Toshiyuki Ishiwata

Tokyo Metropolitan Institute of Gerontology | TMIG · Research Team for Geriatric Pathology

Telomeres in most somatic cells shorten with each cell division, and critically short telomeres lead to cellular dysfunction, cell cycle arrest, and senescence. Thus, telomere shortening is an important hallmark of human cellular senescence. Quantitative fluorescence in situ hybridization (Q-FISH) using formalin-fixed paraffin-embedded (FFPE) tissu...

Background: Most pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). Spherical morphology formed in three-dimensional (3D) cultures and the effects of anticancer drugs differ between epithelial and mesenchymal PDAC cell lines. In the human pancreas, cancer cells form 3D tumors, migrate to adjacent tissues, and metastasize to other orga...

Background The number of patients with prolonged critical illness (PCI) has been increasing in many countries, and the adrenal gland plays an important role in maintaining homeostasis during PCI. Chronic disease burden is reportedly associated with shorter telomere lengths in human tissues. Telomere shortening in human somatic cells is largely depe...

Papillary adenocarcinoma is defined as carcinoma with a well-defined papillary or villous structure. Despite sharing clinicopathological and morphological features with tubular adenocarcinomas, papillary adenocarcinomas frequently show microsatellite instability. The present study aimed to clarify the clinicopathological features, molecular classif...

Background The most pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC), which have been classified as cells with epithelial or mesenchymal features. We recently found that the morphology of spheres formed in three-dimensional cultures and the effect of anticancer drugs differed between epithelial and mesenchymal PDAC cell lines. Cancer...

Background: The histology of the cardiac mucosa at the esophagogastric junction (EGJ) at birth is still a controversy. We conducted a histopathological study of the EGJ to clarify the morphology, and to determine the presence or absence of cardiac mucosa at birth. Subjects: We examined 43 Japanese neonates and infants that are born prematurely o...

Introduction Heart failure is caused by various factors, making the underlying pathogenic mechanisms difficult to identify. Since cardiovascular disease tends to worsen over time, early diagnosis is key for treatment. In addition, understanding the qualitative changes in the heart associated with aging, where information on the direct influences of...

Mammary adenocarcinoma, the most common cancer in female dogs, often exhibits the lymph node and lung metastases and has a higher mortality rate. However, mammary adenocarcinoma has no established treatment, except early surgical excision. Canine mammary carcinoma has many common features with human mammary carcinoma, including clinical characteris...

Three-dimensional (3D) culture of cancer cells mimics the in vivo environment. Recently, we reported that pancreatic ductal adenocarcinoma (PDAC) cell lines with epithelial and mesenchymal features formed differently shaped spheres in 3D culture. However, only PK-8 cells, the epithelial PDAC cell line with the highest E-cadherin expression among th...

Phenotypic switching between contractile (differentiated state) and proliferative (dedifferentiated state) vascular smooth muscle cells (VSMCs) is a hallmark of vascular remodeling that contributes to atherosclerotic diseases. Gangliosides, a group of glycosphingolipids, have been detected in atherosclerotic lesions and are suspected to contribute...

Hyperactivation of phosphatidylinositol 3-kinase (PI3K) signaling is a prominent feature in cancer cells. However, the mechanism underlying malignant behaviors in the state remains unknown. Here, we describe a mechanism of cancer drug resistance through the protein synthesis pathway, downstream of PI3K signaling. An optogenetic tool (named PPAP2) c...

Epithelial–mesenchymal transition (EMT) plays a pivotal role in cancer progression and metastasis in many types of malignancies, including colorectal cancer. Although the importance of EMT is also considered in colorectal neuroendocrine carcinoma (NEC), its regulatory mechanisms have not been elucidated. We recently established a human colorectal N...

Objectives: It is challenging to preoperatively distinguish malignant and benign forms of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. The aims of this study were to investigate whether telomere length is associated with pathological grade of IPMNs and age and to clarify the utility of telomere length as a marker to identify m...

