[Resected Metachronous Pancreatic Metastasis from Rectal Cancer-A Case Report].

A 68-year-old woman had undergone laparoscopic high anterior resection for rectal cancer. Two years postoperatively, metachronal pulmonary metastases and cerebellar metastasis were surgically resected. Three and a half years after the primary surgery, computed tomography(CT)demonstrated a nodule at the pancreatic tail. Under suspected primary pancreatic cancer or metastasis from rectal cancer, we performed distal pancreatectomy. Histological examination of the pancreatic tumor suggested a metastasis from the rectal cancer since tumor cells were negative for CK7 and positive for CK20 and CDX2 immunohistochemically. Three months after the pancreatic resection, CT demonstrated hepatic and cerebellar metastases. After subsequent chemotherapy, liver metastasis disappeared. The cerebellar metastasis shrank with radiotherapy.

[A Case of Hepatocellular Carcinoma Treated with Transdiaphragmatic Radiofrequency Ablation under Thoracotomy].

The patient was a 73-year-old man. A liver tumor was found in the posterior segment(S6)during the follow-up period post the interferon treatment for hepatitis C in September 1999. An S6 sub-segmentectomy was performed. The tumor was diagnosed as a moderately differentiated carcinoma, hepatocellular carcinoma(HCC)with pT2N0M0, pStage Ⅱ(UICC TNM 7th edition). The tumor recurred twice post-surgery. The recurrent tumors were treated with local therapies such as transcatheter arterial chemoembolization(TACE), percutaneous ethanol injection(PEI)and radiofrequency ablation(RFA). The third recurrence was found in the posterior segment(S7)in April 2009. RFA was unsuccessful because an appropriate puncture route could not be found. Then, a transdiaphragmatic RFA under thoracotomy was performed as an alternative treatment, which led to an optimal outcome. We report a case of HCC that could not be treated with percutaneous RFA but with a transdiaphragmatic RFA under thoracotomy.

[A Case of Solitary Adrenal Metastasis from Rectal Cancer Treated by Adrenalectomy after Preoperative Chemotherapy].

Adrenal metastasis from colorectal cancer occurs in the presence of multiple synchronous metastases at other sites. We report a case of heterochronous solitary adrenal metastasis from rectal cancer. A 55-year-old man underwent anterior resection with D3 lymph node dissection for rectal cancer. The pathological stage of the tumor was III b, and adjuvant chemotherapy with mFOLFOX6 was administered for 6 months. Eighteen months after surgery, abdominal computed tomography(CT) revealed right solitary adrenal metastasis. His tumor marker levels were considerably elevated; therefore, he received preoperative chemotherapy with FOLFIRI plus bevacizumab(BV). After preoperative chemotherapy, his tumor marker levels decreased, and CT and FDG-PET/CT did not uncover any other metastatic lesions. The patient was diagnosed with solitary adrenal metastasis, and right adrenalectomy was performed. Histological examination confirmed the tumor to be adrenal metastasis from rectal cancer, and the histopathological Grade was 2. The patient received adjuvant chemotherapy with mFOLFOX6, and he is alive 7 months after adrenalectomy without evidence of recurrence. Adrenalectomy is recommended for solitary adrenal metastasis from colorectal cancer. Additionally, adrenalectomy after preoperative chemotherapy is an effective strategy for patients with solitary adrenal metastasis and high tumor marker levels.

Draft Genome Sequence of Saccharomyces cerevisiae DJJ01, Isolated from Dojoji Temple in Gobo, Wakayama, Japan.

Saccharomyces cerevisiae strain DJJ01 was isolated from Dojoji Temple (Gobo, Wakayama, Japan) for development of local breweries. Here, we report the draft genome sequence of this strain to facilitate comparative genomic studies of yeast strains used for Japanese sake brewing.

Solitary Cardiac Metastasis from Colorectal Cancer: A Case Report.

