Heterogeneous Tumor Evolution Initiated by Loss of pRb Function in a Preclinical Prostate Cancer Model

Abstract

Because each change in the evolution of a cancer is predicated on the effects of previous events, a full understanding of selective changes and their effect on tumor progression can only be understood in the context of appropriate initiating events. Here, we define the effect of pRb function inactivation in prostate epithelium on both the initiation of prostate cancer and the establishment of selective pressures that lead to diminished Pten function and tumor evolution. Using genetically engineered mice, we show that inactivation of the pRb family proteins (Rb/p107/p130) induces epithelial proliferation and apoptosis and is sufficient to produce prostatic intraepithelial neoplasia (PIN) lesions. Over time, adenocarcinomas develop in all mice with no evidence of neuroendocrine tumors. Apoptosis is dependent on Pten function and not p53, unlike other epithelial cell types tested previously. Consequently, Pten hemizygosity reduces apoptosis by 50%, accelerating progression to adenocarcinomas with heterogeneous composition. Heterogeneity is associated with concurrent Pten haploinsufficiency and focal selective progression to complete Pten loss, which yields distinct tumor properties. Given that this analysis models the apparent timing of highly penetrant events in human prostate cancer, observed effects may recapitulate the natural evolution of prostate cancer development. (Cancer Res 2005; 65(22): 10243-54)

Human Papillomavirus Type 16 E7 Up-regulates AKT Activity through the Retinoblastoma Protein

“…1B). The up-regulated phosphorylated AKT staining in the E7 rafts was confined to the membrane and cytoplasm of positive cells, which is consistent with other reports (12,13). Thus, it seems that HPV-16 E7 up-regulates AKT activity in both undifferentiated and differentiated primary HFK.…”

“…This antibody has been previously used for immunohistochemistry and immunofluorescent studies evaluating active AKT levels in various cancer tissues (12,13). Control rafts showed weak phosphorylated AKT staining in the basal and suprabasal layers, whereas E7 rafts exhibited strong staining for phosphorylated AKT in cells within the basal and suprabasal layers (Fig.…”

Inactivation of gadd45a Sensitizes Epithelial Cancer Cells to Ionizing Radiation In vivo Resulting in Prolonged Survival

“…The transgenic TgT 121 brain tumor mouse model (16,17), the TgAPT 121 prostate carcinoma mouse model (18), and mice harboring a homozygous deletion of the gadd45a gene (8) null backgrounds, transgenic mice that were heterozygous at the desired locus were crossed to respective homozygous null animals. In every case, the oncogenic transgene was maintained in the hemizygous state.…”

p53 downstream target genes and tumor suppression: a classical view in evolution

“…When this mouse was crossed into a p53-deficient background, epithelial apoptosis and proliferation in the prostate were unaffected. 96 However, the TgAPT 121 ; p53 þ /À mice developed an aberrant mesenchyme and rapid growth of tumors (up to 2 cm 3 by 19 weeks). 27 In TgAPT 121 ; p53 À/À mice, these tumors appeared by 4 weeks, and in addition, poorly differentiated adenocarcinomas were observed by 22 weeks.…”