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PubMed1991

[Haemorheological observation during the process of tumor development after subcutaneous transplantation of non-metastatic mouse lung adenocarcinoma P615].

The haemorheological changes during tumor development in mice with transplanted non-metastatic lung adenocarcinoma (P615) were studied. The tumor cells were injected subcutaneously into 615-strain inbred mice. Animals were sacrificed at days 5, 10, 20, 30 and 35. Each mouse was examined histologically and by haemorheological tests, including plasma viscosity, blood viscosity, haematocrit and aggregation of erythrocytes. The development of subcutaneous tumor was divided into 4 stages after transplantation according to the histological changes, namely, latent stage, proliferative stage, stage of cyst-formation and stage with central necrosis. The haemorheological investigation showed that, compared with the normal animals, plasma viscosity was elevated on days 5, 10, 20, and 35, but was normal at on days 30. The aggregation of erythrocytes showed no change in the whole process of tumor development. The haematocrit and blood viscosity decreased on days 30 and 35 (stage with central necrosis). The significance of the results were discussed.

Adenocarcinoma↗
PubMed2006

Pituitary tumor transforming gene overexpression facilitates pituitary tumor development.

Intrinsic and extrinsic stimuli result in profound pituitary growth changes ranging from hypoplasia to hyperplasia. Pituitary tumor transforming gene (PTTG) abundance correlates with pituitary trophic status. Mice with Pttg inactivation exhibit pituitary hypoplasia, whereas targeted pituitary PTTG overexpression driven by alpha-subunit glycoprotein (alphaGSU) promoter results in focal pituitary hyperplasia. To test the impact of pituitary hyperplasia on tumor development, we crossbred alphaGSU.PTTG with Rb+/- mice, which develop pituitary tumors with high penetrance. Pituitary glands of resulting bitransgenic alphaGSU.PTTGxRb+/- mice were compared with monotransgenic alphaGSU.PTTG, Rb+/-, and wild-type mice. Confocal microscopy showed that PTTG-overexpressing cells have enlarged nuclei and marked redistribution of chromatin, and electron microscopy of alphaGSU.PTTG pituitaries showed enlarged gonadotrophs with prominent Golgi complexes and numerous secretory granules. These morphological findings were even more remarkable in alphaGSU.PTTGxRb+/- pituitaries. Mice from all four genotypes were sequentially imaged by magnetic resonance imaging to evaluate pituitary volume, and glands from alphaGSU.PTTGxRb+/- mice were the largest as early as 2 months of age (P = 0.0003). Cumulative incidence of pituitary tumors visualized by magnetic resonance imaging did not differ between Rb+/- and alphaGSU.PTTGxRb+/- mice. However, anterior lobe tumors determined after necropsy were 3.5 times more frequent in alphaGSU.PTTGxRb+/- than in Rb+/- mice (P = 0.0036), whereas the frequency of intermediate lobe tumors was similar. In summary, alphaGSU.PTTGxRb+/- pituitary glands exhibit enhanced cellular activity, increased volume, and higher prevalence of anterior pituitary tumors, indicating that changes in pituitary PTTG content directly relate to both pituitary trophic status and tumorigenic potential.

Animals↗
PubMed1999

Metabolic targets of cancer chemoprevention: interruption of tumor development by inhibitors of arachidonic acid metabolism.

Tumor promotion is understood as a process that favors the clonal outgrowth of single mutated (initiated) cells to premalignant lesions through co-mitogenic and anti-apoptotic effects. This process can be evoked by repeated induction of a regenerative tissue response as achieved either by irritation and wounding or by agents (tumor promoters) that interact with the corresponding pathways of cellular signaling. Metabolic processes regulated by such pathways and essential for tumor development are potential targets of cancer chemoprevention. Examples are provided by the expression of ornithine decarboxylase and the activation of eicosanoid formation from arachidonic acid. Arachidonic acid metabolism is a particularly attractive and important target of chemopreventive measures. Its induction is a characteristic response to tissue damage and irritation and an apparently critical event in epithelial tumor promotion. Inhibitors of eicosanoid formation, such as nonsteroidal anti-inflammatory drugs, rank among the most powerful chemopreventive agents in animal models and have been shown to halve the incidence of colorectal cancer in man. Recently, the role of cyclooxygenase-2 (COX-2)-catalyzed prostaglandin synthesis has been the subject of much attention. COX-2 is a typical 'emergency enzyme', since in most tissues it is transiently induced only in the course of repair and defense reactions. In epithelial neoplasia, i.e. in skin and colorectal tumors, the enzyme is constitutively overexpressed along different molecular pathways, and it seems to be critically involved in tumor promotion. Consequently, specific COX-2 inhibitors have been shown to exhibit considerable cancer chemopreventive potential. The putative role of other pathways of arachidonic acid metabolism in tumor promotion and malignant progression is presently under investigation.

