Kiyoshi Koshida

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.

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.

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.

DOMINANT ROLE OF E-CADHERIN IN THE PROGRESSION OF BLADDER CANCER

PURPOSE To elucidate factors with a role in the progression of bladder cancer. MATERIALS AND METHODS One invasive (T24) and two superficial (RT4 and KK47) human bladder cancer cell lines, which express metastasis-related genes, were used. Cells were intravenously inoculated into chick embryos to evaluate metastatic potential to the liver. An orthotopic model with severe combined immunodeficiency mice was also used to investigate both histological appearance and changes in metastasis-related gene expression. Finally, gene expression patterns in a clinical setting were compared between superficial and invasive bladder cancers. RESULTS In culture condition metastasis-related genes, including matrix metalloproteinases, urokinase-type plasminogen activator, and integrins alpha2 and alpha3 were continually expressed in T24 but only slightly or not at all in RT4 and KK47, respectively. The expression pattern of the metastasis-related genes in vitro reflected the characteristics of the original tumors. Liver metastasis in chick embryos was demonstrated not only with T24 cells, but also with RT4 cells in which enhanced expression of metastasis-related genes was induced. In the orthotopic model, histological appearances were in accordance with the characteristics of the original tumors, although enhanced gene expression was notable with RT4. Expression of E-cadherin by Western blotting was demonstrated only with RT4 under these experimental conditions. Furthermore, predominant E-cadherin mRNA expression was found in superficial and not in invasive human primary bladder cancers; expression of other genes was similar in the two groups. Dominant expression of E-cadherin in superficial tumors was confirmed by immunohistochemical analysis. CONCLUSIONS These results implicate loss of E-cadherin expression as a critical factor in facilitating the progression of bladder cancer.

Novel HER2 selective tyrosine kinase inhibitor, TAK‐165, inhibits bladder, kidney and androgen‐independent prostate cancer in vitro and in vivo

Purpose:  TAK‐165 is a new potent inhibitor of human epidermal growth factor receptor 2 (HER2) tyrosine kinase. Several reports suggest HER2 expression in bladder cancer, renal cell carcinoma (RCC) and androgen‐independent prostate cancer. We therefore investigated the antitumor effect of TAK‐165 on these urological cancer cells.

Placental-like alkaline phosphatase in seminoma.

SummaryTumor marker identification in testicular cancer has contributed to early detection and monitoring of non-seminomatous disease. A placental alkaline phosphatase-like (PLAP-like) enzyme derived from seminomas has recently been focused upon as a possible marker for this disease. The biochemistry of the PLAP-like enzyme is reviewed, as well as its occurrence in tissue and sera from healthy persons and patients with testicular cancer.

Pathological effects of neoadjuvant hormonal therapy help predict progression of prostate cancer after radical prostatectomy.

Background: It is not clear whether pathological changes following neoadjuvant hormonal therapy (NHT) prior to radical prostatectomy have any value as predictors of progression in prostate cancer.

Long-term exposure of tumor necrosis factor α causes hypersensitivity to androgen and anti-androgen withdrawal phenomenon in LNCaP prostate cancer cells

One of the mechanisms through which prostate cancers relapse during anti‐androgen therapy may involve adaptation to low concentrations of androgen induced by anti‐androgen therapies. Recent studies from our laboratory have reported that tumor necrosis factor‐α (TNFα) is secreted from prostate cancer epithelial cells and LNCaP cells. We hypothesized that TNFα changes androgen‐sensitivity in LNCaP cells.

Immunohistochemical detection of the 150-kDa oxygen-regulated protein in bladder cancer.

Objective To investigate the relationship between the expression of the 150‐kDa oxygen‐regulated protein (ORP150, which functions as a molecular chaperone in the endoplasmic reticulum for the folding and trafficking of newly synthesized proteins) and the aggressiveness of bladder cancer, and the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs), as the former is a secreting protein through the endoplasmic reticulum and the latter are closely involved in tumour invasion.