Tumors derive from a single cell clone but consist of heterogeneous cell subpopulations with diverse features and functions. A limited number of subclones with a selective advantage can initiate tumors when inoculated into immunocompromised mice, and are called cancer-initiating cells (CICs). CICs can be isolated from the bulk of tumors on the basis of their characteristics, such as high reagent efflux, degradation of reactive oxygen species, and aldehyde dehydrogenase (ALDH) activity. Under normal conditions, new CICs are produced by existing CICs rather than non-CICs. However, under stress conditions, non-CICs can occasionally produce CICs, a phenomenon known as plasticity. The dynamic exchange between CICs and non-CICs may enable tumors to survive under unfavorable conditions. CICs are located in a small portion of tumors. This suggests that microenvironmental factors induce or inhibit the CIC phenotype, which might be regulated by intercellular signaling between tumor cells. This review describes isolation of CICs from tumor cell populations and the microenvironmental factors that regulate CIC phenotypes in uterine cancer and lymphoma.
Alloxan (AL) is a material well-known to induce diabetes. Prior to inducing a prolonged diabetic state, AL causes acute tubulointerstitial nephritis. However, the precise primary target site and mechanism of its nephrotoxicity remain unclear. The objective of this study was to evaluate the morphological characteristics relevant to acute renal toxicity following AL administration. Rats were intravenously treated with AL. Eight hours after AL treatment, aquaporin 1-negative and Na/K pump-positive thick ascending limbs of Henle (TAL) were degenerated in the outer medulla. These tubular lesions progressed from the outer medulla to the cortex. At day 2 after AL treatment, the lesions reached a peak, then both proximal and distal tubules also showed degeneration and necrosis, and tubular regeneration was seen in TAL. Immunohistochemically, damaged tubular epithelium included slightly enlarged prohibitin-positive granules, but it expressed no GLUT2, which is an AL transporter. Ultrastructurally, cytoplasmic and mitochondrial swelling was detected in degenerated cells of TAL. These findings suggest that AL initially causes degeneration of TAL, and induces mitochondrial and cellular damage in the tubular epithelium without involving GLUT2.
The aim of this study was to investigate the lethal and sublethal toxicity of a methomyl-based insecticide in Hoplobatrachus rugulosus, as methomyl-based insecticides are applied in massive amounts and agrochemicals have effects on the decline in amphibian populations. To evaluate the toxic effects of methomyl from agricultural application, a methomyl-based insecticide containing 40% methomyl was selected. The median lethal concentration of 96 hours of methomyl exposure was 8.69 ppm for H. rugulosus tadpoles. The lethal concentration also produced severe histological damage in the livers and kidneys of the exposed tadpoles. The sublethal concentration used for methomyl was 144 ppb during the metamorphosis period. It was found that the sublethal concentration of the methomyl compound could decrease growth, metamorphosis time, and size, disturb biochemical parameters, and produce histological damage. In livers, methomyl effects increased oxidative stress and dramatically decreased the glycogen level of the treated froglets. Mononuclear infiltration, blood congestion, amorphous substances, and hepatocytes vacuolization were observed throughout liver tissue. The methomyl-based insecticide also increased oxidative stress and decreased nitric oxide levels in the kidneys of the exposed froglets. Renal tissue damage including blood congestion, amorphous substances, and Bowman’s capsule spaces reduction were found in the methomyl exposure group. The methomyl compound also produced vacuoles in various stages of oocytes, but no histological damage was found in testicular tissue. Our results indicated strong toxic effects of the methomyl-based insecticide on H. rugulosus, a broadly tolerant anuran.
The aim of this study was to identify potential changes that could occur during histological evaluations of CLAWN miniature swine, with potential consequences for subsequent experiments. The systemic organs from male and female CLAWN miniature swine (16.3–42.3 months old) that had been used in long-term studies of coronary stent implantation were examined histologically. Commonly observed histopathological findings were testicular/epididymal atrophy, cyst-like follicles in the ovaries, hemosiderin deposition in the spleen, lipofuscin deposition in the proximal tubular epithelia and presence of eosinophilic globules in the Bowman’s space and the lumen of the proximal tubules in the kidneys, and cellular infiltration in several organs, including the eyelids, respiratory organs, and digestive tract. However, none of these changes were serious enough to indicate a significant impact on research. In conclusion, this study identified CLAWN miniature swine as a suitable animal model for various experiments.