Animals↗
PubMed2005

Control of genomic instability and epithelial tumor development by the p53-Fbxw7/Cdc4 pathway.

Mouse models of cancer have provided novel insights into the timing of p53 loss during tumorigenesis. We have recently identified Fbxw7/Cdc4 as a downstream target of p53 loss that controls genomic instability and tumor development in epithelial tumors. Although p53-deficient mice primarily develop lymphomas and sarcomas, the additional loss of one copy of the Fbxw7 gene drives tumor development in a range of epithelial tissues. These data highlight the importance of genetic instability at the chromosome level in the development of common cancer types, and further illustrate the value of mouse models in identifying causal genetic events in epithelial tumor formation.

Animals↗
PubMed1978

Immunization of mice against murine mammary tumor virus infection and mammary tumor development.

Formalin-inactivated whole murine mammary tumor virus (MuMTV), VuMTV membranes, the acid-soluble component of MuMTV, and purified MuMTV glycoprotein with a molecular weight of 55,000 (gp55; also designated as gp52) were used as vaccines in an attempt to identify the MuMTV antigen(s) that can protect mice from exogenous MuMTV infection and subsequent tumor development. Formalin-inactivated whole MuMTV, MuMTV membranes, and purified MuMTV gp55 were effective immunogens, whereas the acid-soluble component of MuMTV (which consists mainly of MuMTV gp55) failed to protect mice from challenge with live virus. These results suggest that (a) MuMTV gp55 is the major immunizing antigen and (b) its native conformation must be maintained for it to be an effective vaccine.

Acids↗
PubMed2001

Phenotypic expression of colorectal adenocarcinomas with reference to tumor development and biological behavior.

The purpose of this study is to clarify the correlation between cell differentiation and tumor development, including tumor aggressiveness and biological behavior. Eighty-three cases of advanced colorectal adenocarcinoma were randomly selected. Using immunohistochemical staining with antibodies to CD10, MUC2 and human gastric mucin (HGM), the colorectal adenocarcinomas could be classified into five types (18 small intestinal, 27 large intestinal, 2 gastric, 9 mixed and 27 unclassified). Each type had characteristic features. The small-intestinal type showed a relatively lower incidence of lymphatic permeation and higher venous invasion. The large-intestinal type showed a low incidence of venous invasion and lymph node metastasis. The mixed type revealed female and right-side-dominant distribution, large tumor size, high incidence of mucinous carcinoma, and low incidence of venous invasion. Gastric type was seen in only two cases (2%), which exhibited high histologic grade, lymphatic permeation and lymph node metastasis with no venous invasion. Such phenotypic classifications are considered to be useful not only for evaluation of the biological behavior of the carcinoma, but also for analysis of tumorigenesis.

Adenocarcinoma↗
PubMed2003

Loss of PTEN promotes tumor development in malignant melanoma.