Pancreatic ductal adenocarcinoma (PDAC) is an intractable cancer that is difficult to diagnose early, and there is no cure other than surgery. PDAC is classified as an adenocarcinoma that has limited effective anticancer drug and molecular-targeted therapies compared to adenocarcinoma found in other organs. A large number of cancer cell lines have...

Simple Summary The signal transducer and activator of transcription 3 (STAT3) activation correlate with the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). We demonstrated that the autocrine/paracrine interleukin-6 (IL-6) or leukemia inhibitory factor (LIF)/glycoprotein 130 (gp130)/STAT3 pathway contributes to the maintenance of stemness...

Macroscopic lipid observation in the organs of living small animals has not been realized. Here, we visualized sphingomyelin (SM) in the intestines of living mice using an SM-binding protein (EqtII-EGFP-His) under two-photon microscopy. The SM was identified as 10 μm spots in glands of the lamina propria of the mucosa in the large and small intesti...

Background: Anorectal melanoma is a rare disease with poor prognosis and nonspecific symptoms, leading to difficulties in preoperative diagnosis. Here, we describe the establishment of MELS, a novel anorectal melanoma cell line derived from tumor resection of the rectum in a 40-year-old Japanese man. Methods: Histological, electron microscopic,...

Heart failure is caused by various factors, making its underlying pathogenic mechanisms difficult to identify, and tends to worsen over time. Early diagnosis of cardiovascular disease is the key for treatment to promote healthy life. To detect the structural and functional molecular changes associated with cardiovascular disease, we focused on glyc...

Background We have reported that precancerous conditions and lesions invariably have shorter telomeres and associated chromosomal instability relative to normal tissue.Methods Using the Q-FISH method and our original software, Tissue Telo, we estimated telomere lengths in cardiac- and intestinal-type mucosae in 48 cases of Barrett’s esophagus (shor...

Purpose: Fibroblast growth factor receptor 4 (FGFR4), one of the four tyrosine kinase receptors for FGFs, is involved in various cellular processes. Activation of the FGF19/FGFR4 signaling is strongly associated with cancer development and progression. BLU9931 is an irreversible and highly selective small-molecule inhibitor of FGFR4. In this study,...

Nestin, a class VI intermediate filament protein, is known to be expressed in various types of human neoplasms, including breast cancer, and is associated with their progression. However, its expression and role in canine mammary tumors remain unknown. We analyzed nestin expression in canine mammary tumors using in situ hybridization and immunohist...

At the plasma membrane, gangliosides, a group of glycosphingolipids, are expressed along with glycosphingolipids, phospholipids, and cholesterol in so-called lipid rafts that interact with signaling receptors and related molecules. Most cancers present abnormalities in the intracellular signal transduction system involved in tumor growth, invasion,...

Genetic, transcriptional, and morphological differences have been reported in pancreatic ductal adenocarcinoma (PDAC) cases. We recently found that epithelial or mesenchymal features were enhanced in three-dimensional (3D) cultures compared to two-dimensional (2D) cultures. In this study, we examined the differences in the morphological and functio...

Polyvinyl alcohol (PVA) is a water-soluble synthetic polymer used in eye drops, embolization particles, and artificial cartilage. It has also been shown to cause expansion of functional multipotent self-renewing hematopoietic stem cells under serum-free conditions. In this study, we examined the effects of PVA on human pancreatic ductal adenocarcin...

Fibroblast growth factor receptor 4 (FGFR4), one of four tyrosine kinase receptors for FGFs, is involved in diverse cellular processes. Activation of FGF19/FGFR4 signaling is closely associated with cancer development and progression. In this study, we examined the expression and roles of FGF19/FGFR4 signaling in human pancreatic ductal adenocarcin...

(a) Purpose: Gangliosides are molecules composed of glycosphingolipids linked with one or more sialic acids, and are known to be key components of lipid rafts, which act as platforms for signal transduction. Changes in ganglioside levels affect the expression of raft-associated proteins on the cell surface and lead to reduced membrane fluidity, thu...

