Alterations in glycoproteins and lipids in azaserine-induced acinar cell carcinoma of rat pancreas

Glycoproteins and lipids of rat pancreatic acinar cell carcinomas maintained in nude mice and in cell culture, were analyzed. The tumor contained significantly elevated levels of glycoproteins when compared with their normal counterparts. SDS-PAGE of tumor glycoproteins revealed that there were increased amounts of small molecular weight glycoproteins and the tumor also contained a 51,000 dalton glycoprotein which was not detected in the pancreas, liver or the sera of the control animals. The tumor in nude mice and cancer cells in culture had decreased lecithins and triglycerides, and increased amounts of free fatty acids, and both free and esterified cholesterols. The results indicate that altered glycoprotein and lipid compositions represent some of the characteristic features of the acinar cell carcinoma.     

Focal acinar cell dysplasia in human pancreas

A series of 108 prospectively collected human pancreata were evaluated histologically for the presence of acinar cell and ductal lesions. Foci of dysplastic acinar cells were present in 44% of the series. Some of the focal acinar cell abnormalities were similar to atypical acinar cell nodules which have been described in carcinogen-treated experimental animals. The incidence of nodules was higher among patients with a history of heavy cigarette smoking than among nonsmokers, and among patients with a history of alcohol abuse than among abstainers. The presence of dysplastic acinar cell nodules in a pancreas seemed unrelated to the presence of cancer in other sites, or diabetes. Ductal epithelial abnormalities were more frequent than focal acinar cell dysplasia.     

Characterization of a rat oral squamous cell carcinoma cell line UHG-RaC '93 induced by 4-nitroquinoline-1-oxide in vivo

This study describes several characteristics of a cell line,UHG-RaC '93 derived from rat oral squamous cell carcinoma inducedby the carcinogen 4-nitroquinoline-1-oxide (4NQO). The cellline was established from explant cultures without support offibroblast feeder cells and continued for > 30 passages.UHG-RaC '93 had a high mitotic rate with a population doublingtime of 25 h and a high rate of squame production. The firstpassage had a low colony-forming efficiency in agarose gel,whereas later passages did not grow at all in semi-solid medium.Phenotype selection was furthermore apparent from a gradualincrease of the trypsin-detachment time. Cytogenetic analysisshowed that UHG-RaC '93 was hypotetraploid with an average of74 chromosomes. Abnormalities compared to the normal karyotypewere assessed and consisted mainly of breakpoints at (1)(q5?3),(3)(p1), (3)(q11q23), (11)(p?11), (13)(p13) and a derivative(12)t(12;13)(q10;q10). The karyotype remained stable for atleast 26 passages. The expression of typical epithelioid markerslike cytokeratins and desmoglein corresponded with normal ratoral keratinocytes. However expression of 6ß4-integrinwas altered. Squame production, immunophenotype and anchoragedependency indicated that UHG-RaC '93 had the same featuresof a well-differentiated carcinoma with a low degree of agressivenessas the original tumour. The stable karyotype of this cell lineprovides a basis for further analysis of the effect of 4NQOon the genotype, phenotype and behaviour of rat oral keratinocytes.     

Expression of beta-catenin in rat oral epithelial dysplasia induced by 4-nitroquinoline 1-oxide

The aim of this study was to evaluate whether beta-catenin accumulation is useful for diagnosing the malignant potential of oral precancerous lesions. We investigated oral epithelial dysplasia adjacent to early cancer induced by 4-nitroquinoline 1-oxide in rats. Localization of beta-catenin and cell proliferation were detected immunohistochemically, and exon 3 of the beta-catenin gene was analyzed. Accumulation of beta-catenin in the cytoplasm and nucleus was evident in 10 of 16 dysplasia lesions. Since almost all of the dysplastic lesions in these rats transformed to invasive cancer, beta-catenin accumulation may contribute to the early stage of carcinogenesis. The Ki-67 labeling index was significantly higher in dysplasia and early cancer than in no change. However, there were no significant differences between the expression patterns of beta-catenin protein, suggesting that other proliferation pathways are involved in the early stage of tumor development in addition to beta-catenin accumulation. No mutations of exon 3 of the beta-catenin gene were detected in any of the dysplasia or early cancer lesions. These findings suggested that beta-catenin accumulation in the cytoplasm and nucleus without mutation of exon 3 is an early event during carcinogenesis in this tongue cancer model.     