A 73-year-old woman with silent cardiac metastasis underwent high anterior resection for rectal cancer 3 years ago. Follow-up computed tomography showed a tumor in the right atrium. Partial vascular resection of the superior vena cava and right atrium was performed. Early postoperative recurrence occurred, and chemotherapy was unsuccessful. The patient died 7 months after surgery.

Evaluating prognostic significance of preoperative C-reactive protein to albumin ratio in older patients with pathological stage II/III colorectal cancer.

Purpose: This study was performed to evaluate the prognostic value of preoperative C-reactive protein to albumin ratio (CAR) in older patients with colorectal cancer (CRC) undergoing curative resection. Methods: We retrospectively analyzed 244 older patients (aged 75 years or higher) with pathological stage II/III CRC who underwent curative surgery between 2008 and 2016. The optimal value of CAR was calculated and its correlation with the clinicopathological factors and prognosis was examined. Results: The optimal cutoff value of the CAR was 0.085. High preoperative CAR was significantly associated with high carcinoembryonic antigen levels (P=0.001), larger tumor size (P<0.001), and T pathological (pT) factor (P=0.001). On multivariate analysis, high CAR was independent prognostic factor for relapse-free survival (P=0.042) and overall survival (P=0.001). Conclusion: Preoperative elevated CAR could be considered as an adverse predictor of both relapse-free survival and overall survival in older patients with CRC undergoing curative surgery.

Impact of sorafenib on health-related quality of life in Japanese patients with metastatic renal cell carcinoma: a prospective evaluation.

OBJECTIVE: To characterize the impact of sorafenib treatment on health-related quality of life (HRQL) in Japanese patients with mRCC. PATIENTS AND METHODS: We performed a prospective observational study including 85 consecutive patients undergoing radical nephrectomy who were diagnosed as having mRCC refractory to cytokine therapy and subsequently treated with sorafenib for at least 3 months. HRQL in these patients was assessed using the Medical Outcomes Study 36-Item Short Form (SF-36). RESULTS: Before treatment all eight scores in the 85 patients were significantly inferior to those in the age-matched control population in Japan. Three months after sorafenib treatment, one score (mental health) in the 85 patients was significantly higher than what it was before treatment. Three scores (body pain, role limitations because of emotional problems, mental health) in patients who had some degree of tumour shrinkage were significantly better than those in the remaining patients, while there were no significant differences in all but one score (social function) between patients with and without severe AEs. Furthermore, there were no significant differences in any scores 3, 6 and 12 months after sorafenib treatment in 26 patients who could be followed for at least 12 months. CONCLUSIONS: Despite non-randomized study including a comparatively small number of patients, the findings of the present study suggest that sorafenib treatment may not impair HRQL in patients with mRCC, and HRQL in patients receiving sorafenib is likely to be affected by the efficacy rather than AEs during treatment.

Characterization of developmental colony formation in Corynebacterium glutamicum.

We report that Corynebacterium glutamicum colonies exhibit a developmental transition in culture. When cultured on a routinely used complete medium (CM2B), this bacterium first formed a flat translucent colony. Subsequently, some parts of this colony expanded to form small spherical yellow colonies that finally developed into a single large yellow colony. The small flat colony consisted of long thick cells, which were occasionally V or Y shaped, while the large yellow colony consisted of short small rods. A similar colony development pattern was observed in Corynebacterium ammoniagenes and Corynebacterium callunae. Analysis following shotgun cloning revealed that the introduction of a multi-copy-number plasmid carrying amtR, a global transcriptional regulator for nitrogen metabolism, into C. glutamicum cells induced precocious colony development. An amtR-null C. glutamicum mutant exhibited delayed development. Detailed observations of C. glutamicum cells cultured on CM2B medium containing buffers at various pH values revealed that the colony growth was rapid at a pH value of 6.4 or higher and slow but distinct at a pH of less than 6.4. This pH threshold increased to 6.8 following the addition of 0.1% glucose into the medium.

