Yasutaka Kato

Cyclooxygenase‐2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells

Tumor angiogenesis is necessary for solid tumor progression and metastasis. Cyclooxygenase (COX)‐2 is known to play an important role in cancer growth and invasion, and it activates the signaling pathways controlling cell proliferation, migration, apoptosis, and angiogenesis. COX‐2 is reported to be expressed in many cancer cells. Several studies have reported successful treatment of cancer cells with COX‐2 inhibitors (COX‐2is). However, the effect of COX‐2 inhibition on the tumor endothelium remains to be elucidated. Our study shows that COX‐2 is expressed in the vasculature of surgically resected human tumors. To investigate the effects of COX‐2 inhibition on the tumor endothelium in vitro, we isolated tumor endothelial cells (TECs) from human melanoma and oral carcinoma xenografts in mice, in which we confirmed that tumor growth was suppressed by inhibiting angiogenesis with the COX‐2is NS398. COX‐2 mRNA was upregulated in TECs compared to normal endothelial cells (NECs). Cell migration and proliferation were suppressed by NS398 in TECs but not in NECs. The effects of NS398 in vivo were consistent with the in vitro results. The number of CD133+/vascular endothelial growth factor receptor‐2+ cells in circulation was significantly suppressed by COX‐2 inhibition. In addition, the number of progenitor marker‐positive cells decreased in the tumor blood vessels after COX‐2i treatment, which suggests that the homing of progenitor cells into the tumor was also blocked. We conclude that NS398 specifically targets both TECs and vascular progenitor cells without affecting NECs.

DOCK2 regulates cell proliferation through Rac and ERK activation in B cell lymphoma

DOCK2; a member of the CDM protein family, regulates cell motility and cytokine production through the activation of Rac in mammalian hematopoietic cells and plays a pivotal role in the modulation of the immune system. Here we demonstrated the alternative function of DOCK2 in hematopoietic tumor cells, especially in terms of its association with the tumor progression. Immunostaining for DOCK2 in 20 cases of human B cell lymphoma tissue specimens including diffuse large B cell lymphoma and follicular lymphoma revealed the prominent expression of DOCK2 in all of the lymphoma cells. DOCK2-knockdown (KD) of the B cell lymphoma cell lines, Ramos and Raji, using the lentiviral shRNA system presented decreased cell proliferation compared to the control cells. Furthermore, the tumor formation of DOCK2-KD Ramos cell in nude mice was significantly abrogated. Western blotting analysis and pull-down assay using GST-PAK-RBD kimeric protein suggested the presence of DOCK2-Rac-ERK pathway regulating the cell proliferation of these lymphoma cells. This is the first report to clarify the prominent role of DOCK2 in hematopoietic malignancy.

Targeted next‑generation sequencing of cancer‑related genes in thyroid carcinoma: A single institution's experience

Thyroid carcinoma (TC) has characteristic genetic alterations, including point mutations in proto-oncogenes and chromosomal rearrangements that vary by histologic subtype. Recent developments in next-generation sequencing (NGS) technology enable simultaneous analysis of cancer-associated genes of interest, thus improving diagnostic accuracy and allowing precise personalized treatment for human cancer. A total of 50 patients who underwent thyroidectomy between 2014 and 2016 at Hokuto Hospital were enrolled. Total DNA was extracted from formalin-fixed, paraffin-embedded tissue sections and quantified. Targeted regions of 24 cancer-associated genes were amplified by PCR, barcoded and sequenced using an Illumina MiSeq platform. Subjects included 30 patients with papillary carcinoma (PC), two with PC tall cell variant (TVPC), two with PC follicular variant (FVPC), eight with follicular carcinoma, seven with poorly differentiated carcinoma (PDC), and one with anaplastic carcinoma (AC). The BRAF V600E mutation was present in 25 of 30 (83%) patients with PC, 2 of 2 (100%) patients with TVPC, 6 of 7 (86%) patients of PDC, and one patient with AC. PIK3CA mutations were present in 3 of 30 (delPV104P, A1046T and C420R; 10%) patients with PC and 1 of 7 (H1047R; 14%) patients with PDC. The TP53 mutation was present in 1 of 30 (R306*; 3.3%) patients with PC and 1 of 7 (Q152*; 14%) patients with PDC. The NRAS mutation was present in 1 of 2 (Q61K, 50%) patients with FVPC. Statistical analysis showed that patients without the BRAF V600E mutation had advanced pathologic T and N stages compared with those with the mutation (P=0.047 and P=0.019, respectively). The BRAF V600E mutation was not correlated with overall and disease-free survival in patients with PC. A patient with PC with a mutation in EGFR (K852Q) and the PIK3CA mutation had an aggressive course with multiple bone and lung metastases. Detection of mutations in cancer-associated genes using NGS could enhance the understanding of the clinical behavior of TC.

