Sang Hee Park

Suppression of caveolin expression induces androgen sensitivity in metastatic androgen-insensitive mouse prostate cancer cells

Although prostate cancer cells are often initially sensitive to androgen ablation, they eventually lose this response and continue to survive, grow and spread in the absence of androgenic steroids. The mechanism(s) that underlie resistance to androgen ablation therapy remain mostly unknown. We have demonstrated that elevated caveolin protein levels are associated with human prostate cancer progression in pathological specimens. Here we show that suppression of caveolin expression by a stably transfected antisense caveolin-1 cDNA vector converted androgen-insensitive metastatic mouse prostate cancer cells to an androgen-sensitive phenotype. Orthotopically grown tumors and low-density cell cultures derived from antisense caveolin clones had increased apoptosis in the absence of androgenic steroids, whereas similarly grown tumors and cells from vector (control) clones and parental cells were not sensitive to androgens. Studies using a representative antisense caveolin clone showed that selection for androgen resistance in vivo correlated with increased caveolin levels, and that adenovirus-mediated caveolin expression blocked androgen sensitivity. Our results identify a new candidate gene for hormone-resistant prostate cancer in man and indicate that androgen insensitivity can be an inherent property of metastatic prostate cancer.

Transforming growth factor β1 transduced mouse prostate reconstitutions : II. Induction of apoptosis by doxazosin

To study the possible relationship between adrenergic activities and the pathogenesis of benign prostatic hyperplasia (BPH), we tested the effect of doxazosin, an α1‐adrenoceptor antagonist, on prostatic growth in vivo using a mouse model for BPH.

Mouse prostate reconstitution model system: A series of in vivo and in vitro models for benign and malignant prostatic disease

An elucidation of the complex, morphological and molecular changes that underlie benign and malignant prostatic disease will likely lead to improved methods of diagnosis and therapy for those disorders. To identify and understand the interrelation of the phenotypic and genetic changes inherent in these important diseases requires the development and use of in vivo and in vitro models that closely mimic specific aspects of the disease process. Once the suspected molecular underpinnings of prostatic disease are uncovered, in vivo and in vitro models will be required for further testing of the functional significance of specific genetic alterations as they are identified. In addition models of prostatic disease are necessary to evaluate novel therapeutic approaches.

Transforming growth factor-beta localization during mouse prostate morphogenesis and in prostatic growth abnormalities

SummaryGrowth and morphogenesis of the prostate involves mesenchymal-epithelial interactions. Transforming growth factor-beta 1 (TGF-β1) is one growth factor that may play a role in these paracrine interactions. We have localized TGF-β1 by molecular and immunohistochemical analysis in the developing mouse prostate. Accumulations of TGF-β1 protein were localized in the mesenchyme surrounding ductules in fetal and neonatal prostate. Previous studies in the mouse prostate reconstitution (MPR) model system have localized accumulations of TGF-β1 to regions of oncogene-induced abnormalities. In surgically excised adult human prostate tissues, localized accumulations of TGF-β1 are associated with prostate cancer and benign prostatic hyperplasia (BPH). Intracellular TGF-β1 was more often associated with stromal cells in BPH and with neoplastic epithelial cells in prostate cancer. The production and accumulation of TGF-β1 appears to involve interactions between mesenchymal and epithelial cells. Further experimental studies may clarify the relationships between TGF-β1 and abnormal prostatic growth.

Transforming growth factor β1 transduced mouse prostate reconstitutions: I. Induction of neuronal phenotypes

We previously showed that retroviral transduction of transforming growth factor beta 1 (TGF‐β1) induces focally hyperplastic lesions resembling benign prostatic hyperplasia (BPH) and an increase in the number of ganglion‐like cells in the mouse prostate reconstitution (MPR) model in vivo. In the present study we further characterize the neuronal phenotypes induced by TGF‐β1 retroviral transduction in MPRs.

Androgen sensitivity and gene expression in ras + myc-induced mouse prostate carcinomas

We established an androgen-sensitive cell line (BR31-5) from a ras + myc-induced mouse prostate carcinoma and used this cell line together with a previously reported transplantable androgen-independent mouse prostate carcinoma to investigate patterns of expression for apoptosis-related genes in an androgen-deprived environment. Single cell suspensions derived from the BR31-5 cell line were inoculated into the flank of intact or castrated adult male C57BL/6 mice and tumors were harvested 12 days post-inoculation for Northern blotting. A transplantable androgen-independent prostate cancer was also inoculated into intact or castrated mice and tumors harvested 21 days later. Tumor volume analyses showed that BR31-5 carcinomas were androgen-sensitive. Northern blotting showed that mRNA levels for two apoptosis-related genes, transforming growth factor-beta 1 and c-myc, were significantly elevated to a similar extent in carcinomas grown in castrated hosts compared to intact hosts for both the androgen-sensitive BR31-5 and androgen-independent carcinomas. Levels of mRNA for tissue type plasminogen activator, shown previously to be elevated in androgen-independent carcinomas following growth in castrates, were also increased in BR31-5 carcinomas under similar androgen-deprived conditions but to a lesser extent. Interestingly, testosterone repressed prostate mRNA No. 2 levels shown previously to be similar in both the intact and castrated groups for androgen-independent carcinomas were significantly increased in the castrated group compared to the intact group for BR31-5 carcinomas. Therefore, specific patterns of expression for apoptosis-related genes may be able to discriminate androgen-sensitive and androgen-independent prostate cancer under androgen-deprived conditions.

Evidence for the Involvement of Genetic Differences and Mesenchymal Factors in the Progression of Oncogene-Induced Prostate Cancer in Reconstituted Mouse Prostate

Carcinogenesis is a multi-step process involving the accumulation of alterations within the cellular genome (reviewed in 1,2). These alterations can occur in protooncogenes converting them into activated oncogenes, and it has been suggested that the multi-step nature of carcinogenesis may partly reflect the consecutive activation of several dominantly acting oncogenes (3-7). It seems reasonable to presume that prostatic cancer follows this pattern. In support of this notion, oncogene activities have been reported to be present in human prostatic adenocarcinoma (8-10), in cell lines derived from cancerous prostatic tissues (11), and in Dunning R3327 rat prostatic adenocarcinomas (12,13). Recently, utilizing the mouse prostate reconstitution model system, it was demonstrated that activated ras or myc oncogenes singly were able to induce distinct dysplastic and hyperplastic lesions, respectively (14). The two oncogenes in combination induced rapidly growing, poorly differentiated malignant adenocarcinomas. Thus, the activation of the ras and myc oncogenes can induce a step-like progression of carcinogenesis in this experimental animal model.