Akira Nagahara

Infiltration of tumour‐associated macrophages in prostate biopsy specimens is predictive of disease progression after hormonal therapy for prostate cancer

Study Type – Prognostic (case series)

Excision Repair Cross-Complementing Group 1 May Predict the Efficacy of Chemoradiation Therapy for Muscle-Invasive Bladder Cancer

Purpose: Chemoradiation therapy (CRT) is now widely recognized as bladder-preserving therapy for muscle-invasive bladder cancer (MIBC). However, some patients who fail CRT may miss the chance to be cured by cystectomy. Therefore, it is important to select patients with MIBC who are expected to have a good response to CRT. Several reports indicate that the excision repair cross-complementing group 1 (ERCC1) gene is associated with resistance to cisplatin and radiation therapy. In this study, we examined the correlation between ERCC1 and CRT in vitro and in vivo in bladder cancer. Experimental Design: Bladder cancer cell lines T24, 5637, Cl8-2 (multidrug-resistant subline of T24), and CDDP10-3 (cisplatin-resistant subline of T24) were used for in vitro assays to measure ERCC1 expression level and growth inhibition with cisplatin or ionizing radiation (IR). We then examined by immunohistochemistry that whether ERCC1 nuclear staining correlates with the efficacy of CRT using cisplatin in 22 patients with MIBC. Results: Cl8-2 cells expressed ERCC1 mRNA 5.96-fold higher than did T24. Cl8-2 and CDDP10-3 were more resistant to cisplatin or IR than was T24. Resistance to IR, but not to cisplatin, was removed by suppressing ERCC1 using siRNA in both Cl8-2 and CDDP10-3 cells. In immunohistochemistry with ERCC1, 6 of 8 positive cases did not have complete response to CRT, whereas 12 of 14 negative cases had complete response. Sensitivity and specificity were 75% and 85.7%, respectively (P = 0.008). Conclusion: Although further study is needed, ERCC1 expression level may predict the efficacy of CRT for MIBC. Clin Cancer Res; 17(8); 2561–9. ©2010 AACR.

SERPINE2 is a possible candidate promotor for lymph node metastasis in testicular cancer

Testicular germ cell tumors (TGCTs) commonly metastasize to the lymph node or lung. However, it remains unclear which genes are associated with TGCT metastasis. The aim of this study was to identify gene(s) that promoted human TGCT metastasis. We intraperitoneally administered conditioned medium (CM) from JKT-1, a cell-line from a human testicular seminoma, or JKT-HM, a JKT-1 cell sub-line with high metastatic potential, into mice with JKT-1 xenografts. Administration of CM from JKT-HM significantly promoted lymph node metastasis. A cDNA microarray analysis showed that JKT-HM cells highly expressed the Serpine peptidase inhibitor, clade E, member 2 (SERPINE2), which encodes a secreted protein. Administration of CM from SERPINE2-silenced JKT-HM cells inhibited lymph node metastasis in the xenograft model, compared with administration of CM from JKT-HM cells. There was no significant difference in xenograft volume. Moreover, administration of CM from SERPINE2-over-expressing JKT-1 was likely to promote lymph node metastasis in the xenograft model. There was no difference in the in vitro proliferation or migration of JKT-1 cells cultured with CM from JKT-HM cells, compared to that with CM from JKT-1. There was no promotion of proliferation or lymphangiogenesis in the xenografts, as measured by Ki-67 and LYVE-1 immunohistochemistry, respectively. Although we could not clarify how SERPINE2 promoted lymph node metastasis, it may be a promoter in the development of lymph node metastasis in the human seminoma cells in a mouse xenograft model.

Brain metastases from testicular germ cell tumors: A retrospective analysis

Objectives:  To review our series of testicular germ cell tumors with brain metastases and to establish an optimal treatment strategy for them.

Serum fucosylated haptoglobin as a novel prognostic biomarker predicting high-Gleason prostate cancer

Fucosylation is an oligosaccharide modification associated with cancer and inflammation, which is catalyzed by fucosyltransferases. Fucosylated haptoglobin (Fuc‐Hpt) has been identified as a novel biomarker for pancreatic cancer.

Testis-specific protein on Y chromosome (TSPY) represses the activity of the androgen receptor in androgen-dependent testicular germ-cell tumors

Testis-specific protein on Y chromosome (TSPY) is an ampliconic gene on the Y chromosome, and genetic interaction with gonadoblastoma has been clinically established. However, the function of the TSPY protein remains to be characterized in physiological and pathological settings. In the present study, we observed coexpression of TSPY and the androgen receptor (AR) in testicular germ-cell tumors (TGCTs) in patients as well as in model cell lines, but such coexpression was not seen in normal testis of humans or mice. TSPY was a repressor for androgen signaling because of its trapping of cytosolic AR even in the presence of androgen. Androgen treatment stimulated cell proliferation of a TGCT model cell line, and TSPY potently attenuated androgen-dependent cell growth. Together with the finding that TSPY expression is reduced in more malignant TGCTs in vivo, the present study suggests that TSPY serves as a repressor in androgen-induced tumor development in TGCTs and raises the possibility that TSPY could be used as a clinical marker to assess the malignancy of TGCTs.

