[Issues of Equalization of Cancer Genomic Medicine-Focusing on the Current Status in Nagasaki Prefecture].

Nagasaki University Hospital, which was designated as a"Designated Core Hospital for Cancer Genomic Medicine"by the Ministry of Health, Labor and Welfare in 2019, started an initiative for cancer genomic medicine in collaboration with 2 "Cooperative Hospital for Cancer Genomic Medicine"in Nagasaki prefecture. However, there are various issues such as 1 . eligibility criteria and strategies for inspections, 2 . training of specialized medical personnel, 3 . information dissemination and dissemination and enlightenment, etc. in the"equalization"of cancer genomic medicine in the prefecture, and we believe that measures against these issues are urgently needed.

Pathological significance and prognostic role of LATS2 in prostate cancer.

BACKGROUND: Large tumor suppressor 2 (LATS2) is an important regulator of the Hippo pathway and it plays crucial roles in cell survival and behaviors. Herein, we evaluated the pathological roles of LATS2 in prostate cancer (PC), for which very little information is available. METHODS: Cell proliferation, migration, and invasion in response to the siRNA-mediated knockdown (KD) LATS2 expression were evaluated in two PC cell lines (LNCaP and PC3). The expression of LATS2 in specimens from 204 PC patients was investigated immunohistochemically, and the relationships between its expression and clinicopathological features, proliferation index (PI; measured using an anti-KI-67 antibody), and biochemical recurrence (BCR) were investigated. RESULTS: KD of LATS2 increased the growth, migration, and invasion in LNCaP cells and only increased migration in PC3 cells. The expression of LATS2 was negatively associated with the grade group, T, N, M stage, and PI. In addition, the expression of LATS2 was a useful predictor of the histological effects of neoadjuvant hormonal therapy and BCR-free survival periods. A multivariate analysis model including clinicopathological features showed that negative expression of LATS2 had a significantly higher risk of BCR (odds ratio = 2.95, P < 0.001). CONCLUSIONS: LATS2 acts as a tumor suppressor in PC. LATS2 expression is a useful predictor for BCR. LATS2-related activities are possibly dependent on the androgen-dependency of PC cells. Therefore, we suggest that LATS2 could be a potential therapeutic target and a useful predictor for outcome in patients with PC.

Differential expression of androgen receptor variants in hormone-sensitive prostate cancer xenografts, castration-resistant sublines, and patient specimens according to the treatment sequence.

BACKGROUND: Androgen receptor variants (AR-vs), especially AR-v7 and AR-v 5, 6, and 7 exon-skipped (AR-v567es), are reportedly key players in the development of castration-resistant prostate cancer (CRPC). We previously established a mouse xenograft model (JDCaP) from a metastatic skin lesion from a Japanese patient with CRPC and that was revealed to exhibit androgen sensitivity. In the present study, we established multiple castration-resistant xenograft models from JDCaP mice to investigate the biological features of CRPC. METHODS: Tissue from JDCaP mice was transplanted into male and female nude mice, and after serial passaging, castration-resistant sublines (JDCaP-CR2M and JDCaP-CR4M in male mice, JDCaP-CR2F and JDCaP-CR4F in female mice) were established. We investigated anti-androgen and testosterone sensitivity and the messenger RNA expression pattern of full-length AR and AR-vs. In addition, we compared AR protein levels of patient specimens among primary, local-recurrent, and two skin-metastatic tumors. RESULTS: All JDCaP-CR sublines showed continuous growth following the administration of bicalutamide, although the effects of testosterone varied among sublines. Parental JDCaP and JDCaP-CR2M, JDCaP-CR4M, and JDCaP-CR4F sublines expressed AR-v7, whereas JDCaP-CR2F exhibited elevated AR-v567es expression resulting from genomic deletion, which was confirmed by DNA sequencing. Moreover, we confirmed AR-v7 expression in the tumor of the original patient after androgen-deprivation therapy. CONCLUSIONS: Each JDCaP-CR subline showed different AR-v-expression patterns, with JDCaP-CR2F expressing AR-v567es due to genomic deletion. Our results indicated that AR-vs emerged after androgen-deprivation therapy and appeared essential for acquisition of castration resistance.