We have previously demonstrated that diphenylarsinic acid (DPAA) promotes liver carcinogenesis in rats in a medium-term liver carcinogenicity bioassay. However, the effects of DPAA on other organs have not been determined. In the present study, the effects of DPAA on carcinogenesis were investigated using a rat multiorgan carcinogenicity bioassay. A total of 60 six-week-old male F344 rats were treated with the carcinogens diethylnitrosamine, N-butyl-N-(4-hydroxybutyl) nitrosamine, N-methyl-N-nitrosourea, N-bis (2-hydroxypropyl) nitrosamine, and 1,2-dimethylhydrazine dihydrochloride to initiate carcinogenesis in multiple organs. After initiation, DPAA was given at a dose of 0, 5, or 20 ppm in drinking water for 27 weeks. The incidences of moderate and severe bile duct hyperplasia were significantly increased in the 20 ppm DPAA group (29.4%, 70.6%, respectively) compared with the 0 ppm DPAA group (0%, 0%, respectively), and the incidence and multiplicity of cholangioma were significantly increased in the 20 ppm DPAA group (29.4%, 0.4 ± 0.8/rat) compared with the 0 ppm DPAA group (0%, 0/rat). The total number and average area of glutathione S-transferase placenta form-positive foci, preneoplastic lesions in rat livers, were significantly increased in the 20 ppm DPAA group (10.5 ± 2.2/cm2, 5.3 ± 1.7 mm2/cm2) compared with the 0 ppm DPAA group (6.2 ± 2.9/cm2, 2.4 ± 1.4 mm2/cm2). In conclusion, our results demonstrate that DPAA promotes hepatobiliary carcinogenesis in a rat medium-term multiorgan carcinogenicity bioassay; no promotion effects were observed in other organs.
Diabetes and salivary gland dysfunction are major factors that induce dental caries in experimental animals, but there are no reports analyzing the association of dental caries and salivary glands in an animal model of diabetes mellitus (DM). To clarify the initial development of dental caries and preceding salivary gland disorder, we performed a histopathological analysis on teeth and salivary glands in diabetic Wistar rats 7 weeks after alloxan treatment (DM group) in comparison with nondiabetic rats (Non-DM group) and functional analysis on saliva secretion during the experimental period. Pilocarpine-induced salivary fluid secretion in diabetic rats gradually decreased with continuous hyperglycemia from immediately after alloxan treatment to the time of autopsy. Histopathologically, Oil Red O-positive lipid droplets accumulated in the acinar cells of the parotid gland. No tooth was stereoscopically defined as having dental caries in any of the rats in either group; however, the external appearance remarkably changed owing to occlusal wear in almost all molars in the DM group. The initial lesions of dental caries, appearing as micro-defects in dentin with bacterial colonization on the molar surface, were identified using histopathological analysis, and the incidence in the DM group was more than twice that in the Non-DM group. In conclusion, hyperglycemia simultaneously induces initial caries development and enhances spontaneous occlusal wear in molar teeth of Wistar rats 7 weeks after alloxan treatment. The parotid gland dysfunction caused by hyperglycemia may be mostly involved in the pathogenesis of occlusal wear as well as in dental caries in this diabetic model.
Spontaneous massive infarction of mammary gland tumors has been reported to occur infrequently in humans. A subcutaneous mass (18 × 17 × 10 mm) was observed in the right axilla extending to the chest region of a 110-week-old female Wistar Hannover GALAS rat. Histopathologically, a well-circumscribed mass with lobular structures was present in the subcutis. Most of the mass was occupied by extensive coagulative necrosis of neoplastic cells with relatively uniform acinar and ductal structures. Although each necrotic acinar structure was separated by reticular fibers, periacinar stromal collagen fibers were not abundant. Considering the site of occurrence and histological features, the necrotic tissue was diagnosed as adenoma of the mammary gland. The necrotic region lacked hemorrhage and obvious inflammatory cell infiltration, indicating the necrosis was caused by infarction. Although multiple necrosis and focal infarction are occasionally observed in large-sized tumors in rodents, especially in adenocarcinomas, the present case was characteristic, with the massive infarction involving most parts of the tumor despite the relatively small size and low atypia of neoplastic cells. This is a rare case of spontaneous infarcted adenoma of the mammary gland in rats histologically resembling human cases.
