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Accurate diagnosis of the localization of prostate cancer (PCa) on magnetic resonance imaging (MRI) remains a challenge. We aimed to assess discrepancy between the location of PCa pathologically diagnosed using surgical specimens and lesions indicated as possible PCa by the Prostate Imaging Reporting and Data System on MRI. The primary endpoint was the concordance rate between the site of probable clinically significant PCa (csPCa) identified using biparametric MRI (bpMRI) and location of PCa in the surgical specimen obtained using robot-assisted total prostatectomy. Among 85 lesions identified in 30 patients; 42 (49.4%) were identified as possible PCa on MRI. The 85 PCa lesions were divided into positive and negative groups based on the bpMRI results. None of the patients had missed csPCa. Although the diagnostic accuracy of bpMRI was relatively high for PCas located in the middle of the prostate (p = 0.029), it was relatively low for PCa located at the base of the prostate, all of which were csPCas. Although current modalities can accurately diagnose PCa, the possibility that PCa is present with multiple lesions in the prostate should be considered, even if MRI does not detect PCa.

Abstract Background Triple‐negative breast cancer (TNBC) is characterized by the loss of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The aggressive clinicopathological features and resistance to currently available therapeutics of the disease warrant an urgent need for the development of novel alternate therapeutic options. We have previously reported adiponectin‐expressing regulatory T cells (A‐Tregs), which can induce apoptosis in TNBC through the cell‐in‐cell phenomenon. In this study, we aimed to elucidate the molecule that allows TNBC cells to engulf A‐Tregs. Methods A monoclonal antibody, which repressed the engulfment of A‐Tregs by TNBC cells, was developed. Immunoprecipitation followed by mass spectrometry and small interfering RNAs‐mediated gene silencing was performed to characterize the antigen. Results We successfully generated a monoclonal antibody, designated G1D7, which abrogated the engulfment of A‐Tregs by TNBC and subsequent A‐Treg‐mediated apoptosis. G1D7 detected the immunoglobulin‐like type I membrane protein IZUMO2, a molecule related to IZUMO1 that is essential for cell–cell membrane binding and fusion of sperm to oocyte. Conclusion The findings highlight the importance of IZUMO2 on TNBC cells in facilitating the cell‐in‐cell phenomenon by A‐Tregs.

Abstract Background In our previous study, we identified a population of adiponectin expressing regulatory T cells (Tregs) residing within thymic nurse cell complexes, which were capable of inhibiting the development of breast cancer in vitro. Triple‐negative breast cancer (TNBC) with no proper treatment at present is characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor‐2. In this study, we aimed to investigate the potential of a cultured T cell fraction comprising adiponectin‐expressing Tregs, referred to as A‐TregTF (adiponectin‐expressing Treg‐containing T cell fraction), in inhibiting the progression of TNBC in vivo. Methods The efficacy of a spontaneously expanding T cell fraction comprising adiponectin‐expressing Treg in inhibiting tumor growth was analyzed in a murine orthotopic 4 T1‐Luc TNBC model. Results The treatment with T cell fraction containing adiponectin‐expressing Tregs significantly inhibited the growth and metastasis of orthotopically transplanted 4 T1‐Luc tumor cells. Histopathological examination further revealed that the adiponectin‐expressing Tregs infiltrated the tumor tissue via a cell‐in‐cell mechanism and were found to be specifically localized around the necrotic areas. Conclusions Based on our findings, the T cell fraction comprising adiponectin‐expressing Tregs, represents a potential candidate for adoptive cell therapy against TNBC.

Abstract Background A population of regulatory T cells (Treg), which reside within thymic nurse cell complexes, express adiponectin and abrogate breast cancer development in transgenic mice. In this study, we examined whether adiponectin‐expressing Treg could impair triple‐negative breast cancer, which is defined by a lack of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor‐2. Methods CD4‐ and CD25‐positive cells were sorted from cultured T lymphocytes of a previously characterized experimental thymic tumor model composed of thymic nurse cells and abundant lymphoid stroma. These sorted cells were examined for FOXP3 and adiponectin immunoreactivity and subsequently exposed to triple‐negative breast cancer MDA‐MB‐157 and ‐231 cells. Results Adiponectin‐expressing Treg were obtained by CD4‐ and CD25‐positive sorting and cell death was induced in triple‐negative breast cancer cells through the cell‐in‐cell phenomenon. Conclusions Adiponectin‐expressing Treg may be candidates for adoptive cell therapy against triple‐negative breast cancer.