Loss of tumor suppressor genes on chromosome 10 plays an important role in the development of 30-60% of melanomas; however, the identity of these genes and the mechanisms by which loss of these genes leads to tumor formation remain uncertain. The phosphatase and tensin homologue deleted from chromosome 10 (PTEN) is one of the genes on chromosome 10 whose of which the loss or inactivation may play an important role in melanoma tumorigenesis, but functional studies directly demonstrating PTEN involvement in melanomas are necessary to confirm this role. To determine the biological importance of PTEN loss in melanomas, we established a novel model in which an intact chromosome 10 was transferred into melanoma cells lacking PTEN protein to express the protein at normal physiological levels and to measure the consequent effects on melanoma tumorigenesis. PTEN expression in these cells retarded tumor development in mice unless, by analogy with loss of heterozygosity, the PTEN gene was deleted or inactivated during tumor formation. Mechanistically, PTEN loss led to the activation of Akt, which consequently down-regulated the apoptotic pathway of melanoma cells. In contrast, expression of PTEN attenuated Akt activation, thereby increasing sensitivity to apoptotic stimuli in cell culture and in vivo in animal models. This model demonstrated that PTEN loss is critical for melanoma tumorigenesis and allowed a dissection of the underlying mechanism by which PTEN loss facilitated melanoma tumor development. In summary, loss of PTEN reduces apoptosis and promotes cell survival, thereby favoring melanoma tumor formation. Thus, these observations provide an etiological basis for PTEN loss during the genesis of sporadic melanomas.

Apoptosis↗
PubMed1999

ras activity and cyclin D1 expression: an essential mechanism of mouse skin tumor development.

ras is a family of small GTP-binding proteins that transduce signals from tyrosine-kinase receptors to the nucleus and thus play a role in the regulation of cell proliferation and differentiation. Several lines of evidence have shown that the cell-cycle machinery, specifically the circuit cyclin D1/cyclin-dependent kinase (cdk) 4 and 6-p16-pRb, lies downstream of ras. Point mutations that activate the ras protein and its downstream cascade have been observed in human and experimental tumors. In particular, ras mutations have been well characterized in the mouse skin two-stage carcinogenesis model, and a large body of literature has indicated that initiation with the genotoxic carcinogen 7,12-dimethylbenz[a]anthracene induces a specific point mutation in Ha-ras gene in this model. In the last few years, several studies have shown a correlation between ras activation and alterations in the expression of cyclin D1 as well as other cell cycle-regulated proteins, but the actual role of these alterations in tumor development had not been determined until a recent study provided genetic and biochemical evidence that cyclin D1 is a critical target of oncogenic ras in mouse skin carcinogenesis. Here we review these results, including the evidence that cyclin D1 has a role as a downstream mediator of ras activity during tumor development. We propose a model in which cyclin D1 has a unique growth-promoting role in tumor development but does not act as an oncogene independently of ras activity.

Animals↗
PubMed1998

Estrogen treatment enhances hereditary renal tumor development in Eker rats.

Hormonal influences are known to affect the development of renal cell carcinoma in man and laboratory animal models. We tested the hypothesis that estrogen treatment or ovariectomy of rats modulates renal tumor development using tuberous sclerosis 2 (Tsc2) heterozygous mutant (Eker) rats in which a germline mutation predisposes the animals to renal cell tumor development. Two-month-old female wild-type and Eker rats were ovariectomized or sham-operated and treated with placebo or 5 mg 17beta-estradiol in s.c. pellets for 6 or 10 months. Rats were examined at 8 or 12 months of age, at which time the numbers of renal tumors and preneoplastic foci were quantitated and the severity of nephropathy was assessed. In contrast to what may have been expected, prolonged estrogen treatment enhanced the development of hereditary renal cell tumors, with a 2-fold greater number of preneoplastic and neoplastic renal lesions compared with untreated Eker rats. Ovariectomized Eker rats had 33% fewer renal lesions than the unmanipulated control group. No tumors or preneoplastic lesions were present in wild-type rats at either time point. Estrogen treatment increased the severity of nephropathy in both wild-type and Eker rats, whereas ovariectomy was protective against nephropathic changes. Although estrogen is not a rat renal carcinogen, it enhanced the development of hereditary renal cell tumors when administered to Eker rats. Eker rats heterozygous for a mutation in the Tsc2 locus provide a good model in which to study how genetic and hormonal factors contribute to the development of renal cell tumors and to understand the influence genetic susceptibility has on the development of renal cell carcinoma.

Animals↗
PubMed2005

Deregulation of DNA methyltransferases and loss of parental methylation at the insulin-like growth factor II (Igf2)/H19 loci in p53 knockout mice prior to tumor development.