Significance of radical cystectomy for bladder cancer in patients over 80 years old.

OBJECTIVES: The objective of this study was to evaluate the usefulness of radical cystectomy for bladder cancer in elderly patients. MATERIALS AND METHODS: This study included 72 patients aged > or =80 years (group A) who underwent radical cystectomy and urinary diversion between January 1995 and December 2003, and the clinical outcome of these patients were compared with those of 557 patients aged <80 years (group B) undergoing radical cystectomy during the same period as group A. RESULTS: As the procedure for urinary diversion, ureterocutaneostomy was most frequently performed in group A (87.5%), while neobladder creation was most common in group B (43.8%). Despite the absence of significant differences in tumor grade and incidence of lymph node metastasis between these two groups, pathological stage in group A was significantly greater than that in group B. The perioperative mortality rate in group A was significantly higher than that in group B, whereas the incidences of both early and late postoperative complications in group A were similar to those in group B. Cancer-specific survival in group A was significantly lower than that in group B; however, among patients with disease < or =pT2, there was no significant difference in cancer-specific survival between these two groups. CONCLUSIONS: These findings suggest that an aggressive surgical approach may be an optimal therapeutic strategy for properly selected elderly patients who require definitive therapy for locally invasive bladder cancer, particularly in those with disease < or =pT2.

Lobe-Specific Lymph Node Dissection as a Standard Procedure in Surgery for Non-Small Cell Lung Cancer: A Propensity Score Matching Study.

INTRODUCTION: Systematic lymph node dissection (SND) is the standard procedure in surgical treatment for NSCLC, but the value of this approach for survival and nodal staging is still uncertain. In this study, we evaluated the potential of lobe-specific lymph node dissection (L-SND) in surgery for NSCLC by using a propensity score matching method. METHODS: From 2005 to 2007, 565 patients with cT1a-2b N0-1 M0 NSCLC underwent lobectomy with lymph node dissection at our 10 affiliated hospitals. Patients were classified into groups that underwent nodal sampling, L-SND, and systematic dissection SND on the basis of pathological data for the number and extent of nodal resection. A total of 77 patients with insufficient pathological data were excluded from the study. RESULTS: Overall, survival did not differ significantly among the groups (p = 0.552), but the rate of detection of pN2 in the SND group (13.1%) was significantly higher than in the nodal sampling (3.3%) and L-SND (9.0%) groups (p = 0.010). However, given the many confounding factors in the patient characteristics in each group, outcomes were reevaluated using a propensity score matching method for the L-SND and SND groups. After matching, the two groups had no significant differences in 5-year overall survival (73.5% for L-SND versus 75.3% for SND, p = 0.977) and pN2 detection (8.2% in both groups, p = 0.779). CONCLUSIONS: These results suggest that lobe-specific lymph node dissection has the potential to be a standard procedure in surgical treatment for NSCLC.

Enhanced expression of heat shock protein 27 following neoadjuvant hormonal therapy is associated with poor clinical outcome in patients undergoing radical prostatectomy for prostate cancer.

BACKGROUND: The objectives of this study were to characterize changes in the expression of heat shock protein 27 (HSP27) in prostate cancer before and after androgen withdrawal therapy and to assess the prognostic significance of HSP27 expression in patients undergoing radical prostatectomy (RP) following neoadjuvant hormonal therapy (NHT). MATERIALS AND METHODS: This study included 97 patients with clinically localized prostate cancer who received NHT followed by RP. Paired needle biopsy and corresponding RP specimens obtained from these patients were analyzed for expression of the HSP27 protein by immunohistochemical staining. These findings were evaluated with respect to several clinicopathological factors. RESULTS: HSP27 expression in the RP specimens following NHT was significantly up-regulated compared with that in the corresponding needle biopsy specimens. The expression level of HSP27 in the biopsy specimens was significantly associated with the biopsy Gleason score, but not with other factors available before RP. HSP27 expression in the RP specimens was significantly correlated with the pre-operative value of serum prostate-specific antigen and pathological stage, but not with other pathological factors. Biochemical recurrence-free survival in patients with strong HSP27 expression in the RP specimens was significantly lower than that in those with weak HSP27 expression; however, the expression level of HSP27 was not an independent predictor of biochemical recurrence. CONCLUSION: Despite the lack of independent significance, the expression level of HSP27 in prostate cancer tissue after NHT, which may inversely reflect the therapeutic effect of NHT, could be a useful parameter predicting biochemical recurrence in patients undergoing RP.