A 152-week-old male Royal College of Surgeons (RCS) rat kept as a non-treated animal in a long-term animal study presented with a soft mass in the anterior mediastinum, which adhered to the pleura of the lung. Histopathologically, the mass mainly consisted of round to short spindle-shaped tumor cells that had infiltrated through the hyperplastic thymic tissue. The tumor cells were arranged in loose to dense sheets. Nuclei were moderate in size and round to spindle-shaped, with small nucleoli. Almost all tumor cells exhibited abundant eosinophilic cytoplasm, including eosinophilic granules of a range of sizes. The granules of tumor cells exhibited metachromasia with toluidine blue stain and were positive for c-kit and mast cell protease II. These findings indicate that the tumor described here represents a rare case of spontaneous malignant mast cell tumor with thymic epithelial hyperplasia.
The Spontaneously Diabetic Torii (SDT) rat is a rat model of nonobese type 2 diabetes mellitus, and hepatocellular adenomas have not been reported in this model. We report a hepatocellular adenoma with severe fatty change in a male 42-week-old SDT rat fed a high-fat diet. At necropsy, the animal had a whitish nodular mass of approximately 2 cm in diameter in the right medial lobe. Histologically, the mass was well demarcated from the surrounding tissues, slightly compressing the adjacent hepatic parenchyma and widely compartmented by fibrous connective tissues. The mass consisted of vacuolated tumor cells resembling hepatocytes with a solid and occasionally trabecular growth pattern. Abundant neutral lipids, which were positive for fat with Oil Red O stain and which ultrastructurally had moderately dense material, were contained within the vacuoles of the tumor cells. Immunohistochemically, the tumor cells showed an increase in immunoreactivity or number for Cytokeratin 8/18 and proliferating cell nuclear antigen but were negative for mesenchymal markers. From these findings, the mass could be distinguished from hepatocellular hyperplasia and was diagnosed as hepatocellular adenoma. In rats, hepatocellular adenoma accompanied by severe fatty change is rare, and this is the first report of a hepatocellular tumor with severe fatty change in a SDT rat.
Spontaneous hemangiosarcoma is generally uncommon in rats. Furthermore, there are only a few case reports in young rats. This report describes a spontaneous hemangiosarcoma in a young 7-week-old rat. At necropsy, no remarkable changes were noted in any organs including the liver. Histopathologically, multifocal small tumors were located mainly in the perilobular region of the liver. The tumors comprised polygonal to short spindle-shaped cells that showed cellular atypia and local infiltration. In the foci, there were blood-filled spaces lined by spindle-shaped cells. Reticular fibers, which were loosely connected together and formed an irregular network within the foci, were noticed with Azan and silver stain. Immunohistochemistry revealed that tumor cells expressed vascular endothelial cell markers: von willebrand factor and CD34, respectively. These features indicate that the tumor originated from vascular endothelial cells. Although the primary lesion was uncertain, the foci were all small and multicentrically located mainly in the perilobular region, indicating that the liver lesion likely formed by hematogenic metastasis. Taken together, we diagnosed this case as a metastatic hemangiosarcoma.
With the aims of sharing information about the technical aspects of immunohistochemistry (IHC) and making it possible to make a suitable choice of antibody for histopathological examination, this technical report describes the results of a questionnaire administered during the period of 2014 to 2015 to members of the Conference on Experimental Animal Histopathology. It also describes the immunological properties of primary antibodies (clone, supplier, catalog number, species reactivity, etc.) and the IHC staining conditions (fixing solution, fixing time, embedding, antigen retrieval method, antibody dilution, incubation time, incubation temperature, positive control tissue, secondary antibody information, etc.) for a total number of 733 primary antibodies (425 kinds of primary antibody).
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