Abstract Background Late recurrence of gastric cancer at 10 years post-gastrectomy is extremely rare, and the underlying mechanism remains unclear. We report a para-aortic lymph node metastasis case that recurred 12 years postoperatively. Case presentation A 44-year-old woman pathologically diagnosed with moderately to poorly differentiated adenocarcinoma with pT2(SS)pN2cM0pStageIIIA according to the Japanese Classification of Gastric Carcinoma (the 13th Edition) underwent laparoscopic distal gastrectomy with D1 + lymph node dissection. She received adjuvant chemotherapy with tegafur-uracil (400 mg/day) for 2 years. At postoperative year (POY) 5, a swollen lymph node was detected in the No.16b1lat lymph node station. However, positron emission tomography (PET) revealed normal uptake, and the levels of tumor markers were within normal limits; hence, the possibility of metastasis was considered low, and the patient was placed under observation. At POY 12, computed tomography revealed an enlargement of the No.16b1lat lymph node station, and PET showed abnormal uptake. Endoscopic ultrasound-guided fine-needle aspiration revealed a moderately differentiated adenocarcinoma. Hence, a diagnosis of recurrence of gastric cancer was made. The patient underwent para-aortic nodal dissection (PAND) of No.16b1lat & int stations. Immunochemical staining results also suggested the recurrence of gastric cancer. However, the expression of CD44 variant 9 (CD44v9), a cancer stem cell marker for gastric adenocarcinoma, was attenuated in the recurrent lesions compared with that in the primary lesions. Postoperatively, she received chemotherapy with tegafur–gimeracil–oteracil (80 mg/day) for 1 year. Bone metastasis was observed at POY 4 after PAND, and the IHC analysis showed a HER2 score of 3 + in a needle biopsy specimen of bone metastasis. The expression of CD44v9 was slightly positive. The patient is being treated with chemotherapy with FOLFOX + trastuzumab. Conclusions A defense mechanism against reactive oxygen species has been reported as a mechanism causing recurrence of CD44v9-positive gastric cancer. Consequently, CD44v9-positive gastric cancer grows in metastatic organs, repeatedly self-renews, and proliferates to form recurrent lesions. In the present case, the degree of CD44v9 staining in recurrent lesions was suggested to be related to the recurrence time.

Abstract Background Micronodular thymic neoplasm with lymphoid stroma (MNT), a subtype of thymic tumor, is histopathologically characterized by micronodular thymic epithelial cell nests with lymphoid stroma. Despite the distinct histopathology of MNT, its pathogenesis remains unclear. Methods In this study, we aimed to examine a thymic tumor harboring thymic epithelial and lymphoid cells in a nonobese diabetic/severe combined immunodeficiency mouse. Results The excised tumor cells were cultured in vitro and comprised epithelial tumor cells and lymphoid cells. During a three‐dimensional cell culture, the epithelial tumor cells formed micronodular cell nests surrounded by lymphoid stroma. Notably, the lymphoid cells underwent apoptosis when they were separated from the epithelial tumor cells. Cutaneous transplantation of the cultured epithelial cells with splenocytes from BALB/c mice led to tumor formation, and these cells demonstrated a histopathology similar to that of human MNT in a nonobese diabetic/severe combined immunodeficiency mouse. Conclusion Given its overlapping features with human MNT, the transplanted tumor could serve as an experimental model of this disease.

Malignant pleural mesothelioma (MPM) develops primarily from asbestos exposures and has a poor prognosis. In this study, The Cancer Genome Atlas was used to perform a comprehensive survival analysis, which identified the CHST4 gene as a potential predictor of favorable overall survival for patients with MPM. An enrichment analysis of favorable prognostic genes, including CHST4, showed immune-related ontological terms, whereas an analysis of unfavorable prognostic genes indicated cell-cycle-related terms. CHST4 mRNA expression in MPM was significantly correlated with Bindea immune-gene signatures. To validate the relationship between CHST4 expression and prognosis, we performed an immunohistochemical analysis of CHST4 protein expression in 23 surgical specimens from surgically treated patients with MPM who achieved macroscopic complete resection. The score calculated from the proportion and intensity staining was used to compare the intensity of CHST4 gene expression, which showed that CHST4 expression was stronger in patients with a better postoperative prognosis. The median overall postoperative survival was 107.8 months in the high-expression-score group and 38.0 months in the low-score group (p = 0.044, log-rank test). Survival after recurrence was also significantly improved by CHST4 expression. These results suggest that CHST4 is useful as a prognostic biomarker in MPM.

Abstract Background As mesothelioma generally has an unfavorable prognosis, further advances are needed to improve the outcomes in patients with mesothelioma. In the present study, we generated and characterized a monoclonal antibody that could inhibit mesothelioma cell proliferation in a xenotransplantation mouse model. Methods We generated monoclonal antibodies by immunizing mice with cultured mesothelioma cells. These antibodies were then characterized by immunofluorescence staining, immunohistochemical staining, secondary antibody‐drug conjugate assay, antibody inoculation in a xenotransplantation mesothelioma mouse model, and mass spectrometry followed by small interfering RNA (siRNA) analysis. 5' rapid amplification of complementary DNA ends followed by sequencing was performed to deduce the amino acid sequences of the variable regions of the light and heavy chains of AX10. Results An IgG2b κ‐type AX10 antibody against the cell surface membrane of sarcomatoid mesothelioma cells was generated. AX10 immunoreactivity was detected in 12 out of 22 different mesothelioma tissue specimens, but there was little AX10 immunoreactivity in a normal human tissue array. AX10 decreased Matrigel invasion by MPM‐1 cells but did not affect cell proliferation. Notably, AX10 significantly inhibited the proliferation of MPM‐1 cells xenotransplanted into Severe combined immunodeficiency‐Nonobese diabetic mice. Matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry followed by siRNA silencing indicated that AX10 reacted to a unique alternatively spliced isoform of sarcolemma‐associated protein. AX10 is composed of as yet unregistered amino acid sequences in its variable region. Conclusions AX10 could have therapeutic potential for patients with sarcomatoid mesothelioma.