BACKGROUND: The current incidence of neuroendocrine tumor (NET) is 0.6 cases per 100,000 people, although it has increased 50-fold over the last 35 years and is becoming increasingly clinically important. Neuroendocrine carcinoma (NEC) is a type of malignant NET associated with poor prognoses. However, the molecular basis and clinical characteristi...

The clinicopathological significance of carbohydrate antigen 19-9 (CA19-9) in gastric cancer (GC) remains obscure. Therefore, the current study aimed to clarify the clinicopathological value of CA19-9 in GC utilizing autopsy cases. We examined the expression of CA19-9 and mucin core proteins in GC immunohistochemically, and analyzed serum CA19-9 le...

Gangliosides, a group of glycosphingolipids, are known to be cell surface markers and functional factors in several cancers. However, the association between gangliosides and pancreatic ductal adenocarcinoma (PDAC) has not been well elucidated. In this study, we examined the expression and roles of ganglioside GM2 in PDAC. GM2+ cells showed a highe...

In pancreatic cancer, morphologically and functionally heterogeneous cancer cells reside within the same patient. The heterogeneity is believed to promote metastasis and resistance to chemoradiotherapy. MIA PaCa-2, an established human pancreatic ductal adenocarcinoma (PDAC) cell line, contains round and spindle-shaped adherent cells, as well as, r...

Context Although numerous theories are reported on sex differences in longevity, the underlying biological mechanisms remain unknown. We previously reported that telomere length in the zona reticularis (ZR) cells of the human adrenal cortex was significantly longer in older than that in younger subjects. However, we could not evaluate sex differenc...

The incidence of rare neuroendocrine tumors (NET) is rapidly increasing. Neuroendocrine carcinoma (NEC) is a NET with poorly differentiated histological features, high proliferative properties and associated poor prognoses. Since these carcinomas are so rare, and thus, affect only a small number of patients allowing for few cell lines to be derived...

Cancer stem cells (CSCs) are a small group of cells within a tumor that preserve stemness and enhance regrowth of cancer cells. CSCs have important implications in resistance to conventional therapies and tumor relapse, although their detailed properties remain unknown. Thus, CSCs represent promising targets to improve cancer treatment. So far, a n...

Carbohydrate sulfotransferase 15 (CHST15) synthesizes matrix proteoglycan that regulates various pathogenic mediators and contributes to tissue remodeling and fibrosis during injury. CHST15 has been reported to promote tumor growth and invasion in various types of cancer. Our previous study reported the safety and efficacy of EUS-guided fine-needle...

Background: Progressive telomere shortening with age or chronic inflammation may lead to genomic instability that characterizes the early stage of carcinogenesis. Certain risk factors, such as drinking alcoholic beverages, or smoking, predispose the oral mucosa to squamous cell carcinoma. The ADH1B and ALDH2 genotypes can influence the risk of can...

A 2-year-old neutered female Shiba dog exhibited laboured breathing for 1 month. Computed tomography of the thoracic cavity revealed multiple nodules (2-5 mm diameter) in the lungs. Grossly, the lungs were firm and normal in shape. The nodules were grey-white in colour. Microscopically, the nodules were non-encapsulated and exhibited an irregular s...

Objectives: This study aimed to clarify clinicopathological features of pancreatic cysts. Methods: Pancreata from 280 autopsies (median, 83 years; male, 146; female, 134) were sectioned every 5 mm. Cysts (<10 mm) were diagnosed as a simple cyst or low-grade, intermediate-grade, or high-grade dysplasia. Results: We found 236 cysts in 93 patient...

Pancreatic cancer, composed of heterogeneous cancer cells, alters epithelial to mesenchymal features during growth and metastasis. In this study, we aimed to characterize pancreatic ductal adenocarcinoma (PDAC) cells showing epithelial or mesenchymal features in 3D culture. In 3D culture, PK-1 cells had high E-cadherin and low vimentin expression a...