Tumor budding and human chorionic gonadotropin-β expression correlate with unfavorable patient outcome in colorectal carcinoma

Tumor budding is thought to represent a manifestation of epithelial-to-mesenchymal transition (EMT) and it has been correlated with poor patient outcomes in colorectal cancer (CRC). Our group recently demonstrated that human chorionic gonadotropin-β (hCGβ) modulates EMT in CRC. In the current study, based on the likely relationships between tumor budding and hCGβ expression, we examined their clinicopathologic significance in CRC. Twenty-eight of 80 (35.0%) CRC showed tumor budding. Tumor budding significantly correlated with lymph node metastasis (P < 0.01), pathologic stage (P < 0.01), lymphatic invasion (P = 0.044), and vascular invasion (P = 0.013). Thirteen of 80 (16.3%) CRC were hCGβ positive on immunohistochemistry. More tumor buds were present in the hCGβ-positive cases (P < 0.01), and tumor budding was significantly correlated with hCGβ positivity (P < 0.01). Cases with both tumor budding and hCGβ expression had the poorest prognosis compared with all other groups (P < 0.01). In conclusion, tumor budding and hCGβ expression are closely associated with EMT, and they are independent prognostic factors in CRC. They identify patients with an “EMT phenotype” who may respond to targeted molecular therapies.

Glomangiopericytoma of the Nasal Cavity with CTNNB1 p.S37C Mutation: A Case Report and Literature Review

Glomangiopericytoma (GPC) is a rare mesenchymal tumor arising from the nasal cavity or paranasal sinuses. GPC was categorized as a borderline and low-malignant-potential tumor by the World Health Organization in 2005 and accounts for less than 0.5% of all sinonasal tumors. We report a case of GPC in a 74-year-old woman with a history of recurrent epistaxis and nasal obstruction. A reddish tumor was seen in the right nasal cavity. Enhanced computed tomography showed a mass lesion occupying the right nasal cavity. The tumor, which originated from the nasal septum in the olfactory fissure area, was resected with 5-mm mucosal margins by endoscopic sinus surgery. Histologic examination revealed a uniform proliferation of oval-to-short spindle-shaped cells beneath the epithelium. Immunohistologic analysis demonstrated the tumor cells were positive for α-smooth muscle actin, β-catenin and Vimentin, and negative for AE1/AE3, Bcl-2, CD34, CD117, Factor VIIIR Ag, S-100 protein, or STAT6. The percentage of Ki-67-positive cells was approximately 5%. Genetic analysis using next-generation sequencing revealed a missense mutation in the CTNNB1 gene (c.110C > G, p.S37C). While other CTNNB1 mutations have been described in GPC; this is the first report of this specific mutation. The mutation was confirmed using Sanger sequencing.

Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome

Title Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome Author(s) Yabe, Ichiro; Yaguchi, Hiroaki; Kato, Yasutaka; Miki, Yasuo; Takahashi, Hidehisa; Tanikawa, Satoshi; Shirai, Shinichi; Takahashi, Ikuko; Kimura, Mari; Hama, Yuka; Matsushima, Masaaki; Fujioka, Shinsuke; Kano, Takahiro; Watanabe, Masashi; Nakagawa, Shin; Kunieda, Yasuyuki; Ikeda, Yoshio; Hasegawa, Masato; Nishihara, Hiroshi; Ohtsuka, Toshihisa; Tanaka, Shinya; Tsuboi, Yoshio; Hatakeyama, Shigetsugu; Wakabayashi, Koichi; Sasaki, Hidenao Citation Scientific Reports, 8: 819 Issue Date 2018-01-16 Doc URL http://hdl.handle.net/2115/68138 Rights(URL) http://creativecommons.org/licenses/by/4.0/ Type article Additional Information There are other files related to this item in HUSCAP. Check the above URL. File Information 41598_2018_19198_MOESM1_ESM.pdf (Supplementary data)

A case of cervical juxtafacet cyst with extensive rim enhancement on Gd-DTPA MRI

The authors reported a case of cervical juxtafacet cyst with extensive rim enhancement on gadolinium-diethylenetriamine pentaacid magnetic resonance imaging. Operative finding revealed the epidural space around the mass filled with abundant venous plexus. Histological examination demonstrated that cyst wall was composed of the well-vascularized fibrous connective tissue with some inflammatory changes. We speculate that extensive rim enhancement of juxtafacet cyst may be attributed not only to the chronic inflammatory changes of cyst wall, but to engorged venous plexus within the widened epidural space.