Abstract Background Gastric carcinosarcoma is most frequently diagnosed at an advanced stage when the tumor is generally large with invasion into other organs, lymph node metastasis, and distant metastasis. Standard chemotherapy has not been established, and surgery is the only curative treatment. Here, we present a case of postoperative recurrence of gastric carcinosarcoma under long-term tumor control with pazopanib. Case presentation A 77-year-old man was referred to our hospital because of nausea and vomiting. Computed tomography and upper gastrointestinal endoscopy revealed a type 1 tumor arising from the gastric antrum and extending into the duodenal bulb. He underwent distal gastrectomy (D2) with Roux-en-Y reconstruction. Histopathologically, the tumor had mixed adenocarcinoma and sarcoma components. According to the tumor–node–metastasis classification, the diagnosis was primary gastric carcinosarcoma pT1bN1M0 stage IB. Liver metastasis was detected 2 months after surgery; multiple lung metastases were detected 17 month after surgery. A genomic profiling test was performed using liver specimens as the patient became refractory to chemotherapy commonly used for gastric cancer, and the test revealed FGFR2 amplification along with TP53 R209*, AKT3 N127D, NOTCH1 A2036T, and POLD1 M161I. The patient was treated with pazopanib (800 mg/daily), and the tumor growth was controlled for 11 months. Conclusions We report a case of postoperative recurrence of gastric carcinosarcoma under long-term tumor control with pazopanib. This case suggested that pazopanib may be effective in treating gastric carcinosarcoma.

Three cases of primary thymic neuroendocrine tumors resembling a vascular neoplasm were reported as “Angiomatoid neuroendocrine carcinoma of the thymus.” Recently, we encountered another case of a thymic neuroendocrine cell tumor that grossly mimicked a vascular neoplasm. A man in his early 60 s, who presented with right thoracic pain, was admitted to our hospital. He had a 45 × 35 mm vascular-rich tumor in the thymus and underwent total thymectomy. Histopathological examination revealed that the tumor was composed of many blood‑filled caverns lined with stratified conventional neuroendocrine tumor cells expressing insulinoma-associated protein 1 and synaptophysin immunoreactivity. Notably, the blood-filled caverns were not lined with CD31-positive endothelial cells, as previously reported. By contrast, the caverns were focally lined with cells expressing SRY-Box Transcription Factor 17, which is well characterized to drive the conversion of fibroblast progenitor cells to endothelial cells by its transcriptional property. However, SRY-Box Transcription Factor 17 immunoreactivity was not restricted to the nucleus in blood-filled caverns and was also detected in the nucleus of endothelial cells in tumor vessels in the canonical carcinoid area. Dismaturation of endothelial cells might participate in the angiomatoid features of thymic neuroendocrine cell tumors.

Abstract Objectives JAG2 is one of Notch ligands, which recently appear to exert various carcinogenesis. In the present study, we aimed to unveil the relation of JAG2 expression and clinicopathological features in oral squamous cell carcinoma (OSCC). Materials and Methods We examined JAG2 expression in OSCC plus adjacent nontumorous epithelia in eight patients. Ninety‐one OSCC tissue specimens were immunohistochemically stained with specific antibodies to JAG2. The immunoreactivities of JAG2 were correlated with clinicopathological factors, including the prognosis of patients. Chi‐square test, Kaplan–Meier survival, and Cox proportional hazard analysis were used to determine the statistical value of JAG2 expression in OSCC. Results JAG2 mRNA expression was much expressed in OSCC tissues compared with adjacent tissue specimens in five of eight patients. JAG2 immunoreactivity was found at invasion front in 31 of 91 OSCC. JAG2 immunoreactivity was significantly associated with age, less than 50 years old of patients (P = .048). Kaplan–Meier analysis demonstrated that the patients with JAG2 immunoreactvty have a short overall survival. With the Cox proportional hazard regression mode, the independent factors predictive of poor overall survival included JAG2 immunoreactivity (P < .05). Conclusions The present findings suggest that JAG2 overexpression, especially at the cancer invasion front, has potential prognostic value.

Esophageal cancer rarely grows as an intramural tumor with an intact surface epithelium. A previous report described submucosal tumor-like esophageal cancer that had an overlapping morphological phenotype similar to that of a cutaneous sweat gland tumor. Here, we encountered another case of submucosal esophageal cancer mimicking skin adnexal carcinoma. A man in his early 60s who presented with difficulty in swallowing was admitted to our hospital. He had a 30 × 30 mm submucosal tumor in the abdominal esophagus and underwent partial esophagogastrectomy. Histopathological examination revealed that the tumor was composed of cord-like squamoid cell nests that was partially accompanied by gland structure in the inner layer, as found in cutaneous squamoid ductal eccrine carcinoma. The tumor exhibited CK7 immunoreactivity as did the neighboring dilated ducts of the esophageal gland. We describe a unique submucosal tumor-like esophageal cancer that had overlapping morphological features with squamoid ductal eccrine carcinoma and putatively originated in the esophageal submucosal gland ducts.