Comparison of ERG and SPINK1 expression among incidental and metastatic prostate cancer in Japanese men.

BACKGROUND: TMPRSS2:ERG fusion is the most common genetic event in prostate cancer (PCa). However, its association with prognosis is controversial. Overexpression of serine protease inhibitor Kazal-type 1 (SPINK1) was almost exclusively defined in ERG-negative PCa in most studies. This study aimed to determine the association between ERG and SPINK1 expression and the biological aggressiveness of PCa by analyzing their expression in incidental and metastatic cohorts. METHODS: A total of 143 cystoprostatectomy specimens of invasive bladder cancer and 98 biopsy specimens from de novo metastatic PCa were analyzed. The prostate gland of cystoprostatectomy specimens was fixed and sliced in step sections. Immunohistochemistry of ERG and SPINK1 was conducted, and the results were correlated with the clinicopathological characteristics of the patients. RESULTS: The overall prevalence of incidental cancer was 32.2% (46/143). The frequencies of both ERG and SPINK1 expression were not significantly different between incidental and metastatic cohorts (15.2% and 14.3%; P = 1.00, and 6.5% and 12.2%; P = 0.38, respectively). In the metastatic cohort, any pre-treatment factors were not significantly associated with the frequencies of ERG and SPINK1 expression. However, SPINK1 expression was significantly associated with a shorter time to castration-resistant PCa (CRPC) (P = 0.048). Meanwhile, overall survival was not significantly associated with the expression status of ERG and SPINK1 (P = 0.71). CONCLUSIONS: ERG and SPINK1 expression may not have significant influence on the metastatic behavior of PCa. SPINK1 expression was significantly associated with a shorter time to CRPC in metastatic PCa. The expression profile of ERG and SPINK1 may be a useful predictor for effect of androgen deprivation therapy in patients with metastatic castration-sensitive PCa.

Expression of phosphatase and tensin homolog and programmed cell death ligand 1 in adenosquamous carcinoma of the lung.

BACKGROUND: Lung adenosquamous carcinoma (ASC) is a rare variant of non-small cell lung cancer (NSCLC) with poor prognosis. Certain biological differences may exist between these tumors and other common histological types of NSCLC, including adenocarcinoma (ADC) and squamous cell carcinoma (SCC). The phosphoinositide 3-kinase (PI3K) pathway, which links oncogenes and multiple receptor classes to essential cellular functions, is activated by phosphatase and tensin homolog (PTEN) loss. The PTEN loss has been suggested to induce programmed cell death ligand 1 (PD-L1) expression in various cancer types. OBJECTIVE: Here, we sought to determine the relationships between the expression of PTEN and PD-L1 in each component of ASC with ADC and SCC, and clinical parameters. MATERIAL AND METHODS: Tissue microarrays of 148 cases of surgically resected lung ADC and 102 cases of SCC, as well as full sections from 28 ASC cases, were analyzed immunohistochemically for the expression of PTEN and PD-L1. RESULTS: PD-L1 expression was similar between the adenocarcinoma component of ASC vs. lung ADC and between the squamous component of ASC vs. lung SCC. PTEN loss was higher in lung ADC than in the adenocarcinoma component of ASC and significantly higher in lung SCC than in the squamous component of ASC. PD-L1 expression was higher in the squamous component than in the glandular component of the 28 ASC cases, but PTEN loss was similar. Overall, PTEN loss was higher in lung SCC than in lung ADC and both components of ASC. In lung SCC and glandular portions of ASC, PD-L1 expression levels were significantly associated with those of PTEN. The loss of PTEN correlated with smoking status in patients with lung ADC. CONCLUSIONS: Our results implied that both squamous and glandular components of ASC may share the same oncogenic driver pathway for carcinogenesis. However, the squamous cell components of ASC likely escape the immune surveillance better than the glandular components due to higher PD-L1 expression.

Neoadjuvant hormonal therapy for low-risk prostate cancer induces biochemical recurrence after radical prostatectomy via increased lymphangiogenesis-related parameters.