To ascertain whether p53 deficiency in vivo leads to the deregulation of DNA methylation machinery prior to tumor development, we investigated the expression profile of DNA methyltransferases in the thymus and the liver of p53(+/+), p53(+/-), and p53(-/-) mice at 7 weeks of age before tumor development. The expression of DNA methyltransferases was examined in the thymus at 7 weeks of age, since the malignant T-cell lymphoma develops most frequently in p53(-/-) mice around 20 weeks of age. Both mRNA and protein levels of Dnmt1 and Dnmt3b were increased in the thymus and the liver of p53-deficient mice. The expression of Dnmt3a was also increased in the liver but not in the thymus of p53-deficient mice. Dnmt3L expression was reduced in the thymus of p53(+/-) and p53(-/-) mice. The total 5-methylcytosine (5-MeC) in the genomic DNA of p53(+/+), p53(+/-), and p53(-/-) mice was quantitated by dot-blot using antibody against 5-MeC. Global methylation was increased in the thymus and the liver of p53-deficient mice. To correlate the deregulated expression of DNA methyltransferases with the disturbance of the epigenetic integrity, we examined the DNA methylation of the imprinting control region (ICR) at the insulin-like growth factor II (Igf2)/H19 loci in the thymus and the liver of p53(+/+), p53(+/-), and p53(-/-) mice. The region containing two CCCTC binding factor (CTCF) binding sites in the 5'-ICR tended to be hypomethylated in the thymus of p53(-/-) mice, but not in the liver. The expression profile of Igf2 and H19 indicated that the thymus-specific changes of Igf2 and H19 expression were coherent to the hypomethylation of the ICR in the thymus. Our results suggest that p53 is required for the maintenance of DNA methylation patterns in vivo.

Animals↗
PubMed2006

Juvenile syndecan-1 null mice are protected from carcinogen-induced tumor development.

We previously showed that mice with a null mutation in syndecan-1 (Sdc1; CD138) were resistant to Wnt1-induced mammary tumor initiation. The absence of Sdc1 inhibited the increase in the mammary stem cell fraction that is characteristic of preneoplasia in this model. As the tumor precursor cells are recruited from the stem/progenitor cell compartment, tumor development was also inhibited (Liu et al., 2004; PNAS 101, 4158). Although Sdc1-/- mice are grossly normal, they are systemically smaller, suggesting that developmental abnormalities may extend further than their mammary glands. We have therefore evaluated the multi-organ response of Sdc1-/- mice to carcinogen-induced tumor development (7,12-dimethylbenz[a]anthracene, DMBA), and find these mice to be resistant to tumorigenesis in all the predominant carcinogen-susceptible lineages. Thus, Sdc1-/- mice administered DMBA during juvenile development are resistant not only to epithelial tumors, including liver (60-80%) and lung tumors (C57BL6 mice, 60-80%), but also to lymphoma (over 70%, depending upon strain and carcinogen dose). We demonstrate that CD138 is expressed (heterogeneously) in the hematopoietic stem cell fraction (and not only in pre-B and plasma cells), and that tumors arise in both myeloid and lymphoid lineages. Furthermore, carcinogen-induced mammary tumors are bilineal, implying a bipotent precursor cell. Both observations imply that the DMBA-induced tumor precursor cells are drawn from the stem/progenitor fraction, and we suggest that pathogenic activation of these cells could be abnormal in Sdc1-/- mice.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Estrogen binding component in the pilosebaceous tumor developed in Suncus murinus.