Residual Prostate Cancer Cells after Docetaxel Therapy Increase the Tumorigenic Potential via Constitutive Signaling of CXCR4, ERK1/2 and c-Myc

Despite an increasing prevalence of patients with docetaxel-refractory prostate cancer, little is known about the tumor biology of the docetaxel-resistant residual tumor cells compared with primary tumor cells. In this study, tumorigenic potential was increased in the docetaxel-resistant residual prostate cancer cell lines (DRD, 1G7 and PC3DR) compared with parental cells (DU145 or PC3). Enhanced tumorigenic potential was conferred by oncogenic c-Myc, which was stabilized by constitutively activated ERK1/2 in DRD, 1G7, and PC3DR cells. Constitutively activated ERK1/2 was maintained by CXCR4, which was upregulated in DRD, 1G7, and PC3DR cells. In docetaxel-treated DU145 cells, transiently activated ERK1/2 induced CXCR4 expression by stabilizing c-Myc. Furthermore, constitutive activation of CXCR4, ERK1/2, and c-Myc signaling was evident in clinical tissue samples from human patients with docetaxel-resistant prostate cancer. In DTX-resistant residual prostate cancer cells, the enhanced tumorigenic potential was reduced by ERK1/2 inhibition, or by AMD3100, a CXCR4 antagonist. Thus, docetaxel treatment constitutively activated the CXCR4, ERK1/2, and c-Myc signaling loop in docetaxel-resistant residual prostate cancer cells. Implications: Constitutive signaling pathways are viable therapeutic targets for residual prostate tumor cells following acquisition of docetaxel resistance. Mol Cancer Res; 11(9); 1088–100. ©2013 AACR.

Proteomic analysis of urinary extracellular vesicles from high Gleason score prostate cancer

Extracellular vesicles (EVs) are microvesicles secreted from various cell types. We aimed to discover a new biomarker for high Gleason score (GS) prostate cancer (PCa) in urinary EVs via quantitative proteomics. EVs were isolated from urine after massage from 18 men (negative biopsy [n = 6], GS 6 PCa [n = 6], or GS 8–9 PCa [n = 6]). EV proteins were labeled with iTRAQ and analyzed by LC-MS/MS. We identified 4710 proteins and quantified 3528 proteins in the urinary EVs. Eleven proteins increased in patients with PCa compared to those with negative biopsy (ratio >1.5, p-value < 0.05). Eleven proteins were chosen for further analysis and verified in 29 independent urine samples (negative [n = 11], PCa [n = 18]) using selected reaction monitoring/multiple reaction monitoring. Among these candidate markers, fatty acid binding protein 5 (FABP5) was higher in the cancer group than in the negative group (p-value = 0.009) and was significantly associated with GS (p-value for trend = 0.011). Granulin, AMBP, CHMP4A, and CHMP4C were also higher in men with high GS prostate cancer (p-value < 0.05). FABP5 in urinary EVs could be a potential biomarker of high GS PCa.

Retrospective Analysis of an Oral Combination of Dexamethasone, Uracil plus Tegafur and Cyclophosphamide for Hormone-refractory Prostate Cancer

OBJECTIVE To evaluate the clinical utility of an oral combination of dexamethasone, uracil plus tegafur and cyclophosphamide as a treatment for patients with hormone-refractory prostate cancer. METHODS Fifty-seven patients with hormone-refractory prostate cancer were treated with an oral administration of dexamethasone (1.0 mg/day), uracil plus tegafur (400 mg/day) and cyclophosphamide (100 mg/day). The median patient age was 71 years. Sixteen patients had symptomatic bone metastasis, 31 had asymptomatic bone metastasis and 8 showed lymph node metastasis. Eight patients presented with only biochemical progression as evaluated by serum prostate-specific antigen levels. RESULTS Thirty-six (63%) of 57 patients demonstrated a ≥50% decline in serum prostate-specific antigen levels. The median time to prostate-specific antigen progression was 7.2 months. In patients with a prostate-specific antigen decline of ≥50%, the median time to progression was 13.3 months. With respect to pre-treatment markers, the duration of response to initial hormonal treatment was associated with the time to prostate-specific antigen progression. In 11 of 16 (69%) patients who complained of bone pain, the pain improved and became stable in 5 of those patients (31%). Most adverse events were mild and only three (5%) patients showed neutropenia of Grade 3 or higher. CONCLUSIONS The combination of dexamethasone, uracil plus tegafur and cyclophosphamide is an effective and well tolerated regimen for hormone-refractory prostate cancer. To evaluate the survival benefits, further randomized studies are required.

Decreased infiltration of macrophage scavenger receptor-positive cells in initial negative biopsy specimens is correlated with positive repeat biopsies of the prostate

Macrophage scavenger receptor (MSR)‐positive inflammatory cells and tumor‐associated macrophages (TAMs) have been reported to regulate the growth of various cancers. In this study, the infiltration of MSR‐positive cells and TAMs was analyzed to predict the outcome of repeat biopsy in men diagnosed as having no malignancy at the first prostate biopsy. Repeat biopsy of the prostate was carried out in 92 patients who were diagnosed as having no malignancy at the first biopsy. Of these, 30 patients (32.6%) were positive for prostate cancer at the repeat biopsy. Tumor‐associated macrophages and MSR‐positive cells were immunohistochemically stained with mAbs CD68 and CD204, respectively. Six ocular measuring fields were chosen randomly under a microscope at ×400 power in the initial negative biopsy specimens, and the mean TAM and MSR counts for each case were determined. No difference in TAM count was found between the cases with or without prostate cancer. By contrast, the MSR count in patients with cancer was significantly lower than that in patients without cancer at the repeat biopsy (P < 0.001). Logistic regression analysis indicated that the MSR count at first biopsy is a significantly better predictive factor for positive repeat biopsy than PSA velocity, interval between first and repeat biopsies, or TAM count. Decreased infiltration of MSR‐positive cells in negative first biopsy specimens was correlated with positive findings in the repeat biopsy. The MSR count might be a good indicator for avoiding unnecessary repeat biopsies. (Cancer Sci 2010)