BACKGROUND: The effects of neoadjuvant hormonal therapy (NHT) on pathological features and lymphangiogenesis in patients with prostate cancer (PCa) for each pre-operative risk classification are unclear. METHODS: To clarify the anti-cancer effects of NHT, we investigated 153 patients (non-NHT group = 80 and NHT group = 73) who underwent radical prostatectomy (RP) in Nagasaki University Hospital. Lymph vessel density and area (evaluated by D2-40-positive vessels), vascular endothelial growth factor (VEGF)-C and VEGF-D expressions, and biochemical recurrence (BCR)-free survival were compared between these two groups for each D'Amico risk classification (low = 33, intermediate = 58, high = 62 patients). RESULTS: In low-risk PCa patients, the risks of lymph vessel invasion and BCR were significantly higher in the NHT group than in the non-NHT group (P = 0.040 and 0.022, respectively). Such significant difference was not seen in the intermediate- or high-risk PCa groups. Lymph vessel density of the peri-tumoral and intra-tumoral areas and the lymph vessel area were significantly higher (P < 0.001) in the NHT group than in the non-NHT group in low-risk PCa. In regard to the expression of VEGF-C or VEGF-D, significant difference was not detected in low-risk PCa. CONCLUSIONS: NHT stimulated cancer cell progression and BCR via up-regulation of lymphangiogenesis-related parameters in patients with low-risk PCa. Although VEGF-C and VEGF-D expressions were not changed by NHT, lymph vessel density and area were increased in low-risk PCa patients. We suggest that NHT for patients with low-risk PCa may have a high risk for BCR after RP.

Clinicopathological importance of anterior prostate cancer in Japanese Men.

Prostate cancer of transition zone origin or anterior location has been recognized as infrequent, smaller in size and indolent, whereas, our previous report showed that transition zone/anterior cancer was frequently experienced in Japanese men. The current study was conducted to show clinicopathological characteristics of transition zone/anterior cancer. A total of 201 radical prostatectomy specimens were categorized as cancer of anterior or posterior prostate where more than two thirds of the tumor existed in the specific area. Clinicopathological characteristics including Gleason score, pathological stage, lymph node metastasis, extraprostatic extension, surgical incision into the prostate (shown as pT2+), and surgical margin status were compared between anterior and posterior cases. Cases were divided as 83, 73, and 45 of anterior, posterior cancer, and no dominance, respectively. Anterior cancers included significant numbers of high grade tumors (13/83 cases: 15.7%), which was less than posterior cancers (28.8%: 21/73). The cases in pT2+ were significantly more frequent in anterior cases than posterior ones (22.9% vs. 4.1%). No seminal vesicle invasion was shown in anterior cases. Thus, although anterior cancers are less aggressive than posterior cancers, a significant numbers of clinically important cancers were located in the anterior portion in Japanese men.

Time Trends in Histological Features of Latent Prostate Cancer in Japan.

PURPOSE: The incidence of prostate cancer is reported to be increasing in Asia, including Japan. Although this trend has been attributed partly to a more Western diet, this assumption may involve variable confounders. Thus, we examined the histological features of contemporary vs historical latent prostate cancer. MATERIALS AND METHODS: Prostate specimens from a consecutive autopsy series (127, present study, 2008 to 2013) were examined. Each prostate gland was fixed and sliced in step sections. The findings were compared to those from another autopsy series (501 subjects, 1983 to 1987) at our institution. RESULTS: The mean age of subjects in the present study was 68.9 years while the mean age was not available from the earlier study. However, the mean age of the 566 entrants in the expanded database (1983 to 1989) was 63.5 years (p=0.0001). Prostate weight was significantly greater in the present study (p <0.0001). Latent prostate cancer was found more frequently in the present study than in the previous study (43.3% and 20.8%, respectively, p <0.0001). No distinct difference was seen in the proportion of tumor grade between the groups. An increasing trend of moderately to poorly differentiated tumors with advancing age was more evident in the present study. Index cancer volume was greater in the present study with 25.5% measuring 500 mm(3) or greater vs only 9.6% of cancers in the previous study (p=0.008). CONCLUSIONS: Chronological changes in the histological characteristics of Japanese latent prostate cancer were noted as it is more prevalent in the contemporary series. Our data may reflect a worldwide trend in increasingly aging societies.