Background: Decision-making and selection of treatment modalities for newly diagnosed prostate cancer (PCa) are often determined by risk stratification using grade group (GG), prostate-specific antigen (PSA), and clinical stage. The discrepancies between needle biopsy (NB) and radical prostatectomy (RP) specimens often occur because of the sampling errors in NB or multifocal features of PCa. Thus, we aimed to estimate the preoperative clinical factors for predicting GG upgrading after robot-assisted RP (RARP). Methods: In this retrospective study, we reviewed the clinical and pathological records of patients who underwent RARP at Gifu University Hospital. We focused on patients with organ-confined PCa who had not received neoadjuvant therapy prior to RARP. The primary endpoint was identified as the predictive factor of GG upgrading for RARP specimens compared to those of NB specimens. Results: Eighty-one patients were included in this study. The enrolled patients were divided into two groups: those who had GG upgrading for RARP specimens (the NB upgrade group) or those who did not have GG upgrading (the no upgrade group). The median age of all patients was 70 years, and the median body mass index (BMI) was 22.9 kg/m2. The median neutrophil count was 3720/μL, lymphocyte count was 1543/μL, and neutrophil-to-lymphocyte ratio (NLR) was 2.24. In univariate analysis, BMI, PSA, neutrophil count, and NLR were significantly associated with GG upgrading in RARP specimens compared to NB specimens. BMI and NLR were identified as strong predictive factors for GG upgrading in RARP specimens in the multivariate analysis. Conclusions: Although this study’s small number of enrolled patients was a vital weakness, BMI and NLR might have been significantly correlated with GG upgrading for RP specimens compared with NB specimens. Therefore, BMI and NLR may have potential benefits for newly diagnosed patients with PCa in terms of decision-making and the selection of treatment modalities.

Approximately 24 cases of cytokeratin-positive interstitial reticulum cell tumors have been reported in English literature. In this paper, we report a case of cytokeratin-positive interstitial reticulum cell tumor that was localized in the parafollicular region of the axillary lymph node and was an incidental finding in a patient with breast cancer. A 50 year-old woman underwent a mastectomy and lymph node dissection following a preoperative diagnosis of bilateral breast cancer. Histopathological examination revealed that the patient had non-invasive and invasive ductal carcinoma in the right and left mammary glands. Although we could not detect breast cancer metastasis in the lymph nodes, one of eight right axillary lymph nodes harbored an 11 × 8 mm discohesive sheet of large polygonal epithelioid tumor cells in the parafollicular area. Tumor cells were immunoreactive for AE1/AE3, CAM5.2, CK18 and l-caldesmon and negative for CD1a, CD21, CD23, CD31, CD68, and S‑100 protein markers. Based on these findings, the lesion was diagnosed as a cytokeratin-positive interstitial reticulum cell tumor of the lymph node. Notably, this early-stage cytokeratin-positive interstitial reticulum cell tumor demonstrated focal nuclear YAP/TAZ proto-oncogene products, which were recently identified as critical for differentiation, maturation, and function of fibroblastic reticular cells. To the best of our knowledge, this is the first report to describe nuclear YAP/TAZ immunoreactivity in cytokeratin-positive interstitial reticulum cell tumors.

The spleen has no epithelial element; thus, primary carcinoma of the spleen is quite rare. We present the case of a patient with serous carcinoma of the spleen. A 76-year-old woman with no significant medical history presented with a huge lesion in the spleen. Except this lesion, clinical examination, including imaging examination, revealed no remarkable findings. She underwent excision of the spleen for treatment and diagnosis. Postoperative pathological examination revealed neoplastic cells with pleomorphic and hyperchromatic nuclei, prominent nucleoli, and frequent mitotic activity. The neoplastic cells exhibited a papillary pattern with psammoma bodies. Immunohistochemistry showed positivity for cytokeratin 7, PAX-8, WT-1, p16, p53, and Ber-EP4 and negativity for cytokeratin 20, thyroid transcription factor-1, carcinoembryonic antigen, CD10, estrogen receptor, calretinin, D2-40, intelectin-1, and sialylated HEG1. We inferred that this tumor was a primary splenic serous carcinoma. Serous tubal intraepithelial carcinoma is the plausible origin of most pelvic serous carcinomas. However, the origin of serous carcinoma of the spleen remains unknown. We speculated that endosalpingiosis might be the origin of the tumor.

Overexpression of Cleft Lip and Palate Transmembrane 1-Like (Clptm1L) confers cancer cell survival through the endoplasmic reticulum (ER) stress survival signaling pathway, while TMEM207 impairs the tumor suppressor function of WW domain containing oxidoreductase (WWOX), which sensitizes cancer cells to ER stress-induced apoptosis. In the present study, we examined whether these two ER stress-related proteins, Clptm1L and TMEM207, could be prognostic markers in oral squamous cell carcinoma (OSCC). Immunohistochemical staining using specific antibodies to Clptm1L or TMEM207 revealed that 31 of 89 tissue specimens exhibited concomitant expression of Clptm1L and TMEM207 at the cancer invasion front. A Kaplan–Meier plot of the patient survival curve followed by a log-rank test revealed that the coexpression of Clptm1L and TMEM207 was significantly associated with poor outcome in patients with OSCC (P = 0.00252). Coexpression of Clptm1L and TMEM207 was closely related to lymph node metastasis (P=0.000574). Both univariate and multivariate analyses demonstrated that coexpression of Clptm1L and TMEM207 predicted the poor prognosis of the patients with OSCC. The present study indicated that the double positive Clptm1L and TMEM207 immunoreactivity was closely related to lymph node metastasis with prognostic value in patients with OSCC.