Atypical and neoplastic acinar cell lesions of the pancreas in an autopsy study of Japanese patients

A histopathologic examination of the pancreas was performed on a series of adult Japanese autopsies. In ten of 162 pancreases (6%) with adequate tissue available, two types of focal atypical acinar cell lesions, composed of acidophilic or basophilic cells, were found. Acidophilic atypical acinar cell lesions were more frequent than basophilic ones, although the one case of acinar cell adenoma and two cases of acinar cell carcinomas showed high incidences of basophilic atypical acinar cell lesions. The findings are concluded to support the possibility that atypical acinar cell lesions are precursors for acinar cell carcinomas.     

Production of pancreatic acinar cell carcinoma by combined administration of 4-hydroxyaminoquinoline 1-oxide and azaserine in partial pancreatectomized rats.

The effect of azaserine on the pancreatic tumorigenesis of 4-hydroxyaminoquinoline 1-oxide (4-HAQO) after partial pancreatectomy in rats was studied. Pancreatic acinar cell carcinomas were produced in 7 out of 10 rats (70%), which received 7 mg/kg body wt. 4-HAQO 3 days after partial pancreatectomy, followed by 10 weekly injections of 30 mg/kg body wt. azaserine. Partial pancreatectomy enhanced the carcinogenesis of 4-HAQO, which was further promoted by azaserine.     

Kinetics of induction and growth of putative precancerous acinar cell foci in azaserine-induced rat pancreas carcinogenesis

The kinetics of induction and growth of acinar cell lesions has been investigated in rat pancreas after a single dose of the carcinogen azaserine. The time--response relationship was studied in male Wistar-related rats given a single i.p. injection of 30 mg L-azaserine/kg body weight at 18 days of age. Rats were killed between 4 and 78 weeks after treatment and ATPase-stained pancreas sections were quantitatively evaluated for the number and size of acidophilic, ATPase-positive and basophilic, ATPase-deficient foci. The number of acidophilic foci remained constant from 8 weeks onwards, while the number of basophilic foci slightly increased with time. The size of both acidophilic and basophilic foci increased throughout the experimental period. Due to two times higher number/cm3 and faster growth of the acidophilic foci, four times more acidophilic than basophilic focus tissue was present at the end of the experiment. Progression of acidophilic foci to adenomas and carcinomas was occasionally seen at later time points (greater than 34 weeks) in this rat strain. The dose--response relationship was studied in male and female Sprague--Dawley rats given a single i.p. injection of 0-45 mg azaserine/kg body weight at 19 days of age. Rats were autopsied at 17 weeks after treatment, and pancreas sections were quantitatively evaluated after ATPase histochemistry. The relationship between dose and number of foci was linear up to 30 mg/kg azaserine for both acidophilic and basophilic foci in males and females. For each individual dose, the number of foci induced was the same in males and females, and there were two to three times more acidophilic than basophilic foci. The percentage of pancreatic tissue occupied by focus tissue was 1.75 times higher in males, pointing to a higher growth-potential of acidophilic foci in males than in females. The first-order dose--response kinetics indicate that the conversion of a normal acinar cell into a focus-forming cell occurs by one specific azaserine-mediated rare event, occurring probably at the genetic level of the target cell.     

胰腺腺泡细胞癌的CT表现

背景与目的：胰腺腺泡细胞癌(acinar cell carcinoma of the pancreas,ACCP)是一种罕见的胰腺恶性肿瘤,相关的影像学报道较少。该研究旨在探讨ACCP的CT表现。方法：收集自2011年1月-2014年1月经手术病理证实为ACCP的9例患者资料,回顾性分析其CT征象。结果：在9例ACCP患者中,肿块最大径均值为52 mm,肿瘤边缘不清的6例(66.7%),外生型生长者有6例(66.7%),强化程度低于正常胰腺组织者8例(88.9%),强化不均者6例(66.7%),累及血管者7例(77.8%),淋巴结转移者5例(55.6%),无出现肝转移病例,仅1例出现胰管扩张。结论：较大体积的乏血供胰腺肿块,内部异质性明显,呈外生型生长而无显著胰管扩张时,提示ACCP的可能。     

Alteration of pRb expression in the development of rat tongue carcinoma induced by 4-nitroquinoline 1-oxide