Cancer consists of heterogeneous cells that contain a small population of cells that possess stem cell properties; these cells, referred to as cancer stem cells (CSCs) or tumor-initiating cells, are involved in tumor progression and metastasis. Using a sphere-forming assay, canine mammary CSCs were found to be similar to human breast CSCs. Metaboli...

The long non-coding RNA is highly expressed and carries out various functions in different types of cancers. Recently, we reported that contributes to the metastasis of pancreatic ductal adenocarcinoma (PDAC) cells and its inhibition reduces metastasis in vivo. However, the molecular mechanisms underlying the metastasis-promoting role of in PDAC ce...

p>The H19 long non-coding RNA is highly expressed and carries out various functions in different types of cancers. Recently, we reported that H19 contributes to the metastasis of pancreatic ductal adenocarcinoma (PDAC) cells and its inhibition reduces metastasis in vivo . However, the molecular mechanisms underlying the metastasis-promoting role of...

Context: Adrenocortical zonation is associated with a markedly complex developmental process, and the pathogenesis and/or etiology of many disorders of adrenocortical zonal development have remained unknown. Cells from the three adrenocortical zones are morphologically and functionally differentiated, and the mature stage of cell development or se...

An 84-year-old man with chronic renal failure, anemia, and diabetes was admitted for hemodialysis initiation. His vital signs were stable until the eighteenth hospital day, before having an influenza A virus infection. Three days later, he died of septic shock with severe liver impairment. His leukocyte count, prothrombin time (PT-INR), and liver e...

Pancreatic ductal adenocarcinoma (PDAC) is a major histological type of pancreatic cancer and remains one of the most lethal cancers with a high mortality rate owing to its aggressive growth, high metastatic rate, and recurrence. Recent studies on cancer stem cells (CSCs) have suggested that the aggressive growth, high metastatic rate, and recurren...

The intermediate filament nestin is upregulated in stem/progenitor cells and cancers, and regulates cell proliferation, migration, invasion and stemness. The present study comparatively analyzed serial autopsies of Japanese patients (n=2,206; males, 1,225; females, 981; median, 80.7 years old; range, 33-104 years old) with malignant tumors of whole...

S100A4 (metastasin), a member of the S100 protein family, was initially identified in metastatic cells and is well established as a marker of aggressive human cancer. However, expression and roles of S100A4 in canine mammary tumors have not been clarified. In this study, expression of S100A4 was examined immunohistochemically in normal, hyperplasti...

A 13-year-old neutered female mixed-breed dog with a clinical history of emaciation, inappetence and vomiting for 2 months was presented. Blood tests showed marked leucocytosis with increased neutrophil and basophil count, mild thrombocytosis and anaemia. Seven days after the initial visit, the dog died and was submitted for necropsy examination. G...

A 14-year and 8-month-old intact male Amur tiger presented with an enlarged left testis, measuring 5.7 × 5.5 × 4.5 cm. The cut surface was mottled dark red to reddish brown in color. Microscopically, the enlarged left testis comprised round or polygonal neoplastic cells arranged in a diffuse sheet pattern. These neoplastic cells had a hyperchromati...

Background Accurate diagnosis of malignant and benign pancreatic lesions can be challenging, especially in case of endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) samples that are small and/or degraded. In the present study, we determined how to best evaluate abnormal SMAD4 expression by immunohistochemical staining on cell‐block spec...

Mucin-producing urothelial-type adenocarcinoma of the prostate (MPUAP) is a rare, aggressive neoplasm thought to originate from the prostatic urethral urothelium. Our case is the first reported to show significantly increased serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 in MPUAP. An autopsy revealed occult MPUAP...

The long non-coding RNA H19 is highly expressed in several cancers, and the functions of H19 vary among cancer cell types. Recently, we reported that H19 contributes to the metastasis of pancreatic ductal adenocarcinoma (PDAC) cells and that inhibition of H19 reduces metastasis in vivo. However, the molecular mechanisms underlying the metastasis-pr...

