Naoki Nihei

Neuroendocrine differentiation in the progression of prostate cancer

Neuroendocrine (NE) cells originally exist in the normal prostate acini and duct, regulating prostatic growth, differentiation and secretion. Clusters of malignant NE cells are found in most prostate cancer (PCa) cases. NE differentiation (NED) is the basic character of the prostate, either benign or malignant. NE cells hold certain peptide hormones or pro‐hormones, which affect the target cells by endocrine, paracrine, autocrine and neuroendocrine transmission in an androgen‐independent fashion due to the lack of androgen receptor. NED is accessed by immunohistochemical staining or measurement of serum levels of NE markers. The extent of NED is associated with progression and prognosis of PCa. Chromogranin A (CGA) is the most important NE marker. In metastatic PCa, pretreatment serum CGA levels can be a predictor for progression and survival after endocrine therapy. It is recommended to measure longitudinal change in serum CGA. The NE pathway can also be a therapeutic target.

Location of KAI1 on the short arm of human chromosome 11 and frequency of allelic loss in advanced human prostate cancer.

We recently isolated the KAI1 gene, a metastasis suppressor gene for prostate cancer, from human chromosome region 11p13–cen‐containing rat prostate cancer cells. The present study was performed to further locate the region of the KAI1 gene on the short arm of chromosome 11, and to examine whether loss of this region is significant during progression of human prostate cancer.

The role of testosterone in the pathogenesis of prostate cancer

Abstract:  Relationships between androgenic hormones and prostatic tissue growth are complex. It is certainly true that the prostate will not develop without androgens and the gland will atrophy if androgen support is withdrawn. The hormonal hypothesis remains one of the most important hypotheses in the etiology of prostate cancer (PCa), and efforts are continuing to improve the understanding of androgen actions in PCa. Although evidence from epidemiological studies of associations between circulating levels of androgens and PCa risk has been inconsistent, the traditional view that higher testosterone (T) levels represent a risk factor for PCa appears to have little evidentiary support. Reinvestigation of the relationship between T and PCa seems important and necessary if a new, clinically and scientifically rewarding concept is to be constructed. The present review considers the metabolism and intraprostatic action of T, epidemiological evidence, and the association between T and PCa risk.

Combination of Gemcitabine and Paclitaxel as Second-line Chemotherapy for Advanced Urothelial Carcinoma

OBJECTIVE The aim of this study was to evaluate the efficacy and toxicities of the gemcitabine and paclitaxel combination regimen as second-line chemotherapy for patients with advanced or metastatic urothelial carcinoma (UC) who have previously been treated with platinum-based chemotherapy for the metastatic disease. METHODS Thirty-three patients with advanced or metastatic UC who had received platinum-based chemotherapy were treated with an outpatient gemcitabine and paclitaxel combination regimen. A dose of 180 mg/m(2) paclitaxel was administered by intravenous (IV) infusion on Day 1, and 1000 mg/m(2) gemcitabine was administered by IV on Days 1, 8 and 15.The course was repeated every 28 days. Patients were evaluated after every 2 cycles of therapy using computed tomography. RESULTS Of the 33 patients enrolled in this study, 30 could be evaluated to determine treatment efficacy; 10 had an objective response [overall response rate: 33.3%, 95% confidence interval (CI), 19.2-51.2%]. The median overall survival was 11.3 months (95% CI, 7.2-13.6 months). The chemotherapy sensitivity differed with disease site. The response rates of lung and bone metastases were 27% and 14%, and the progressive disease (PD) rates of lung and bone metastases were 13% and 14%, respectively. On the other hand, the response rate of liver metastasis was 14%, and its PD rate was 57%. None of the patients (n = 3) with adrenal metastasis responded to this regimen. Toxicities were mild, and no life-threatening complications occurred. CONCLUSIONS Gemcitabine and paclitaxel combination therapy is a tolerable and active regimen for patients with advanced UC after failure of platinum-based chemotherapy.

The insulin-like growth factor-1 elevates urokinase-type plasminogen activator-1 in human breast cancer cells: a new avenue for breast cancer therapy.

Tumor recurrence is a common problem in the treatment of breast cancer. In breast cancer, the expression of high protein levels of the insulin‐like growth factor‐1 receptor (IGF‐1R) and urokinase‐type plasminogen activator‐1 (uPA) is strongly associated with breast cancer recurrence and decreased survival. The expression of uPA by tumors is thought to not only stimulate tumor invasion but also facilitate angiogenesis. In this study, our goal was to address whether IGF‐1R could influence the expression of the extracell ular matrix proteases, matrix metalloproteinase (MMP), or uPA thus allowing a selective advantage for tumor invasion and concomitant neovascularization. Initially, we determined whether or not insulin‐like growth factor (IGF)‐1 regulated the production MMP or uPA in the human breast cancer MDA‐MB‐231 cells. There was no increase in MMP activity when the cells were treated with IGF‐1 (10 ng/mL) for 24 h. In contrast, uPA mRNA and protein were induced in a time‐dependent manner. Furthermore, clones expressi ng a dominant negative inhibitor of IGF‐1R termed 486stop had less uPA mRNA, and the clones were less invasive through Matrigel. Taken together, these data illustrate that IGF‐1R stimulates uPA production. Hence, these two prognostic indicators may be interrelated, suggesting they may function in a synergistic manner to facilitate local tumor invasion as well as angiogenesis. Our data suggest that disruption of IGF‐1 signaling in breast cancer may lead to breast cancer prevention and intervention by decreasing uPA expression. Mol. Carcinog. 27:10–17, 2000.