We investigated the immunohistochemical expression of Rb protein (pRb), which plays an important role in the regulation of the cell cycle, in rat tongue carcinoma induced by 4-nitroquinoline 1-oxide. In addition, we made an immunohistochemical investigation of cyclin D1 and cdk4, which are involved in the Rb pathway. The labeling index of pRb expression in cases with carcinoma was significantly decreased compared with that in cases with a premalignant lesion (P<0.01), while the labeling index of cyclin D1 and cdk4 increased gradually during the course of carcinogenesis. We analyzed the phosphorylation of pRb by immunoblotting using G3-245 monoclonal antibody, which recognizes both the phosphorylated and unphosphorylated forms of pRb. Although expression of the phosphorylated pRb band was notably increased in dysplastic membrane compared with the control membrane, it almost disappeared in cases with carcinoma. Unphosphorylated pRb bands were also expressed in control membrane and dysplastic membrane but not in cases with carcinoma. In conclusion, a decrease of pRb and an increase of cdk4 and cyclin D1 were shown to occur during the premalignant stage. The decrease of pRb in quantity and the increase of its phosphorylation may prevent G1 arrest and consequently accelerate proliferation of the chemically injured cells contributing to the initiation of carcinogenesis.     

Differentiation of muscarinic cholinergic receptors in acinar carcinoma of rat pancreas

Analysis of muscarinic cholinergic receptors in pancreatic acinar carcinoma of rat by measurement of N-[methyl-3H]scopolamine binding has revealed a single homogenous population of muscarinic receptors in the tumor. The plasmalemma density (approximately 25 receptors/micron 2 of cell membrane surface) and dissociation constant (approximately 0.4 nM) of muscarinic receptors in acinar carcinoma cells are identical to the density and affinity of muscarinic receptors in normal acinar cells of rat pancreas. Muscarinic receptors in the carcinoma are functionally linked to cholinergic stimulation of cellular Ca2+ release. An equivalent number of functional muscarinic receptors is present in poorly differentiated carcinoma cells which are deficient in zymogen granules and protein secretion, as compared to well-differentiated carcinoma cells which contain granules and secrete protein in response to cholinergic stimulation. These observations indicate that muscarinic cholinergic receptors are displayed in normal fashion on tumor membranes and are fully expressed in carcinoma cells regardless of their degree of secretory development. Expression of muscarinic cholinergic receptors is thus a stable phenotypic property of pancreatic acinar carcinoma cells. This suggests that muscarinic receptor maturation is an early event in the differentiation of pancreatic exocrine cells, preceding acquisition of secretory responsiveness to cholinergic stimulation.     

Differential expression of cytokines in rat osteosarcoma and malignant fibrous histiocytoma cell lines induced by 4-(hydroxyamino)quinoline-1-oxide

Cytokines are considered to play an important role in tumor pathogenesis and progression, and recent studies have demonstrated that a variety of forms, including interleukins (ILs) and transforming growth factor-beta(s) (TGF-beta(s)), may regulate tumors. In the present study, the expression of TGF-beta isoforms and ILs was investigated in cell lines from a rat osteosarcoma and a malignant fibrous histiocytoma (MFH), both established from transplantable tumors induced by 4-(hydroxyamino) quinoline 1-oxide (4-HAQO) in syngeneic F344 male rats. The results of a multiprobe RNase protection assay showed TGF-beta1 expression to be remarkably elevated, with no TGF-beta2 and beta3 detectable in MFH cells, while TGF-beta1 and -beta2 were found to be moderately and TGF-beta3 weakly expressed in osteosarcoma lines. All cell lines of osteosarcomas and MFHs expressed macrophage migration inhibitory factor at similar levels. In contrast to the lack of ILs in the MFH cells, moderate IL-6 and very weak IL-1beta expression was detected in the osteosarcoma cells. These results suggest that variation in expression pattern of these cytokines in osteosarcomas and MFHs might be involved in differences in histological appearance and biological behavior, including metastatic ability, between these two mesenchyme-derived tumor types.     

An experimental recurrence model for malignant fibrous histiocytoma induced by 4-hydroxyaminoquinoline 1-oxide in the rat

To clarify the relationship between local recurrence of mesenchymal tumors and their malignant potentiality, we made an experimental recurrence model for malignant fibrous histiocytoma (MFH) induced by 4-hydroxyaminoquinoline 1-oxide in the rat by repeated exicisional operations. By the repeated exicision, the number of recurrent tumors increased, and the doubling time of tumor growth was shortened. The mean doubling time of primary tumors was 6.6 days, that of the first locally recurrent tumors was 4.3 days, and that of the second locally recurrent tumors was 3.3 days. However, mitotic count and 5-bromo-2-deoxyuridine (BrdU) labeling index did not change. this study proved experimentally that MFH shows more rapid growth through repeated local recurrences, and this experimental model may provide a better understanding of the local recurrence of MFH. © 1993 Wiley-Liss, Inc.