We transplanted a pilosebaceous tumor developed on the sidegland of Suncus murinus to male nude athymic (BALB/c-nu/nu) mice. This tumor can be transplanted to female hosts as well, with a lower rate of graft-taking and slower growth rate. In this study we demonstrated the presence of macromolecules which specifically bind to estrogen. Measurement of 17 beta-estradiol (E2) binding by a dextran-coated charcoal assay revealed that the number of binding sites and the dissociation constant were 22.3 +/- 4.6 fmol/mg protein and 1.4 +/- 0.24 X 10(-9) M, respectively. This binding was specific for E2 and diethylstilbestrol (DES). Sucrose gradient centrifugation of the [3H]E2-labeled cytosol yielded a sharp peak of radioactivity at 3.5S-4S under high salt conditions and a 9S peak with a shoulder at 3.5S under low salt conditions. This 3.5S shoulder was due to dissociation of [3H]E2 from the 9S peak during the centrifugation, since only the 9S peak was obtained by postlabeled density gradient analysis. An assay of the in vivo binding of [3H]E2 showed significant radioactivity in the nuclear extract from the tumor. This nuclear uptake was markedly decreased by simultaneous administration of 100-fold excess of E2. In tumor-bearing castrated nude mice, 1-100 micrograms/day of E2 did not affect tumor growth, whereas it counteracted the stimulative effect of testosterone propionate.

Animals↗
PubMed1999

KDR/Flk-1 is a major regulator of vascular endothelial growth factor-induced tumor development and angiogenesis in murine hepatocellular carcinoma cells.

Vascular endothelial growth factor (VEGF), which is one of the most potent angiogenic factors, has been shown to play a pivotal role in tumor angiogenesis, including hepatocellular carcinoma (HCC). The effects of VEGF are mediated mainly through two distinct receptors, flt-1 and KDR/Flk-1. It has been suggested that KDR/Flk-1 plays an important role in tumor development. However, the role of KDR/Flk-1 in HCC has not been examined. We previously reported that VEGF tightly regulated murine HCC development, based on the results of a study using a retroviral tetracycline-regulated (Retro-Tet) gene expression system. This system allows VEGF gene expression to be manipulated in vivo by providing tetracycline in the drinking water. In the present study, we combined the KDR/Flk-1-specific neutralizing monoclonal antibody (KDR/Flk-1mAb) and the Retro-Tet system to elucidate the role of KDR/Flk-1 in VEGF-induced tumor development and angiogenesis in a murine HCC experimental model. In a xenograft study, tumor augmentation induced by VEGF overexpression was almost abolished by means of KDR/Flk-1mAb treatment, with accompanying inhibition of angiogenesis, KDR/Flk-1 autophosphorylation, but not interference of flt-1 activation. This inhibitory effect was achieved even on established tumors and regardless of whether the tumor size was small or large. On the contrary, KDR/Flk-1mAb treatment significantly increased the apoptosis in the tumor. With orthotopic transplantation, KDR/Flk-1mAb also inhibited HCC development in the liver. These results suggest that KDR/Flk-1 is a major regulator of VEGF-mediated HCC development and angiogenesis not only at the initial stage, but also after the tumor has fully developed.

Animals↗
PubMed2005

The rac activator Tiam1 is a Wnt-responsive gene that modifies intestinal tumor development.

Mutations in the canonical Wnt signaling pathway leading to its activation are known to cause the majority of intestinal tumors. However, few genes targeted by this pathway have been demonstrated to affect tumor development in vivo. Here we show that Tiam1, a selective Rac GTPase activator, is a Wnt-responsive gene expressed in the base of intestinal crypts and up-regulated in mouse intestinal tumors and human colon adenomas. Moreover, by comparing tumor development in APC mutant Min (multiple intestinal neoplasia) mice expressing or lacking Tiam1, we found that Tiam1 deficiency significantly reduces the formation and growth of polyps in vivo. However, invasion of malignant intestinal tumors is enhanced by a lack of Tiam1. In line with this, knock-down of Tiam1 reduced the growth potential of human colorectal cancer cells and their ability to form E-cadherin-based adhesions, a prerequisite for local invasion of tumor cells. Our data indicate a novel cross-talk between Tiam1-Rac and canonical Wnt-signaling pathways that influences intestinal tumor formation and progression.

Adenoma↗
PubMed1996

Alterations in expression of CYP1A1 and NADPH-cytochrome P450 reductase during lung tumor development in SWR/J mice.

