Search

Frequent allelic losses on chromosome arm 13q are observed in carcinomas of the head and neck, breast, ovary, and pituitary gland. We analyzed 59 primary prostate tumors (stage B, 18 patients; C, 12 patients; D1, 4 patients; and endocrine therapy-resistant cancer death, 25 patients), as well as 18 metastatic tissues from 14 of the 25 cancer death patients for loss of heterozygosity (LOH) using 35 microsatellite markers on chromosome arm 13q. Of the 59 primary tumors, 31 (53%) showed LOH involving at least one locus. Detailed deletion mapping identified a distinct commonly deleted region in the I-cM interval flanked by D13S153 and D13S273 on 13q14 and this region overlapped a part of the RB1 gene. Paired DNAs were available from both primary and metastatic tumors in the 14 cases of cancer death; among those pairs, we detected LOH on 13q in seven (50%) primary tumors, and in all metastatic foci (P = 0.0029). Moreover, the regions lost in metastatic tissues were more extensive than those seen in the corresponding primary tumors. These results suggest that inactivation of a putative tumor suppressor gene(s) including the RB1 gene on 13q14 plays an important role in human prostate cancer.

Allelotype analyses of human prostate cancer indicate that allelic losses on human chromosome arms 7q, 8p, 10q, 13q, 16q, 17q, and 18q are observed frequently. For the study of the possible biological significance of the frequently observed deletions on chromosome arm 7q in human prostate cancer, human chromosome 7 was introduced into highly metastatic rat prostate cancer cells by use of a microcell-mediated chromosome transfer technique. The introduction of human chromosome 7 resulted in the suppression of metastatic ability of the microcell hybrids, whereas no suppression of tumorigenicity was observed. To identify the portion of chromosome 7 containing the metastasis-suppressive function gene, the derivative chromosome 7 that was generated with the initial transfer was retransferred into rat prostate cancer cells. Human chromosome 7-containing rat prostate cancer cells could be used as the donor cells, because rodent cells produced a sufficient number of microcells with colchicine treatment. Cytogenetic and molecular analyses of these clones demonstrated that loss of segments on 7q was related to the reexpression of the metastatic phenotype. These results show that human 7q contains a metastasis suppressor gene or genes for rat prostate cancer. The findings also suggest that this gene may play an important role in the progression of human prostate cancer.

We analyzed normal/tumor DNA pairs obtained from 46 patients with prostate cancers (stage B, 16 cases; C, 10 cases; D1, 4 cases; and endocrine therapy-resistant cancer-death, 16 cases) for loss of heterozygosity using 32 microsatellite markers on chromosome 18. Seventeen of the 46 cases (37%) showed loss of heterozygosity (LOH) for at least one locus on the long arm. Detailed deletion mapping in these tumors identified a distinct commonly deleted region within a 5-cM interval in 18q21.1. There was a statistical correlation between the frequency of LOH on 18q and clinical stage (chi 2 = 12.3; P = 0.0064). LOH on 18q was observed more frequently in Stage D1 cases (4/4; 100%) than in stage B+C cases (5/26; 19%; P = 0.0046, Fisher's exact test). In 8 of 9 (89%) cancer-death patients from whom DNAs were available from both primary and metastatic tumors, the primary tumors had either no detectable abnormality of chromosome 18 or the region involving loss of heterozygosity was limited while the metastatic foci showed more frequent and extended allelic losses on this chromosome. No abnormalities were detected in the DCC and DPC4 genes when their exons were analyzed separately by single strand conformation polymorphism assay. These results suggest that inactivation of one or more putative tumor suppressor genes on 18q21 other than DCC and DPC4 plays an important role in the progression of human prostate cancer.

Rat transplantable prostatic tumors (Dunning R-3327) were treated with flutamide before tumors grew palpable, in order to examine the effect of short term treatment of antiandrogen for prostatic cancer in latent period on the growth after appearance of tumor. Flutamide delayed an appearance of the tumor nodule and retarded the growth rate in proportion as treatment began earlier. Flutamide also reduced final tumor volume. Flutamide-treated tumors histologically consisted of small or dilated glandular structure with an increase in stromal area, but androgen receptors were preserved. Flutamide-treated tumor showed slow growth with androgen sensitivity when transplanted to intact rats, showing prolonged influences of antiandrogen on tumor growth. There was no significant difference between flutamide-treated and control groups in weight of accessory sex organs and serum androgen or estrogen levels. In conclusion, flutamide treatment may retard an appearance of prostatic cancer concomitant in benign prostatic hyperplasia.

Argyrophilic nucleolar organizer regions (AgNORs) were examined histologically in cells of benign hyperplastic and cancerous human prostates. Individual dots of AgNORs inside nucleus that were stained as separate granules or as parts of clusters were counted as one, and the average number of dots per cell was obtained by counting 100 nuclei. The number in epithelial cells was similar to that in stromal cells of hyperplastic prostates. In cancerous prostates, the number was larger than in hyperplastic prostates and increased along with upgrading. The number in incidental cancers was smaller than in clinical cancers as compared with cells of the same Gleason pattern. Number correlated with T factor, but not with N and M factors. Response to treatment and cause-specific survival in stage D2 patients receiving endocrine therapy did not correlate with number, although a relationship between Gleason pattern and survival was shown in these patients. It was concluded that AgNORs might not be an indicator to predict prognosis after endocrine therapy, since a number of AgNORs did not influence response to the therapy.

Androgen receptor was detected immunohistochemically in benign as well as malignant prostatic tissues by using a monoclonal rat anti-human androgen receptor antibody (AN 1-15). In both benign and malignant cells, the androgen receptor was exclusively localized in nuclei. In hyperplastic prostate, the androgen receptor was stained in the glandular and the stromal cells. In the gland, cells facing the lumen were stained more intensively than those adjacent to the basal membrane. In cancer tissue, receptor-positive and -negative cancer cells were intermingled. The percent of strongly positive cancer cells was correlated inversely with grade. Relapsed cells showed a low population of strongly positive cells irrespective of grade.

The presence of androphilic protein identified histochemically with R 1881-CMO-BSA-FITC correlated with response to endocrine therapy and prognosis. Ras P21 was not a useful indicator of the subsequent course of the disease. Conventional X ray assessment of boney metastases still seems of use in monitoring overall progress of the disease.