Clinicopathological features of recurrence after radical cystectomy for patients with transitional cell carcinoma of the bladder.

BACKGROUND: The objective of this study was to investigate the clinicopathological features of recurrent transitional cell carcinoma (TCC) of the bladder in patients who had previously undergone radical cystectomy. MATERIALS AND METHODS: This study included 124 patients who underwent radical cystectomy for transitional cell carcinoma (TCC) of the bladder in our institution. Several clinicopathological factors were analyzed to characterize differences between patients with and without disease recurrence, and determined predictive factors for disease recurrence using multivariate analysis. We further analyzed prognostic parameters that affect survival after disease recurrence was diagnosed. RESULTS: Of the 124 patients, 24 (19.5%) developed recurrence, and the median time to recurrence was 9.5 months (range, 1-44 months). The 5-year recurrence-free survival in these 124 patients was 75.6%. The incidence of disease recurrence was significantly associated with gender, pathological stage, lymph node metastasis, lymphatic invasion and blood vessel invasion. Multivariate analysis identified gender, pathological stage and lymph node metastasis as independent predictors of disease recurrence following radical cystectomy. After disease recurrence, the 1-year cancer-specific survival of the 24 patients was 16.7%; that is, 23 of the 24 patients had died of progressive recurrent diseases, while the remaining 1 who survived had developed recurrence in the upper urinary tract. CONCLUSIONS: These findings suggest that careful follow-up should be performed after radical cystectomy for TCC of the bladder considering gender, pathological stage and nodal involvement; however, once recurrent disease develops, the prognosis of such patients is extremely poor. Therefore, it would be potentially important to establish a multimodal therapeutic approach targeting recurrent TCC of the bladder.

[Pathological prognostic factors of renal pelvic and ureteral cancer].

OBJECTIVE: To determine the pathologic risk factors after nephroureterectomy in patients with urothelial carcinoma of the renal pelvis and ureter. PATIENTS AND METHODS: We investigated the clinicopathological features of 131 patients (94 males and 37 females) with urothelial carcinoma of the renal pelvis and ureter who underwent nephroureterectomy at our department and related facilities from August, 1994 to August, 1997. The mean age of the patients was 68 years, ranging from 24 to 86 years. RESULTS: The 1-, 3- and 5-year cause-specific survival rates (Kaplan-Meier's method) for all of the patients were 91.8%, 76.7%, and 67.8%, respectively. The significant prognostic factors for survival rates by univariate analysis using the log rank test were tumor stage, infiltration pattern, lymphatic invasion, vessel invasion and lymph node metastasis. On the other hand, multivariate analysis using Cox proportional hazards regression model showed the most influential prognostic factors to be vessel invasion and tumor stage. CONCLUSIONS: From these results, in urothelial carcinoma of the renal pelvis and ureter underwent nephroureterectomy, we suggested that vessel invasion and tumor stage were the independent prognostic factors.

Heat shock protein 27 increases after androgen ablation and plays a cytoprotective role in hormone-refractory prostate cancer.