Mapping of metastasis suppressor gene(s) for rat prostate cancer on the short arm of human chromosome 8 by irradiated microcell-mediated chromosome transfer

Our previous studies demonstrated that human chromosome 8 contains metastasis suppressor gene(s) for rat prostate cancer. However, it is still unknown which portion of human chromosome 8 is associated with suppression of metastatic ability, because all of the clones in which metastatic ability is suppressed contain at least one copy of intact human chromosome 8. In the present study, we used the irradiated microcell‐mediated chromosome transfer technique to enrich for specific chromosomal arm deletions of selected chromosomes. The resultant series of human chromosomes 8 with a variety of chromosomal deletions was introduced into highly metastatic Dunning rat prostate cancer cells. All of the resultant microcell hybrids showed reduced metastatic ability. To obtain a smaller size of human chromosome 8 and to locate further the region of metastasis suppressor gene(s), the most reduced size of human chromosome 8 that was generated with the initial irradiated chromosome transfer was retransferred into the Dunning cancer cells without irradiation. The resultant microcell hybrids were analyzed to determine which portion of human chromosome 8 suppressed the metastatic ability of the recipient cells. This analysis demonstrates that the portion of human chromosome 8 containing metastasis suppressor gene(s) for rat prostate cancer cells lies on human chromosome segment 8p21‐p12, where frequent allelic losses have been detected in allelotype analyses of human prostate cancer. This suggests that one of the metastasis suppressor genes for rat prostate cancer on human chromosome 8 may also play an important role in the progression of human prostate cancer. Genes Chromosom Cancer 17:260–268 (1996).

Renal cell carcinoma with unusual metastasis to the gallbladder

Gallbladder involvement in patients with renal cell carcinoma (RCC) is extremely rare. We present a report of a 61-year-old man with a synchronous RCC metastasis to the gallbladder presenting as an intraluminal polypoid mass simulating primary gallbladder carcinoma. Enhanced abdominal computed tomography demonstrated a well-enhanced polypoid lesion in the gallbladder. Intraoperative rapid pathological examination of the gallbladder tumor showed clear cell-type cancerous cells. Microscopically, tumor cells of both the resected kidney and gallbladder had round uniform nuclei, clear cytoplasm, and well-defined cytoplasmic borders, forming alveolar patterns. Immunohistochemically, the tumor cells were negative for cytokeratin 7 (CK7) and carcinoembryonic antigen (CEA), which is usually positive in primary clear cell carcinoma of the gallbladder. Therefore, the final diagnosis was RCC with a synchronous gallbladder metastasis.

Metastasis suppressor gene(s) for rat prostate cancer on the long arm of human chromosome 7

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. Genes Chromosomes Cancer 24:1–8, 1999.

FOXA1 promotes tumor progression in prostate cancer via the insulin-like growth factor binding protein 3 pathway.

Fork-head box protein A1 (FOXA1) is a “pioneer factor” that is known to bind to the androgen receptor (AR) and regulate the transcription of AR-specific genes. However, the precise role of FOXA1 in prostate cancer (PC) remains unknown. In this study, we report that FOXA1 plays a critical role in PC cell proliferation. The expression of FOXA1 was higher in PC than in normal prostate tissues (P = 0.0002), and, using immunohistochemical analysis, we found that FOXA1 was localized in the nucleus. FOXA1 expression levels were significantly correlated with both PSA and Gleason scores (P = 0.016 and P = 0.031, respectively). Moreover, FOXA1 up-regulation was a significant factor in PSA failure (P = 0.011). Depletion of FOXA1 in a prostate cancer cell line (LNCaP) using small interfering RNA (siRNA) significantly inhibited AR activity, led to cell-growth suppression, and induced G0/G1 arrest. The anti-proliferative effect of FOXA1 siRNA was mediated through insulin-like growth factor binding protein 3 (IGFBP-3). An increase in IGFBP-3, mediated by depletion of FOXA1, inhibited phosphorylation of MAPK and Akt, and increased expression of the cell cycle regulators p21 and p27. We also found that the anti-proliferative effect of FOXA1 depletion was significantly reversed by simultaneous siRNA depletion of IGFBP-3. These findings provide direct physiological and molecular evidence for a role of FOXA1 in controlling cell proliferation through the regulation of IGFBP-3 expression in PC.

Influence of visceral obesity on oncologic outcome in patients with renal cell carcinoma.

Objective: At present, computed tomography (CT) is used in almost all patients with renal tumors. We aimed to investigate the relationship between visceral adipose tissue (VAT), as assessed by CT, and various other factors in patients with renal cell carcinoma (RCC). Methods: We undertook an examination of VAT in 117 male patients undergoing nephrectomy or partial nephrectomy at Chiba University Hospital using software designed to detect VAT in the horizontal plane of the body cavity. Pathological stage, microvascular invasion, tumor grade, performance status, C-reactive protein, BMI, hypertension, hyperlipemia, hyperglycemia, history of smoking and cause-specific survival rate were examined in relation to VAT, and multivariate Cox regression analysis was used to determine significant predictors of cause-specific survival. Results: VAT in patients with stage I disease was significantly greater than that in patients with more advanced disease (p = 0.0219). VAT in patients with microvascular invasion was significantly smaller than in those without microvascular invasion (p = 0.0260). Patients with high VAT had significantly higher cumulative cause-specific survival when compared to patients with low VAT (p = 0.0257). Conclusion: VAT was associated with better clinical features in patients with RCC. Further study is necessary in order to clarify the role of VAT in RCC.