Ovarian tumors include neoplasms derived from somatic cells and germ cells, including teratoma. Sometimes, tumors of the somatic cell type may develop from teratoma, causing diagnostic perturbation. We experienced a case of a tumor composed of several types of tissue in the ovary with a teratoma. When findings of teratoma and somatic tumor coexist in an ovary, it is difficult to differentiate whether a somatic tumor was mixed with a teratoma or a teratoma unitarily caused transformation to a somatic cell tumor. A 72-year-old Japanese woman (gravida, 3; para, 1) presented to our hospital with severe constipation and frequent urination, and a large intrapelvic tumor was detected by computed tomography (CT). Soon after admission, ultrasonography (US) and magnetic resonance imaging (MRI) revealed a large multilocular cystic tumor on her left ovary. Based on the clinical diagnosis of ovarian cancer, she underwent a left ovariectomy, appendectomy, and partial omentectomy. We observed an ovarian tumor consisting of teratoma, primitive neuroectodermal tumor (PNET), adenocarcinoma, various types of sarcomas, and clear cell carcinoma on the H and E-stained sections. The component of clear cell carcinoma showed a nuclear positive reaction against PAX8 and napsin A, as well as a loss of ARID1A, suggesting typical endometriosis-derived clear cell carcinoma. On the other hand, the expression of ARID1A was maintained in teratoma, PNET, non-specific adenocarcinoma, and various types of sarcomas, suggesting that these tumors had an origin different from that of clear cell carcinoma. These findings indicated that the ovarian tumor of this patient contained a clear cell carcinoma derived from a somatic cell and a teratoma that transformed to a wide variety of somatic cell types of tumors, which coexisted on one ovary. The appropriate use of immunohistochemistry was diagnostically effective in this case.

Transmembrane protein 207 (TMEM207) is an important molecule involved in invasiveness of gastric signet ring cell carcinoma. To understand the pathobiological effects of TMEM207, we generated thirteen transgenic mouse lines, designated C57BL/6-Tg (ITF-TMEM207), where mouse TMEM207 is expressed heterotrophically, regulated by the proximal promoter of the murine intestinal trefoil factor (ITF) gene (also known as Tff3). A C57BL/6-Tg (ITF-TMEM207) mouse line unexpectedly exhibited a high incidence of a spontaneous condition resembling myeloproliferative disease-like phenotype. Increased numbers of CD117+ cells and appearance of dysplastic myeloid cells in bone marrow were observed. These histopathological features suggested human myeloproliferative disease or its precursor manifestations, and were found in almost all mice within 1 year. TMEM207 immunoreactivity was identified in megakaryocytes and erythroblasts of the transgenic mice. The ITF-TMEM207 construct was inserted into Atg4b on murine chromosome 1. Myeloproliferative disease was not observed in other C57BL/6-Tg (ITF-TMEM207) transgenic mouse lines. However, although several other genetically manipulated animal models of myeloproliferative disease and Atg4b knockout mice exist, this mouse line harboring a mutated Atg4b gene, and with overexpression of TMEM207 protein, has not been reported as a model of myeloproliferative disease to date. The present study demonstrated that the C57BL/6-Tg (ITF-TMEM207) mouse may be a valuable model for improved understanding of human myeloproliferative disease.

“Amphicrine” (in Greek, amphi - means “both” or “double”) refers to cells that synchronously exhibit the endocrine and exocrine phenotypes. Gastric amphicrine carcinoma is very rare, and only a few case reports are found in the English literature; thus, its pathobiological features remain unclear. Here, we report a case of amphicrine gastric carcinoma. A woman in her sixth decade of life presented with anemia and underwent upper endoscopy, followed by histopathological examination of biopsy specimens. She appeared to have gastric cancer with a tumor measuring 5.0 cm × 4.0 cm in size. Subsequently, the patient underwent total gastrectomy with lymph node dissection. Histopathological examination revealed a poorly cohesive carcinoma that sparsely coexisted with signet-ring cell carcinoma cells with regional lymph node metastasis. Interestingly, synaptophysin immunoreactivity with the coexistence of Alcian blue was found in individual signet-ring cell carcinoma cells. Furthermore, the present amphicrine carcinoma cells immunohistochemically expressed CD44 variant 9, a functional cancer stem cell marker. We believe that the present case findings may support the idea of multipotent stem cells being an origin of amphicrine gastric cancers.

Recent findings indicate that the WW domain-containing oxidoreductase (WWOX) is a tumor suppressor protein that contains two N-terminal WW domains and a central short-chain dehydrogenase/reductase domain. WWOX protein mediates multiple signaling networks that suppress carcinogenesis through binding of its first WW domain to various cancer-associated proteins, i.e., p73, AP-2γ, and others. Although the tumor suppressor property of WWOX is inarguable, WWOX is not inactivated in the manner characteristic of the canonical Knudson hypothesis. Impairment of both alleles of WWOX is thought to be a rare event, only occurring in a few cancer cell lines. How is the tumor suppressor function of WWOX impaired in cancer cells? Recent advances highlight that a small transmembrane protein possessing a PPxY motif, called TMEM207, and its relatives are aberrantly expressed in various cancer cells and hinder the tumor suppressor function of WWOX through inhibiting its WW domain. Here, we review the recent findings related to the pathobiological properties of TMEM207 and its relatives based on clinicopathological and experimental pathological studies.

Clear cell sarcoma (CCS) is an aggressive type of soft tissue tumor that is associated with high rates of metastasis. In the present study, we found that CPI-613, which targets tumorous mitochondrial energy metabolism, induced autophagosome formation followed by lysosome fusion in HS-MM CCS cells in vitro. Interestingly, CPI-613 along with chloroquine, which inhibits the fusion of autophagosomes with lysosomes, significantly induced necrosis of HS-MM CCS cell growth in vitro. Subsequently, we established a murine orthotropic metastatic model of CCS and evaluated the putative suppressive effect of a combination of CPI-613 and chloroquine on CCS progression. Injection of HS-MM into the aponeuroses of the thigh, the most frequently affected site in CCS, resulted in massive metastasis in SCID-beige mice. By contrast, intraperitoneal administration of CPI-613 (25 mg/kg) and chloroquine (50 mg/kg), two days a week for two weeks, significantly decreased tumor growth at the injection site and abolished metastasis. The present results imply the inhibitory effects of a combination of CPI-613 and chloroquine on the progression of CCS.