Heat shock protein 27 (Hsp27) is a chaperone implicated as an independent predictor of clinical outcome in prostate cancer. Our aim was to characterize changes in Hsp27 after androgen withdrawal and during androgen-independent progression in prostate xenografts and human prostate cancer to assess the functional significance of these changes using antisense inhibition of Hsp27. A tissue microarray was used to measure changes in Hsp27 protein expression in 232 specimens from hormone naive and posthormone-treated cancers. Hsp27 expression was low or absent in untreated human prostate cancers but increased beginning 4 weeks after androgen-ablation to become uniformly highly expressed in androgen-independent tumors. Androgen-independent human prostate cancer PC-3 cells express higher levels of Hsp27 mRNA in vitro and in vivo, compared with androgen-sensitive LNCaP cells. Phosphorothioate Hsp27 antisense oligonucleotides (ASOs) and small interference RNA potently inhibit Hsp27 expression, with increased caspase-3 cleavage and PC3 cell apoptosis and 87% decreased PC3 cell growth. Hsp27 ASO and small interference RNA also enhanced paclitaxel chemosensitivity in vitro, whereas in vivo, systemic administration of Hsp27 ASO in athymic mice decreased PC-3 tumor progression and also significantly enhanced paclitaxel chemosensitivity. These findings suggest that increased levels of Hsp27 after androgen withdrawal provide a cytoprotective role during development of androgen independence and that ASO-induced silencing can enhance apoptosis and delay tumor progression.

Synergistic antitumor effect of combined use of adenoviral-mediated p53 gene transfer and antisense oligodeoxynucleotide targeting clusterin gene in an androgen-independent human prostate cancer model.

Our recent studies showed that antisense oligodeoxynucleotide targeting antiapoptotic gene, clusterin, enhanced apoptosis induced by conventional therapeutic modalities using several prostate cancer models. In this study, to establish a more effective therapeutic strategy against prostate cancer, we investigated the effect of combined treatment with antisense clusterin oligodeoxynucleotide and adenoviral-mediated p53 gene transfer (Ad5CMV-p53) in an androgen-independent human prostate PC3 tumor model. Treatment of PC3 cells with 500 nmol/L antisense clusterin oligodeoxynucleotide decreased clusterin mRNA by >80% compared with that with 500 nmol/L mismatch control oligodeoxynucleotide. Clusterin mRNA expression in PC3 cells was highly up-regulated by Ad5CMV-p53 treatment; however, antisense clusterin oligodeoxynucleotide treatment further suppressed clusterin expression in PC3 cells after Ad5CMV-p53 treatment. Antisense clusterin oligodeoxynucleotide treatment significantly enhanced the sensitivity of Ad5CMV-p53 in a dose-dependent manner, reducing the IC50 of Ad5CMV-p53 by 75%. Apoptotic cell death was detected after combined treatment but not after treatment with either agent alone. In vivo administration of antisense clusterin oligodeoxynucleotide and Ad5CMV-p53 resulted in a significant inhibition of s.c. PC3 tumor growth as well as lymph node metastases from orthotopic PC3 tumors compared with administration of either agent alone. Furthermore, combined treatment with antisense clusterin oligodeoxynucleotide, Ad5CMV-p53, and mitoxantrone completely eradicated s.c. PC3 tumors and lymph node metastases from orthotopic PC3 tumors in 60% and 100% of mice, respectively. These findings suggest that combined treatment with antisense clusterin oligodeoxynucleotide and Ad5CMV-p53 could be a novel strategy to inhibit progression of hormone-refractory prostate cancer and that further addition of chemotherapeutic agents may help to enhance the efficacy of this combined regimen.

A novel antisense oligonucleotide inhibiting several antiapoptotic Bcl-2 family members induces apoptosis and enhances chemosensitivity in androgen-independent human prostate cancer PC3 cells.