Differences in prostate cancer grade, stage, and location in radical prostatectomy specimens from United States and Japan.

BACKGROUND: To compared prostate cancer at radical prostatectomy between men in the United States (US) and Japan in the modern era. METHODS: Three hundred seventy consecutive totally embedded RP cases (159 US; 211 Japan) from 2010 to 2012 were reviewed. RESULTS: US men were significantly younger (mean age 58.8 years) than Japanese men (mean age 64.6 years; P < 0.00001). Japanese patients presented with higher PSA levels (mean = 10.9 ng/ml) compared to US patients (mean = 5.8 ng/ml, P < 0.00001) and higher clinical stage (P = 0.003). Japanese tumors were: higher grade; larger; more advanced stage; with increased lymphovascular invasion; and more commonly TZ in location (P < 0.00001). In multivariate analysis, independent predictors of high tumor volume were PSA level, clinical stage, TZ location, Gleason grade, and country of origin (Japan). Independent predictors of TZ location were clinical stage, tumor volume, and country of origin (Japan). CONCLUSION: A major factor for larger, higher grade and stage tumors in Japanese patients is the lower prevalence of screening for prostate cancer in Japan. Another contributing factor may be their TZ location, where they are not palpable until advanced and where they are difficult to sample on needle biopsy possibly leading to a delay in diagnosis. The finding of a difference in zonality of prostate cancer between US and Japanese cases is novel and may reflect differences in biology rather than different health care practice between the groups. If this data is confirmed, consideration should be given to TZ sampling as part of routine needle biopsies in Japanese men.

Evaluation of ERG responsive proteome in prostate cancer.

BACKGROUND: Gene fusion between TMPRSS2 promoter and the ERG proto-oncogene is a major genomic alteration found in over half of prostate cancers (CaP), which leads to aberrant androgen dependent ERG expression. Despite extensive analysis for the biological functions of ERG in CaP, there is no systematic evaluation of the ERG responsive proteome (ERP). ERP has the potential to define new biomarkers and therapeutic targets for prostate tumors stratified by ERG expression. METHODS: Global proteome analysis was performed by using ERG (+) and ERG (-) CaP cells isolated by ERG immunohistochemistry defined laser capture microdissection and by using TMPRSS2-ERG positive VCaP cells treated with ERG and control siRNA. RESULTS: We identified 1,196 and 2,190 unique proteins stratified by ERG status from prostate tumors and VCaP cells, respectively. Comparative analysis of these two proteomes identified 330 concordantly regulated proteins characterizing enrichment of pathways modulating cytoskeletal and actin reorganization, cell migration, protein biosynthesis, and proteasome and ER-associated protein degradation. ERPs unique for ERG (+) tumors reveal enrichment for cell growth and survival pathways while proteasome and redox function pathways were enriched in ERPs unique for ERG (-) tumors. Meta-analysis of ERPs against CaP gene expression data revealed that Myosin VI and Monoamine oxidase A were positively and negatively correlated to ERG expression, respectively. CONCLUSIONS: This study delineates the global proteome for prostate tumors stratified by ERG expression status. The ERP data confirm the functions of ERG in inhibiting cell differentiation and activating cell growth, and identify potentially novel biomarkers and therapeutic targets.

Expression of ERG oncoprotein is associated with a less aggressive tumor phenotype in Japanese prostate cancer patients.

To investigate and characterize ERG oncoprotein expression in Japanese patients with prostate cancer (PCa), we evaluated 92 index tumors from Japanese patients who had undergone radical prostatectomy for PCa, using an antibody-based detection method to determine ERG expression. Expression status was compared with clinicopathological findings including patient age, body mass index and preoperative prostate-specific antigen (PSA) levels, specimen Gleason score, pathological stage, positive surgical margin, size of index tumor, prostatic volume, zonal origin of index tumor and biochemical failure. Overall, ERG protein was expressed in 16.3% (15/92) of the index tumors, but not in benign glands. Younger patient age, lower Gleason score and negative surgical margins were found to be independently associated with its expression in the multivariate analysis (P= 0.015, 0.003 and 0.038, respectively). ERG expression was not associated with biochemical failure. Though not statistically significant, ERG expression was more frequently observed in peripheral zone than in transition zone cancers (28.2% vs 10%, respectively). In conclusion, ERG protein was less frequently expressed in this Japanese PCa cohort compared with Western reports. ERG expression was associated with a less aggressive tumor phenotype, and its biological significance needs to be further investigated.