Elongin A increases the rate of RNA polymerase II (pol II) transcript elongation by suppressing transient pausing by the enzyme. Elongin A also acts as a component of a cullin-RING ligase that can target stalled pol II for ubiquitylation and proteasome-dependent degradation. It is not known whether these activities of Elongin A are functionally interdependent in vivo. Here, we demonstrate that Elongin A-deficient (Elongin A−/−) embryos exhibit abnormalities in the formation of both cranial and spinal nerves and that Elongin A−/− embryonic stem cells (ESCs) show a markedly decreased capacity to differentiate into neurons. Moreover, we identify Elongin A mutations that selectively inactivate one or the other of the aforementioned activities and show that mutants that retain the elongation stimulatory, but not pol II ubiquitylation, activity of Elongin A rescue neuronal differentiation and support retinoic acid-induced upregulation of a subset of neurogenesis-related genes in Elongin A−/− ESCs.

Background: Recent studies have revealed that the adiponectin-associated protein belonging to the C1qTNF family mediates various biological processes. However, the pathobiological property of C1qTNF6 in carcinogenesis remains unclear. Here, we investigated the expression status of C1qTNF6 in human hepatocellular carcinomas and subsequently attempted to determine the role of C1qTNF6 in tumor neovascularization. Methods: Immunohistochemical staining was performed to evaluate the expression of C1qTNF6 in hepatocellular carcinoma tissue specimens. Various eukaryotic recombinant C1qTNF6 proteins were prepared to ask whether C1qTNF6 could activate Akt pathway in human liver sinusoidal microvascular endothelial cells. Xenograft assay was carried out to know the effect of C1qTNF6 on tumor neovascularization. Results: C1qTNF6 was not immunohistochemically detected in any non-cancerous liver tissues but was detected in 21 of 30 hepatocellular carcinoma tissue specimens. C1qTNF6 was not uniformly distributed but rather focally localized in hepatocellular carcinoma cells. Interestingly, it was also localized on the tumor endothelial cells, which were in close proximity of C1qTNF6-expressing hepatocellular carcinoma cells. Eukaryotic recombinant C1qTNF6 increased the level of active phosphorylated Akt molecules in cultured vascular endothelial cells via its C-terminal C1q domain. In the xenograft assay, enforced expression of C1qTNF6 markedly reduced the central hypovascular necrosis areas of the transplanted HepG2 hepatocellular carcinoma cells. Conclusion: These results indicate that C1qTNF6 is overexpressed and possibly contributes to tumor angiogenesis by activating the Akt pathway in many hepatocellular carcinomas.

We examined the pathobiological properties of beclin-1, which is a key regulator of autophagosome formation in invasive ductal carcinoma of the breast, with a particular focus on the cancer microenvironment. Immunohistochemistry demonstrated that cancer cells and stromal mesenchymal cells expressed beclin-1 in 68 and 38 of 115 invasive ductal cancers, respectively. Expression of beclin-1 in cancer or stromal cells alone did not correlate with patient prognosis. In contrast, loss of beclin-1 in cancer cells and overexpression in stromal mesenchymal cells was associated with local cancer recurrence, postoperative lymph node metastasis, and a poor disease-free survival rate. A comprehensive gene expression analysis was performed on a co-culture of breast cancer cells and mesenchymal stromal cells, that latter of which either expressed beclin-1 or was depleted of beclin-1 by siRNA. Notably, siRNA-mediated downregulation of beclin-1 in mesenchymal cells co-cultured with breast cancer cells decreased the levels of various pro-inflammatory cytokines, their receptors, and collagen receptors. Quantitative reverse transcription polymerase chain reaction analysis confirmed that reduction of stromal beclin-1 expression decreased the expression of IL-1β and collagen receptor discoidin domain receptor 2 (DDR2). Microenvironmental IL-1β is believed to play an important role in tumor invasion. Recent work has also indicated that overexpression of DDR2 contributes to breast cancer invasion and lymph node metastasis. Taken together, these findings indicate beclin-1 expression in the stroma might be important for shaping the breast cancer microenvironment and thus could be a potent molecular target in patients with invasive ductal carcinoma of the breast.

Overweight is believed to be associated with colorectal cancer risk. Adipose tissue is loose connective tissue composed of adipocytes. It is now recognized as a major endocrine organ, secreting humoral factors collectively called adipokines. Aberrant hormonal systems consisting of modulated adipokines and their receptors are thought to play a role in colorectal carcinogenesis and cancer progression in obese conditions. However, it is still unclear whether and how each adipokine relates to colorectal carcinogenesis. Notably, a couple of molecules that were initially proposed to be obesity-related adipokines were disqualified by subsequent studies. The adipokines, adiponectin, and intelectin-1 (also known as omentin-1), whose levels are decreased in obesity, act as tumor suppressor factors in various cancers. Numerous studies have demonstrated a link between the insufficient expression and function of adiponectin and its receptor, T-cadherin, in colorectal carcinogenesis. Moreover, our recent study indicated that loss of TMEM207, which is critical for the proper processing of intelectin-1 in the colon mucosa, leads to insufficient intelectin-1 production, thus participating in colorectal carcinogenesis. Here, we discuss the recent understanding of the role of adipokines in colorectal carcinogenesis and subsequently describe the potent tumor suppressor roles of intelectin-1 and TMEM207 in colorectal cancer.

