcomes of pCSCs reconstituting tumors may be affected by environmental cues.
Category: Special Category for 2009 - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 10, 2009 9:30 AM
Poster Session III # 218, Tuesday Morning