Age-dependent sex difference of non-alcoholic fatty liver disease in TSOD and db/db mice.

According to previous clinical studies, the prevalence of non-alcoholic fatty liver disease (NAFLD) is higher in men than women only during the reproductive age. Animal models of NAFLD that reflect sex differences in humans have not been established. In this study, we examined sex differences in the hepatic lesions of Tsumura Suzuki obese diabetes (TSOD) and db/db mice, which are representative genetic models of NAFLD. Male and female TSOD and db/db mice were fed with a normal diet and tap water ad libitum. Six male and female mice of each strain were sacrificed at the ages of 3 and 9 months, respectively, and serum biochemical, pathological, and molecular analyses were performed. Serum aspartate aminotransferase (AST) levels were significantly higher in male than female mice of both strains at the age of 3 months; however, at 9 months, significant sex differences were not observed. Similarly, alanine aminotransferase (ALT) levels were significantly higher in male mice than in female TSOD mice at the age of 3 months; however, at 9 months, significant sex differences were not observed. Image analysis of histological slides revealed that the frequency of the steatotic area was significantly higher in male than female db/db mice at the age of 3 months; however, significant sex differences were not observed at 9 months. The frequency of Sirius red-positive fibrotic area was significantly higher in male than female mice in both strains at the age of 3 months; however, significant sex differences were not observed at 9 months. Serum AST and ALT levels and hepatic steatosis and fibrosis in TSOD and db/db mice showed age-dependent sex differences consistent with those observed in human NAFLD. These mice may be suitable for studying sex differences of the disease.

Substantial improvement of histopathological diagnosis by whole-slide image-based remote consultation.

Consultation by subspecialty experts is the most common mode of rendering diagnosis in challenging cases in pathological practice. Our study aimed to highlight the diagnostic benefits of whole-slide image (WSI)-based remote consultation. We obtained diagnostically challenging cases from two institutions from the years 2010 and 2013, with histological diagnoses that contained keywords "probable," "suggestive," "suspicious," "inconclusive," and "uncertain." A total of 270 cases were selected for remote consultation using WSIs scanned at 40 × . The consultation process consisted of three rounds: the first and second rounds each with 12 subspecialty experts and the third round with six multi-expertise senior pathologists. The first consultation yielded 44% concordance, and a change in diagnosis occurred in 56% of cases. The most frequent change was from inconclusive to definite diagnosis (30%), followed by minor discordance (14%), and major discordance (12%). Out of the 70 cases which reached the second round, 31 cases showed discrepancy between the two consultants. For these 31 cases, a consensus diagnosis was provided by six multi-expertise senior pathologists. Combining all WSI-based consultation rounds, the original inconclusive diagnosis was changed in 140 (52%) out of 266 cases. Among these cases, 80 cases (30%) upgraded the inconclusive diagnosis to a definite diagnosis, and 60 cases (22%) changed the diagnosis with major or minor discordance, accounting for 28 cases (10%) and 32 cases (12%), respectively. We observed significant improvement in the pathological diagnosis of difficult cases by remote consultation using WSIs, which can further assist in patient healthcare. A post-study survey highlighted various benefits of WSI-based consults.

Antibody EPR3864 is specific for ERG genomic fusions in prostate cancer: implications for pathological practice.