A negative regulator of the nuclear factor (NF)-κB pathway, A20 (TNFAIP3), is inactivated in several types of lymphomas; particularly in diffuse large B-cell lymphoma (DLBCL), classical Hodgkin's lymphoma, and extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue. These findings suggest that the NF-κB activation is related to A20 inactivation. Recently, A20 inactivation has also been observed in Epstein-Barr virus (EBV)-related lymphomas; however, this occurrence has not been well investigated. Moreover, NF-κB is a key molecule in activated B-cell-like (ABC)-type DLBCL; EBV-associated DLBCL is of the ABC type. Therefore, we focused on A20 deletions in EBV-associated lymphoproliferative disorders/lymphomas. Using fluorescent in situ hybridization analysis, A20 deletions were identified in 4 of 13 samples from patients with pyothorax-associated lymphoma (PAL) (31%), 3 of 20 samples from nasal-type NK/T cell lymphomas (NKTLs) (15%), 1 of 8 samples of EBV-positive DLBCL of the elderly (DLBCL-e) (13%), but not in any of the 11 samples from individuals with methotrexate-related lymphoproliferative disorder (MTX-LPD) (0%). Among the samples with A20 deletions, EBV latent membrane protein 1 (LMP-1) expression was detected in all 4 of the PAL samples with A20 deletions and in the DLBCL-e sample with an A20 deletion, but not in any of the 3 NKTL samples. This finding indicated that A20 deletions were not directly related to the EBV latency pattern of lymphomas, although such deletions might be related to the diagnostic category. Immunohistologically, the A20 protein was absent in 2 (15%) of the 13 PAL samples, 1 (9%) of 11 MTX-LPD samples, and in none of the 20 NKTL (0%) or 8 DLBCL-e samples. In conclusion, A20 deletion and/or dysfunctional expression are frequently associated with PALs, and A20 abnormalities may be related to the pathogenesis of PAL.

Overweight is believed to be associated with colorectal cancer risk. Adipose tissue is loose connective tissue composed of adipocytes. It is now recognized as a major endocrine organ, secreting humoral factors collectively called adipokines. Aberrant hormonal systems consisting of modulated adipokines and their receptors are thought to play a role in colorectal carcinogenesis and cancer progression in obese conditions. However, it is still unclear whether and how each adipokine relates to colorectal carcinogenesis. Notably, a couple of molecules that were initially proposed to be obesity-related adipokines were disqualified by subsequent studies. The adipokines, adiponectin, and intelectin-1 (also known as omentin-1), whose levels are decreased in obesity, act as tumor suppressor factors in various cancers. Numerous studies have demonstrated a link between the insufficient expression and function of adiponectin and its receptor, T-cadherin, in colorectal carcinogenesis. Moreover, our recent study indicated that loss of TMEM207, which is critical for the proper processing of intelectin-1 in the colon mucosa, leads to insufficient intelectin-1 production, thus participating in colorectal carcinogenesis. Here, we discuss the recent understanding of the role of adipokines in colorectal carcinogenesis and subsequently describe the potent tumor suppressor roles of intelectin-1 and TMEM207 in colorectal cancer. [ABSTRACT FROM AUTHOR]

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive and associated with poor prognosis. Basic research to develop new treatment regimens is critically needed. Methods: The effects of imatinib mesylate on MPNSTs were examined in six human MPNST cell lines and in a xenograft mouse model. Results: The results showed expression of platelet-derived growth factor receptor-β and suppression of its phosphorylation by imatinib mesylate in all six cell lines. Imatinib mesylate effectively suppressed MPNST cell growth in vitro at concentrations similar to those used clinically (1.46 - 4.6 μM) in three of six cell lines. Knockdown of PDGFR-β by transfection with a specific siRNA also caused significant reduction in cell proliferation in the sensitive cell lines, but not in the resistant cell lines. Furthermore, imatinib mesylate also significantly suppressed colony formation within soft agar and tumor growth in xenograft models using two of the three sensitive MPNST cell lines. There was excellent agreement between in vitro and in vivo sensitivity to imatinib mesylate, suggesting possible selection of imatinib-sensitive tumors by in vitro analysis. Conclusions: The results suggest that imatinib mesylate may be useful in the treatment of MPNST patients and in vitro studies may help select cells that are sensitive to imatinib mesylate in vivo. [ABSTRACT FROM AUTHOR]

T-cadherin is a unique receptor of adiponectin, which plays a critical role in various angiogenesis. In the present study, T-cadherin expression in tumor vessels of hepatocellular carcinoma (HCC) and, subsequently, the molecular mechanism, which induced T-cadherin expression in sinusoidal endothelial cells were investigated. Sinusoidal endothelium in nontumorous liver, chronic hepatitis, or liver cirrhosis expressed little or no T-cadherin. By contrast, T-cadherin was found in intratumoral capillary endothelial cells of 34 out of 63 HCC specimens. In positive cases, focal T-cadherin expression was found in well-differentiated HCC, whereas diffuse and intense T-cadherin expression was observed in poorly differentiated HCC specimens. T-cadherin was much expressed in intratumoral capillary endothelial cells in a less differentiated HCC region than that in a well-differentiated region in five specimens, in which various differentiated HCC components were coexistent. In a double-cell chamber assay, fibroblast growth factor-2 appeared to have a critical role to induce T-cadherin in cultured liver sinusoidal endothelial cells. The present finding indicated that T-cadherin was selectively expressed in intratumoral capillary endothelial cells of many HCCs, increasingly expressed as tumor progression, and T-cadherin may have a positive role in angiogenesis of HCC. In addition, cross talk between the signal pathways mediated by fibroblast growth factor-2 and adiponectin was suggested. [ABSTRACT FROM AUTHOR]