Aim The telomere is a structure present at the ends of chromosomes, and is known to shorten with aging and successive rounds of cell division. However, very little is known about telomere attrition in post‐mitotic cells, such as neurons. Methods Using our originally developed quantitative fluorescence in situ hybridization method, we analyzed age‐...

Background: Despite predominant microsatellite instability (MSI) in intestinal-type gastric carcinomas, we found the most frequent MSI in solid-type poorly differentiated adenocarcinoma (PDA). Although this tumor is classified as PDA, it is hypothesized to possess peculiar features among PDAs. The present study aimed to clarify the clinicopatholog...

ATP-binding cassette subfamily G member 2 (ABCG2), an important multidrug resistance transporter, can mediate the efflux of various chemotherapy drugs and contribute to drug resistance in cancer cells. The correlation between ABCG2 expression and cancer stem cell (CSC) phenotypes has been examined in hepatocellular carcinoma, as well as in glioma,...

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a high incidence of distant metastasis and recurrence. Cancer stem cells (CSCs), which are pluripotent, self-renewable, and capable of forming tumors, contribute to PDAC initiation and metastasis and are responsible for resistance to chemotherapy and radiation. Three types of...

In order to investigate the population dynamics of telomere status, we measured the telomere lengths of glandular cells in the adenohypophysis (AH) and pituicytes, a type of glial cell, in the neurohypophysis (NH) of 128 autopsied humans (65 men, 63 women, 0 and 102 years) using our original quantitative fluorescence in situ hybridization (Q-FISH)...

H19 is an oncofetal RNA expressed in the developing embryo as well as in bladder, breast, gastric, pancreatic, hepatocellular, and prostate cancers. Recent studies have shown that H19 enhances cancer invasion and metastasis; however, its roles in cancer remain controversial. In the current study, H19 exhibited the second largest increase (82.4-fold...

The infiltration and proliferation of cancer cells in the secondary organs are of great interest, since they contribute to cancer metastasis. However, cancer cell dynamics in the secondary organs have not been elucidated at single-cell resolution. In the present study, we established an in vivo model using two-photon microscopy to observe how infil...

The expression of ATP-binding cassette subfamily G member 2 (ABCG2) is related with tumorigenic cancer stem cells (CSCs) in several cancers. However, the effects of ABCG2 on CSC-related malignant characteristics in pancreatic ductal adenocarcinoma (PDAC) are not well elucidated. In this study, we compared the characteristics of low (ABCG2–) and hig...

Types 1-4 of fibroblast growth factor receptors (FGFR) are all expressed in various cancers. Because of its prominent role in carcinogenesis and cancer progression, FGFR-2, is being considered as a novel target in cancer treatment. Owing to the alternative splicing of its extracellular domain, FGFR-2 exists in two variants: IIIb and IIIc. FGFR-2 II...

With the recent advent of whole genome and transcriptome sequencing technologies, long non-coding RNAs have been brought into the spotlight in molecular biology. H19 was one of the first reported long non-coding RNAs; its expression is high in embryonic organs and absent or greatly reduced in most adult tissues. Accumulating evidence suggests that...

Cancer stem cells (CSCs), which are pluripotent and self-renewable, contribute to the initiation and metastasis of cancer, and are responsible for resistance to chemotherapy and radiation. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of cancer that is associated with a high incidence of distant metastasis and recurrence. Sphere for...

In the original publication of this article, Fig. 5 was published with incorrect color of the approximate lines of CBD and Control.

A 21-year-old neutered female domestic shorthaired cat was presented with a history of inappetence, vomiting and haematuria. The cat was humanely destroyed at the owner's request and a necropsy examination was performed. A 0.8 × 0.5 × 0.5 cm mass was located in the left lobe of the pancreas. The mass was gelatinous in nature and the external and cu...

Background Congenital biliary dilatation (CBD) is a congenital malformation involving both dilatation of the extrahepatic bile duct and pancreaticobiliary maljunction. Persistent reflux of pancreatic juice injures the biliary tract mucosa, resulting in chronic inflammation and higher rates of carcinogenesis in the biliary tract, including the gallb...