Genomic rearrangements involving genes encoding erythroblast transformation-specific transcription factors are commonly present in prostate cancer. The TMPRSS2-ERG gene fusion that leads to ERG overexpression occurs in ~70% of prostate cancers. Implementation of fusion gene detection in pathological practice, however, has been hampered by the lack of reliable ERG antibodies. The objective of this study was first to compare ERG immunohistochemistry using the recently described antibody EPR3864 with ERG mRNA by quantitative PCR and, second, to investigate ERG immunohistochemistry in diagnostic prostate cancer needle biopsies. We analyzed 41 primary prostate adenocarcinomas obtained by radical prostatectomy and 83 consecutive prostate cancer needle biopsies. In the prostatectomy specimens, immunohistochemical ERG expression was highly concordant with the ERG mRNA overexpression (sensitivity 100% and specificity 85%). ERG overexpression was due to TMPRSS2-ERG gene fusion in all cases. ERG protein expression was identified in 51/83 adenocarcinomas (61%) on needle biopsies. ERG expression was more frequent in tumors infiltrating ≥2 needle biopsies (P<0.001) or occupying ≥50% of a single biopsy (P=0.018). Expression of ERG also occurred in 11/21 (52%) high-grade prostate intraepithelial neoplasia lesions. In 5/87 (6%) needle biopsies containing benign secretory glands, weak ERG staining was focally observed. In all of these cases, respective glands were adjacent to adenocarcinomas. In conclusion, immunohistochemistry for ERG strongly correlated with ERG mRNA overexpression and was specific for prostate cancer on needle biopsies. Therefore, ERG immunohistochemistry is an important adjunctive tool for pathophysiological studies on ERG gene fusions, and might support the pathological diagnosis of adenocarcinoma in a subset of prostate needle biopsies.

Immunohistochemical ETS-related gene detection in a Japanese prostate cancer cohort: diagnostic use in Japanese prostate cancer patients.

Chromosomal rearrangements that result in high expression levels of the ETS-related gene (ERG) present in approximately 50% of prostate cancer (PCa) patients, making this one of the most common oncogenic alterations in PCa. However, ERG overexpression at the protein level has not been rigorously evaluated in Japanese PCa patients. In this study, we evaluated ERG expression using antibody-based detection in 230 prostate specimens in a Japanese PCa cohort. Overall, we identified 20.1% ERG-positive PCa cases. ERG was not detected in benign glands. The specificity of ERG staining for detecting PCa was almost 100%; all of the ERG-positive samples were also diagnosed as PCa. The expression level of the ERG protein correlated with clinicopathological variables, including grade (P= 0.038), stage (P= 0.005), and metastatic status (P= 0.014). No correlation was observed with age (P= 0.196) or with preoperative prostate-specific antigen level (P= 0.322). Although the frequency of ERG-positive cases in Japanese PCa patients (20.1%) was lower than that reported in a PCa cohort in Western countries (approximately 50%), our study demonstrates that the clinical utility of ERG detection at the protein level can serve as an ancillary tool for diagnosing PCa in the Japanese population.

Novel human prostate epithelial cell culture models for the study of carcinogenesis and of normal stem cells and cancer stem cells.

Research into the mechanisms of prostate cancer progression has been limited by the lack of suitable in vitro systems. A hurdle in understanding the molecular genetic changes in prostate cancer has been the difficulty in establishing premalignant lesions and primary prostate tumors as in vitro cell cultures. Primary prostate epithelial cells grow for a finite life span and then senesce. Immortalization is defined by continuous growth of otherwise senescing cells and is believed to represent an early stage in tumor progression. To examine these early stages, we and others have developed in vitro models of prostate epithelial cell immortalization. Generation of primary human prostate epithelial (HPE) cells has been achieved using the serum-free condition. Retrovirus containing human telomerase reverse transcriptase (hTERT) was successfully used for the immortalization of primary HPE cells. Putative stem cell markers CD133 and CXCR4 were further identified in hTERT-immortalized primary nonmalignant and malignant tumor-derived HPE lines. In addition, an hTERT-immortalized nonmalignant HPE cell were found to retain the properties of multipotent stem cells. These in vitro prostate cell culture models should be useful for the study of carcinogenesis and of normal and cancer stem cells. Prostate cancer is the most common male cancer in the Western World and second leading cause of male cancer death in the United States [1]. The therapy most widely used against advanced disease is androgen ablation and, initially, it almost always produces objective clinical responses. However, most patients eventually relapse with ablation-resistant prostate cancer and develop metastatic disease; currently, there is no treatment that will cure progressive hormone-refractory metastatic prostate cancer. The mechanisms of progression of prostate cancer have been extensively studied, yet are poorly understood. One of the concepts that has been evolved is that cancer arises from the neoplastic transformation of normal prostate epithelial stem cells or transit amplifying cells. Understanding normal stem cells and cancer stem cells (CSCs) may provide insight into the origin of and new therapeutics for prostate cancer. However, research in this field is limited by the lack of suitable in vitro systems.