Bcl-2 and Bcl-xL are associated with treatment resistance and progression in many cancers, including prostate cancer. The objective of this study was to determine whether a novel bispecific antisense oligonucleotide targeting both Bcl-2 and Bcl-xL induces apoptosis and enhances chemosensitivity in androgen-independent PC3 prostate cancer cells. An antisense oligonucleotide with complete sequence identity to Bcl-2 and three-base mismatches to Bcl-xL selected from five antisense oligonucleotides targeting various regions with high homology between Bcl-2 and Bcl-xL was found to be the most potent inhibitor of both Bcl-2 and Bcl-xL expression in PC3 cells. This selected Bcl-2/Bcl-xL bispecific antisense oligonucleotide reduced mRNA and protein levels in a dose-dependent manner, reducing Bcl-2 and Bcl-xL protein levels to 12% and 19%, respectively. Interestingly, Mcl-1 was down-regulated as well, although levels of Bax, Bad, or Bak were not altered after treatment with this bispecific antisense oligonucleotide. Indirect down-regulation of inhibitor of apoptosis (IAP) family, including XIAP, cIAP-1 and cIAP-2, via second mitochondria-derived activator of caspases was also observed after bispecific antisense oligonucleotide treatment. Executioner caspase-3, caspase-6, and caspase-7 were shown to be involved in apoptosis induced by bispecific antisense oligonucleotide. This Bcl-2/Bcl-xL bispecific antisense oligonucleotide also enhanced paclitaxel chemosensitivity in PC3 cells, reducing the IC50 of paclitaxel by >90%. These findings illustrate that combined suppression of antiapoptotic Bcl-2 family members using this antisense oligonucleotide could be an attractive strategy for inhibiting cancer progression through alteration of the apoptotic rheostat in androgen-independent prostate cancer.

Therapeutic efficacy of adenoviral-mediated p53 gene transfer is synergistically enhanced by combined use of antisense oligodeoxynucleotide targeting clusterin gene in a human bladder cancer model.

To establish a more effective therapeutic strategy against advanced bladder cancer, we investigated the effects of combined treatment with antisense (AS) oligodeoxynucleotide (ODN) targeting the anti-apoptotic gene clusterin and adenoviral-mediated p53 gene transfer (Ad5CMV-p53) using the human bladder cancer KoTCC-1 model. Clusterin expression in KoTCC-1 cells was highly upregulated by Ad5CMV-p53 treatment; however, AS clusterin ODN treatment further suppressed clusterin expression in KoTCC-1 cells after Ad5CMV-p53 treatment. AS clusterin ODN treatment synergistically enhanced the cytotoxic effect of Ad5CMV-p53, and DNA fragmentation characteristic of apoptosis was observed only after combined treatment with AS clusterin ODN and Ad5CMV-p53, but not after treatment with either agent alone. Administration of AS clusterin ODN and Ad5CMV-p53 into nude mice resulted in a significant inhibition of KoTCC-1 tumor growth as well as lymph node metastases compared to administration of either agent alone. Furthermore, combined treatment with AS clusterin ODN, Ad5CMV-p53, and cisplatin completely eradicated KoTCC-1 tumors and lymph node metastases in 60% and 100% of mice, respectively. These findings suggest that combined treatment with AS clusterin ODN and Ad5CMV-p53 could be a novel strategy to inhibit bladder cancer progression, and that further additional use of a chemotherapeutic agent may substantially enhance the efficacy of this combined regimen.

Enhanced radiosensitivity by inhibition of the anti-apoptotic gene clusterin using antisense oligodeoxynucleotide in a human bladder cancer model.