Abstract Three isoforms of carbonic anhydrase-related protein (CA-RP) are evolutionally well conserved among the CA gene family but lack classical CA activity. Although the biological function of CA-RPs is unknown, overexpression of CA-RP VIII has been reported in certain tumor types. Based on the finding that CA-RPs are commonly expressed in the neuronal cells, we investigated expression of all three CA-RPs in gastrointestinal stromal tumor (GIST). In contrast to no detectable signal of any of the three CA-RPs in intestinal cells of Cajal, immunohistochemical analysis showed distinct cytoplasmic expressions of CA-RPs VIII and XI in 13 (59%) and 20 (91%) of 22 GIST tissue specimens, respectively. The positive signals for both CA-RPs VIII and XI were more intense in the periphery than in the central part of GISTs, whereas no significant signal for CA-RP X expression was observed in any of the GISTs. These expression patterns of CA-RPs were consistently observed by reverse transcription–polymerase chain reaction–Southern blot and immunocytochemistry in the cultured GIST cell line GIST-T1. Ectopic expression of CA-RP XI in GIST-T1 cells induced cell proliferation and invasion in vitro. These findings indicate that CA-RP XI plays a role in the development of GIST. [ABSTRACT FROM AUTHOR]

Carbonic anhydrase-related protein (CA-RP) VIII, which is a member of the CA gene family, has been shown to have no catalytic CA activity and its biological function is still unknown. Recently, overexpression of CAs IX and XII has been reported in certain types of malignancy. To investigate a potential role for CA-RP VIII in human colorectal epithelial carcinogenesis, colorectal tissue specimens from surgically resected adenocarcinomas (n = 60) and endoscopically polypectomized adenomas (n = 13) were analysed by immunohistochemistry using monoclonal antibodies to CA-RP VIII and Ki-67 antigen. Less than 5% of epithelial cells in normal colonic mucosae (n = 73) were CA-RP VIII-positive and these were localized to the deep part of the cryptal epithelium. Increased expression of CA-RP VIII was observed in 78% of colorectal carcinomas. An intense signal was frequently observed at the tumour invasion front and its distribution was completely different from that of Ki-67 antigen. Colorectal adenomas also showed significant immunopositivity for CA-RP VIII, but its expression level was much lower than in adenocarcinomas. These findings suggest that CA-RP VIII plays a role in the process of invasion in colorectal cancer. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract. Carbonic anhydrase-related protein (CA-RP VIII) lacks a Zn-binding motif which is essential for carbonic anhydrase activity. Therefore, CA-RP VIII is believed to have a no catalytic activity and a new biological property. In the present study, CA-RP VIII expression in non-tumorous lung and non-small cell lung carcinomas was investigated. Little or no expression of CA-RP VIII was observed in human lungs by Northern-blot analysis. Reverse-transcription polymerase chain reaction analysis demonstrated CA-RP VIII mRNA in developing human lungs and, to a lesser extent, in normal lungs. Subsequent immunohistochemical staining revealed that CA-RP VIII was expressed in the pulmonary epithelium in developing lungs; however, CA-RP VIII expression was restricted in bronchial ciliated cells in adult lungs. Neither bronchial gland nor squamous metaplasia of interstitial pneumonia expressed CA-RP VIII. In contrast, CA-RP VIII was strongly expressed in almost all archival lung cancer specimens, which included 24 squamous cell carcinomas, 25 adenocarcinomas, and 6 adenosquamous cell carcinomas. Cancer cells at the front of tumor progression expressed CA-RP VIII in particular abundance. The present findings suggest that CA-RP VIII may play a role in non-small lung cell carcinomas. [ABSTRACT FROM AUTHOR]

TMEM207 was first characterized as being an important molecule for the invasion activity of gastric signet-ring cell carcinoma cells. In order to unravel the pathological properties of TMEM207, we generated several transgenic mouse lines, designated C57BL/6-Tg (ITF-TMEM207), in which murine TMEM207 was ectopically expressed under a truncated (by ~200 bp) proximal promoter of the murine intestinal trefoil factor (ITF) gene (also known as Tff3). Unexpectedly, a C57BL/6-Tg (ITF-TMEM207) mouse line exhibited a high incidence of spontaneous intradermal tumors with histopathological features that resembled those of various human cutaneous adnexal tumors. These tumors were found in ~14% female and 13% of male 6- to 12-month-old mice. TMEM207 immunoreactivity was found in hair follicle bulge cells in non-tumorous skin, as well as in cutaneous adnexal tumors of the transgenic mouse. The ITF-TMEM207 construct in this line appeared to be inserted to a major satellite repeat sequence at chromosome 2, in which no definite coding molecule was found. In addition, we also observed cutaneous adnexal tumors in three other C57BL/6-Tg (ITF-TMEM207) transgenic mouse lines. We believe that the C57BL/6-Tg (ITF-TMEM207) mouse might be a useful model to understand human cutaneous adnexal tumors., (© 2014. Published by The Company of Biologists Ltd.)