Masayuki Egawa

The Adrenal Androgen Androstenediol Is Present in Prostate Cancer Tissue after Androgen Deprivation Therapy and Activates Mutated Androgen Receptor

Despite an initial response to androgen deprivation therapy, prostate cancer (PCa) progresses eventually from an androgen-dependent to an androgen-independent phenotype. One of the mechanisms of relapse is antiandrogen withdrawal phenomenon caused by mutation of 877th amino acid of androgen receptor (AR). In the present study, we established a method to measure the concentration of androstenediol (adiol) in prostate tissue. We found that adiol maintains a high concentration in PCa tissue even after androgen deprivation therapy. Furthermore, adiol is a stronger activator of mutant AR in LNCaP PCa cells and induces more cell proliferation, prostate-specific antigen (PSA) mRNA expression, and PSA promoter than dihydrotestosterone (DHT). Because antiandrogen, bicalutamide, blocked adiol activity in LNCaP cells, it was suggested that adiol effect was mediated through AR. However, high concentration of bicalutamide was necessary to block completely adiol activity. These effects were specific to LNCaP cells because adiol had less effect in PC-3 PCa cells transfected with wild-type AR than DHT and had similar effect in PC-3 cells transfected with mutant AR. The mechanism that adiol activates mutant AR in LNCaP cells did not result from the increased affinity to mutant AR or from AR’s association with coactivator ARA70. However, low concentration of adiol induced more AR nuclear translocation than DHT in LNCaP cells and not PC-3 cells transfected with AR. These results indicate that adiol may cause the progression of PCa even after hormone therapy.

Inverse correlation of microvessel density with metastasis and prognosis in renal cell carcinoma

Background: Although a correlation between microvessel density (MVD) and tumor aggressiveness has been established for several malignancies, the data for renal cell carcinoma (RCC) is conflicting. In order to clarify the significance of MVD, we investigated the relationships between MVD and tumor stage, grade, size, occurrence of metastasis and patient survival.

New targets for therapy in prostate cancer: Modulation of stromal-epithelial interactions

Changes in genomic and phenotypic expression of progressing prostate tumors and their stroma occur in a dynamic fashion based on bidirectional signaling from stromal-epithelial interactions. These interactions may underlie the ability of prostate cancer cells to survive and proliferate in the prostate and bone. By investigating the phenotypic and genotypic changes of stromal cells adjacent to cancer cells and the reciprocal changes of cancer cells, novel molecular markers may be developed to diagnose cancer earlier before pathologic appearance of cancer cells at the primary site. Attacking epithelial and stromal elements together is a unique approach to both localized and metastatic prostate cancer therapy. Co-targeting both tumor cells and stroma requires identifying a reliable tumor and tissue-specific cis-DNA element, such as osteocalcin (OC) promoter. OC expression is elevated in prostate tumor cells and in prostate and bone stromal cells interdigitating with both localized and metastatic prostate epithelium. We have previously designed an adenovirus-based therapeutic gene vehicle and demonstrated that a replication-competent adenoviral vector (Ad vector) is highly efficient in blocking the growth of cancer cells in culture, including cells without androgen receptor as well as cells that do or do not make prostate-specific antigen. In vivo, intravenous administration of an Ad-OC vector was effective against preexisting human prostate cancer subcutaneous and bone xenografts. The addition of vitamin D(3) enhanced further viral replication at target sites. Co-targeting tumor cells and stroma using systemic Ad vector is a viable and promising option for treatment of both localized and metastatic prostate cancer.

Gene therapy for prostate cancer using the cytosine deaminase/uracil phosphoribosyltransferase suicide system

Cytosine deaminase (CD) activates prodrug 5‐FC to 5‐FU and is used for suicide gene therapy (the CD/5‐FC system). E. coli uracil phosphoribosyltransferase (UPRT) is a pyrimidine salvage enzyme that directly converts 5‐FU into 5‐fluorouridine monophosphate and improves the antitumoral effect of 5‐FU. This study demonstrates the effectiveness of transduction of the UPRT gene in addition to CD/5‐FC cancer suicide gene therapy.

Bilateral epididymal sarcoidosis presenting without radiographic evidence of intrathoracic lesion: Review of sarcoidosis involving the male reproductive tract

Sarcoidosis is a multisystem disorder that rarely involves the genitourinary tract. To date, only 59 cases of histologically proven sarcoidosis involving the male reproductive tract have been reported in the literature. We present here a case of bilateral epididymal sarcoidosis without radiographic evidence of intrathoracic lesion. A 46‐year‐old man presented with a one‐week history of painless bilateral scrotal swellings. Physical examination detected multiple elastic firm nodules on both sides of the scrotum which showed no tenderness. The nodules seemed to involve the entire bilateral epididymides. Some irregularly shaped hypoechoic masses in the bilateral epididymides were identified on gray scale ultrasonography. On magnetic resonance images, the bilateral epididymides were seen to be enlarged, heterogeneous and nodular without any signs of testicular involvement. The lesion showed a slightly high signal intensity on the T2‐weighted image. Pathological evaluation following bilateral epididymectomy found non‐caseating epithelioid cell granulomas with giant cells in epididymal tissue, thus confirming a diagnosis of sarcoidosis. Gallium‐67 scanning showed additional small hot spots in the anterior chest wall and extremities. Open biopsy of a superficial papular lesion in the dermis of the right upper arm was performed and pathological findings indicated sarcoid granulomas. This report also includes a review of the literature pertaining to sarcoidosis of the male reproductive tract.

Antitumor effect of reduction of 150-kDa oxygen-regulated protein expression on human prostate cancer cells

Background: The 150‐kDa oxygen‐regulated protein ORP150, a new member of the heat shock protein family that functions as a molecular chaperone in the endoplasmic reticulum, was found to increase in infiltrating cancer cells. Since enhancement of ORP150 expression and the presence of vascular endothelial growth factor (VEGF) in human prostate cancer glands were immunohistochemically demonstrated, we examined whether transduced antisense ORP150 cDNA can reduce angiogenicity and tumorigenicity through suppression of VEGF secretion.

Retrospective study on stage B prostate cancer in the Hokuriku District, Japan.

Background: The present study was conducted to investigate how patients with clinically localized prostate cancer were treated in the Hokuriku District, Japan.

Comparison of two in vivo models for prostate cancer: Orthotopic and intratesticular inoculation of LNCaP or PC-3 cells

Abstract  Background:  The critical events in the clinical course of prostate cancer are the occurrence of metastasis and the induction of the hormone‐refractory status of the disease. In order to investigate the factors responsible for these events, we need appropriate in vivo models.

In vitro chemosensitivity test for human genito-urinary tumors using collagen gel matrix.

Abstract Background:  Although the aim of chemosensitivity tests is to predict the efficacy of anticancer agents for individual patients, no generally accepted assay has been established.

Antitumor effect of reduction of 150-kDa oxygen-regulated protein expression in human prostate cancer cells.

Heat shock proteins (HSPs)/stress proteins are molecular chaperones that are induced by various environmental and physiological stimuli. Evidence of the relations between the expression of HSPs and the regulation of cell growth or transformation has accumulated. The 150-kDa oxygen-regulated protein (ORP150), a new member of HSP family, functions as a molecular chaperone in the endoplasmic reticulum. We have examined whether transduced antisense ORP150 cDNA reduces tumorigenicity and angiogenicity. Relations between these stress proteins and cancer and possibilities for anticancer gene therapy are described.