Clusterin has been shown to be implicated in the acquisition of resistant phenotype to various kinds of apoptotic stimuli, including radiation. In bladder cancer, our previous study demonstrated that overexpression of clusterin is closely associated with disease progression and recurrence. The objective of this study was to investigate whether radiation sensitivity was enhanced by suppressing clusterin gene expression with antisense (AS) oligodeoxynucleotide (ODN) in the human bladder cancer KoTCC-1 model. Clusterin mRNA in KoTCC-1 cells after radiation was up-regulated in a dose-dependent manner; however, AS clusterin ODN treatment resulted in a marked inhibition of clusterin mRNA even after irradiation. Combined treatment of KoTCC-1 cells with radiation and AS clusterin ODN synergistically decreased plating efficacy and induced apoptotic cell death compared with either radiation or AS clusterin ODN treatment alone. In vivo systemic administration of AS clusterin ODN enhanced radiation sensitivity, significantly reducing subcutaneous KoTCC-1 tumor volume in nude mice, compared with that of mismatch control ODN. Moreover, additional administration of cisplatin to this combined regimen further achieved potential antitumor effects on subcutaneous KoTCC-1 tumor growth in nude mice. Collectively, these findings suggest that clusterin acts as a cell survival protein mediating radioresistance through the inhibition of apoptosis, and that inactivation of clusterin using AS technology might offer a novel strategy to improve the outcome of radiation therapy for patients with bladder cancer.

Enhanced expression of the secreted form of clusterin following neoadjuvant hormonal therapy as a prognostic predictor in patients undergoing radical prostatectomy for prostate cancer.

The objective of this study was to characterize changes in clusterin expression in prostate cancer before and after neoadjuvant hormonal therapy (NHT), and to assess the prognostic significance of clusterin expression following NHT in patients undergoing radical prostatectomy. Paired needle biopsy and corresponding radical prostatectomy (RP) specimens obtained from 76 patients were analyzed for expression of clusterin protein by immunohistochemical staining with an antibody recognizing all of the clusterin isoforms. RP specimens following NHT demonstrated stronger expression of clusterin than the corresponding needle biopsy specimens. Clusterin protein was present in the cytoplasm of both biopsy and RP specimens; however, there was no nuclear staining identified in any specimens. The expression level of clusterin in biopsy specimens was significantly associated with the biopsy Gleason score, but not with other parameters available before RP. Furthermore, clusterin expression in RP specimens was significantly associated with the preoperative prostate specific antigen value and pathological stage, but not with other pathological factors. Biochemical recurrence-free survival in patients with strong clusterin expression in RP specimens was significantly lower than that in those with weak clusterin expression; however, the level of clusterin expression could not be used as an independent predictor of biochemical recurrence. These findings suggest that despite the lack of independent significance, the expression level of the secreted form of clusterin in prostate cancer tissue after NHT, which may inversely reflect the therapeutic effect of NHT, could be a useful parameter predicting biochemical recurrence in patients undergoing RP.

Introduction of insulin-like growth factor binding protein-2 gene into human bladder cancer cells enhances their metastatic potential.

Overexpression of insulin-like growth factor binding protein-2 (IGFBP-2) has been shown to be associated with tumor progression in several human malignant tumors; however, the significance of IGFBP-2 expression in bladder cancer remains poorly defined. The objective of this study was to investigate the effect of IGFBP-2 overexpression in human bladder cancer KoTCC-1 cells on their phenotype associated with tumor progression. We introduced IGFBP-2 cDNA into KoTCC-1 cells, which do not express a detectable level of IGFBP-2 protein, thus generating an IGFBP-2 overexpressing cell line (KoTCC-1/BP2). We also generated a vector-only-transfected cell line (KoTCC-1/C) as a control. Despite the absence of a significant difference in in vitro cell growth rates and motilities among KoTCC-1 sublines, KoTCC-1/BP2 exhibited significantly higher invasive ability than KoTCC-1/C. Gelatin zymography showed a marked increase in matrix metalloproteinase-2 (MMP-2) production by KoTCC-1/BP2 compared with that by KoTCC-1/C. Furthermore, there was no significant difference in sub-cutaneous tumor growth among KoTCC-1 sublines; however, more advanced tumor progression, including lymph node metastasis and hemorrhagic ascites formation, was observed after the implantation of KoTCC-1/BP2 into the bladder wall of nude mice than after the implantation of KoTCC-1/C. These findings suggest that overexpression of IGFBP-2 induces an increase in MMP-2 production, resulting in the enhanced metastatic potential of bladder cancer.