Benign mimics of prostate cancer.

The histopathological diagnosis of prostatic adenocarcinoma is challenged by the existence of numerous benign mimics. Most of these lesions have no clinical significance and many do not need to be reported. Their clinical relevance lies in the risk that they are misinterpreted as cancer. This review presents the histopathological features of benign mimics and discusses their distinction from cancer. The lesions that are most often misdiagnosed as cancer are atrophy and its variants, including simple atrophy, partial atrophy and post-atrophic hyperplasia. Benign proliferations are a group of lesions with crowded small glands with no or little nuclear atypia. The most problematic entity of this group is adenosis, which may have a more alarming architecture than some cancers. A diagnostic problem with atrophy and several of the benign proliferations is that the glands often have a discontinuous or absent basal cell layer. Hyperplastic and metaplastic lesions include basal cell hyperplasia. Basal cell hyperplasia may especially mimic prostate cancer with its small dark glands, variable nuclear atypia and a pseudoinfiltrative pattern, which may be present. The anatomical structure that most often causes diagnostic problems is the seminal vesicle. The mucosa of the seminal vesicle contains small acini, often with very pronounced nuclear atypia that may be misinterpreted as cancer. Pathologists need to be familiar with these mimics, as a false positive diagnosis of prostate cancer may lead to unnecessary radical treatment.

A newly established monoclonal antibody against ERCC1 detects major isoforms of ERCC1 in gastric cancer.

Identifying patients resistant to cisplatin treatment is expected to improve cisplatin-based chemotherapy for various types of cancers. Excision repair cross-complementing group 1 (ERCC1) is involved in several repair processes of cisplatin-induced DNA crosslinks. ERCC1 overexpression is reported as a candidate prognostic factor and considered to cause cisplatin resistance in major solid cancers. However, anti-ERCC1 antibodies capable of evaluating expression levels of ERCC1 in clinical specimens were not fully optimized. A mouse monoclonal antibody against human ERCC1 was generated in this study. The developed antibody 9D11 specifically detected isoforms of 201, 202, 203 but not 204, which lacks the exon 3 coding region. To evaluate the diagnostic usefulness of this antibody, we have focused on gastric cancer because it is one of the major cancers in Japan. When ERCC1 expression was analyzed in seventeen kinds of human gastric cancer cell lines, all the cell lines were found to express either 201, 202, and/or 203 as major isoforms of ERCC1, but not 204 by Western blotting analysis. Immunohistochemical staining showed that ERCC1 protein was exclusively detected in nuclei of the cells and a moderate level of constant positivity was observed in nuclei of vascular endothelial cells. It showed a clear staining pattern in clinical specimens of gastric cancers. Antibody 9D11 may thus be useful for estimating expression levels of ERCC1 in clinical specimens.

CXCR4 and cancer.

The chemokine receptor CXCR4 belongs to the large superfamily of G protein-coupled receptors and has been identified to play a crucial role in a number of biological processes, including the trafficking and homeostasis of immune cells such as T lymphocytes. CXCR4 has also been found to be a prognostic marker in various types of cancer, including leukemia and breast cancer, and recent evidence has highlighted the role of CXCR4 in prostate cancer. Furthermore, CXCR4 expression is upregulated in cancer metastasis, leading to enhanced signaling. These observations suggest that CXCR4 is important for the progression of cancer. The CXCR4-CXCL12 (stromal cell-derived factor 1 (SDF-1)) axis has additionally been identified to have a role in normal stem cell homing. Interestingly, cancer stem cells also express CXCR4, indicating that the CXCR4-SDF-1 axis may direct the trafficking and metastasis of these cells to organs that express high levels of SDF-1, such as the lymph nodes, lungs, liver, and bone. This review focuses on the current knowledge of CXCR4 regulation and how deregulation of this protein may contribute to the progression of cancer.