Mutations within the tumour suppressor gene p53 are not confined to a late event in prostate cancer progression. a review of the evidence.

Mutations in the p53 tumour suppressor gene are generally believed to be a late event in the progression of prostate cancer, and are associated with androgen independence, metastasis, and a worse prognosis. In this review, we examine the current literature available on p53 mutations and focus on stages A (T1) and B (T2) of prostate cancer. We report here that p53 mutations can be found in approximately one third of prostate cancers that are clinically localized to the prostate. In addition, high levels of p53 mutation are found in normal prostate tissue of prostate cancer patients, prostatic intraepithelial neoplasia, and benign prostatic hyperplasia. The limitations of techniques used to determine p53 mutations are discussed, as well as other modes of p53 loss in early stage prostate cancer.

Evidence for post-transcriptional down-regulation of the apoptosis-related gene bcl-2 in human colorectal cancer.

This retrospective study was undertaken to investigate the expression of bcl-2 protein and messenger RNA in colorectal cancer (CRC). Immunohistochemical analysis using a monoclonal mouse antibody to the bcl-2 protein and in situ hybridization using a digoxigenin-labelled bcl-2 cRNA probe were carried out on formalin-fixed and paraffin-embedded specimens from 53 colorectal adenocarcinomas, 27 liver secondaries, and 60 adenomas with various degrees of dysplasia. Normal human tonsil sections were used as positive controls. Expression of bcl-2 protein and of messenger RNA was evaluated semiquantitatively. The expression of bcl-2 protein was gradually and significantly lost during the progression from moderately dysplastic adenoma to primary CRC (moderate/severe dysplasia: Mann-Whitney U-test, p=0.0001; severe dysplasia/primary CRC: p=0.027), whereas the cellular expression of bcl-2 mRNA was gradually increased during the dysplasia/adenoma-carcinoma neoplastic sequence. These observations suggest that in a proportion of colorectal cancer cases, the bcl-2 proto-oncogene expression may be down-regulated at a post-transcriptional level.

Elevated expression of FGF-2 does not cause prostate cancer progression in LNCaP cells.

BACKGROUND: Androgen-independent (AI) prostate cancer (CaP) resulting from progression of disease is untreatable. Such progression may relate to upregulation and autocrinicity of growth factor expression. We studied one candidate growth factor, basic fibroblast growth factor (FGF-2). METHODS: LNCaP cells made autocrine for FGF-2 by stable transfection with FGF-2 were examined for cancer progression, measured by 1) altered response to androgen, 2) ability to grow more quickly when cocultured with bone cells in vitro or to form tumors when coinoculated with bone cells in vivo, or 3) increase in metastatic ability. RESULTS: Stably transfected lines differed in FGF-2 protein expression. LNCaP-HF (high production of FGF-2) expressed more FGF-2 than LNCaP-LF (low production of FGF-2); controls were negative. In vitro, compared with LNCaPs, LNCaP-HF cells showed a slightly increased growth rate, reduced proliferation in response to androgen but not to estrogen or progesterone, and a decreased proliferative response to epidermal growth factor (EGF) and FGF-2. Although giving a slightly faster take rate, LNCaP-HF cells without Matrigel only formed small, fast-regressing tumors in male nude mice, and with Matrigel, did not differ from LNCaPs in growth rate or tumor size. No metastases occurred. No tumors grew in females. Mixed growth of FGF-2 transfectants with human fetal osteoblasts failed to cross-stimulate in vitro, or to allow tumor formation in vivo. CONCLUSIONS: Although FGF-2 is overexpressed in AI CaPs, our experiments show that upregulation of FGF-2 expression is not sufficient to cause androgen independence, tumorigenicity, or metastases production (i.e., prostate cancer progression) in LNCaP cells.

Delayed involution of the mammary epithelium in BALB/c-p53null mice.

In mammals, weaning of neonates and subsequent milk stasis initiates removal of the secretory epithelium of the mammary gland by apoptosis. The p53 tumor suppressor gene is induced rapidly following weaning of neonates, but its role in the process of involution has not been defined. Therefore, experiments were performed to identify the cell types in which the p53 gene is expressed during involution and determine the consequences of its absence in BALB/c-p53null mice. Both p53 mRNA and protein were detected in the mammary epithelium within 48 h following weaning and resulted in an eightfold increase in levels of p21WAF1 mRNA. Induction of p21WAF1 mRNA was absent in BALB/c-p53null mice, and therefore, was shown to be p53-dependent. The BALB/c-p53null mice exhibited delayed involution of the mammary epithelium, as measured by 60% greater epithelial area compared to BALB/c-p53(wt) mice through 5 days post-weaning. The delay was transient with no differences being apparent at 7 days post-weaning. Expression of the stromal protease stromelysin-1 was unaffected by the absence of p53 suggesting that stromal responses were intact. These data demonstrate that p53 participates in the first stage of involution initiated by the epithelium itself, but does not affect the second phase during which stromal proteases are induced.