Matrilysin expression in the involuting rat ventral prostate.

Matrilysin (PUMP-1) is a member of the matrix metalloproteinase (MMP) family of extracellular matrix degrading enzymes that has been found to be overexpressed in human prostate cancer. The rat ventral prostate (RVP) following castration has been used as a model for both tissue involution and apoptosis. Northern analysis and in situ hybridization were used to determine the time course and localization of matrilysin during 8 days of RVP involution. Northern analysis revealed that the 1.2 kb matrilysin mRNA was undetectable in normal RVP. An increase in the steady-state levels of matrilysin mRNA was observed 5 days after castration, and the levels began to decline by 8 days after castration. The mRNAs for tissue inhibitor of metalloproteinase-1 and urokinase-type plasminogen activator also showed a time-dependent induction during the course of involution. Localization of matrilysin by in situ hybridization indicated that the mRNA was produced by epithelial cells of the involuting RVP. The matrilysin message was observed in a small number of glands within the whole RVP. Matrilysin protein was present in the RVP and peaked 3 days after castration. The combination of proteinase genes expressed in the RVP following castration indicate that the MMP and serine protease families of enzymes may interact during tissue remodeling of the RVP following castration.

Evidence that carcinogenesis involves an imbalance between epigenetic high-frequency initiation and suppression of promotion.

Evidence is presented in support of the hypothesis that cancer development depends on an imbalance between highly frequent epigenetic initiation and suppression of promotion of the initiated cells. When irradiated clonogenic mammary epithelial cells are transplanted and hormonally stimulated, they give rise to clonal glandular structures within which carcinomas may arise. In the current study, the cancer incidence in grafts of approximately 13 7-Gy-irradiated clonogens per site indicated that at least 1 of approximately 95 clonogens was radiogenically initiated. A similar initiation frequency had been seen in grafts of approximately 5 methylnitrosourea (MNU)-treated clonogens. Such initiation is thus far more frequent than specific locus mutations. In sites grafted with larger cell inocula, cancer incidences per clonogen were suppressed inversely as the numbers of irradiated or MNU-treated clonogens per graft increased. Addition of unirradiated cells to small irradiated graft inocula also suppressed progression. Radiation and MNU thus produce quantitatively, and perhaps qualitatively, similar carcinogenesis-related sequelae in mammary clonogens.

Restoration of thyroid function after total thyroidectomy and quantitative thyroid cell transplantation.

Quantitative thyroid cell transplantation was used to evaluate the reestablishment of thyroid function in surgically thyroidectomized rats. Donor thyroid glands were enzymatically dispersed, and the cells were quantified, serially diluted, and inoculated into the sc fat pads of syngeneic recipient rats 1 day after surgical thyroidectomy. Blood samples were obtained weekly, and serum T3, T4, and TSH levels were determined by RIA. Recipient rats displayed different patterns of restoration of thyroid function depending on 1) the number of thyroid cells inoculated and 2) their dietary iodine intake. We observed cell dose-dependent differences in both the rapidity and extent of thyroid function after cell transplantation. Recipients fed a normal diet and grafted with 6 x 10(4) or more cells reached near-normal levels of all three hormones. In recipients fed a low iodine diet, T4 and TSH levels remained at significantly hypothyroid levels for the duration of the 7-week study. At the highest cell dose examined (3 x 10(5)), however, serum TSH levels began to decline by the sixth to seventh week. In spite of the iodine deficiency, recovery of T3 levels in these recipients paralleled that in recipients fed normal diets. Intact control animals exhibited the anticipated pattern of decreased T4, increased TSH, and essentially unchanged T3. 125I uptake by the grafts was also dependent on the initial number of thyroid cells grafted independent of diet.