We investigated the expression of the cytochrome P450 isozyme, CYP1A1, during the course of tumor development and examined the distribution of the CYP1A1 protein in hyperplastic foci, adenomas and carcinomas. The expression of NADPH-cytochrome P450 reductase, a flavoprotein that mediates the reduction of cytochrome P450, was also determined. Mice were administered urethane (1 mg/g body wt) and were killed at 10, 22 and 52 weeks to coincide with the time at which hyperplastic foci, adenomas and carcinomas were established, respectively. Protein immunoblotting revealed that the antibody for CYP1A1 detected a protein band of approximately M(r) 56,000 in microsomes from mice treated with beta-naphthoflavone. The antibody for NADPH-cytochrome P450 reductase detected a protein band of approximately M(r) 79,000 in microsomes from control mice and mice treated with beta-naphthoflavone. Immunohistochemical studies showed that CYP1A1 was not detected constitutively in the lungs of both non-tumor- and tumor-bearing mice. Treatment with beta-naphthoflavone evoked high induction of CYP1A1 in morphologically normal tissues of all mice, with localization of the protein mainly in endothelial and alveolar type II cells. In contrast, inducibility of CYP1A1 by beta-naphthoflavone was markedly reduced in early hyperplastic foci seen 10 weeks after urethane exposure. At 22 weeks, CYP1A1 was found at low levels in both solid and papillary tumors, whereas at 52 weeks, lung carcinomas were devoid of expression of this protein. However, CYP1A1 inducibility was highly expressed in late hyperplastic foci manifested at 52 weeks. NADPH-cytochrome P450 reductase was expressed in morphologically normal lung tissue of all mice under control conditions and after treatment with beta-naphthoflavone, and was localized mainly in Clara and alveolar type II cells. In contrast, reductase expression in all tumor sites was diminished and closely paralleled that of CYP1A1. These results demonstrated progressive depression of induced CYP1A1 and reductase expression in early hyperplasias, adenomas and carcinomas, suggesting that the co-ordinate regulation of both enzymes is highly conserved during tumor development. Furthermore, these findings suggested diminished capabilities for metabolic activation of potential toxicants and/or carcinogens after neoplastic transformation.

Animals↗
PubMedDate not supplied

Stage-dependent expression of an angiogenic agent and vascular organization in experimental skin tumor development.

Increased angiogenesis and expression of antibodies to vascular endothelial growth factor (VEGF), an angiogenic agent, have been shown in the tumor development of many tissues. Areas of skin expressing VEGF and total volume of vessels expressing laminin in the wall were measured in chemical carcinogen-exposed mice using CAS-200 morphometry apparatus having a sensitivity exceeding 99% and reproducibility exceeding 99%. The area of VEGF expression was increased in carcinogen-exposed skin, dysplasia and in well-differentiated squamous cell carcinomas, but decreased in squamous cell carcinomas with decreased degree of differentiation. The vessel volume increased prior to the formation of tumors in carcinogen-exposed skin as well as in highly malignant neoplasms. In well-differentiated squamous cell carcinomas with an expansive growth pattern, the vessels were parallel to the basal membrane, in moderately differentiated tumors the vessels were in the direction of tumor invasion, and in poorly differentiated tumors, active angiogenesis consisted of numerous, enlarged vessels within the tumor. This study showed increased VEGF expression and number of vessels occurring in early stages of skin tumor development, pointing to a role of angiogenesis in chemical risk assessment and in cancer prevention. Altered vessel structure and vessel arrangement were distinct in later stages of tumor growth and in malignant neoplasms, pointing to the utility of detailed vessel analysis in neoplasm characterization.

Animals↗
PubMed2003

p27 deficiency desensitizes Rb-/- cells to signals that trigger apoptosis during pituitary tumor development.

Low p27 expression in many human cancers is a prognostic indicator for poor outcome. While analysing the mechanism by which p27 deficiency contributed to tumor development in the Rb+/- mouse model, we identified a role for p27 as a proapoptotic tumor suppressor. We examined the cell cycle and apoptotic response of these pituitary tumor cells to the dopamine analog bromocriptine as well as the expression of Arf and other cell cycle and apoptotic regulators in these tumors. We also examined the expression of Arf and its function in mouse embryo fibroblasts either singly or doubly deficient for Rb and p27. From these studies, we concluded that the absence of p27 disabled the trigger for an Arf-dependent apoptotic response in Rb-/- tumor cells. This suggests a novel mechanism by which the loss of p27 may impact on tumor development.

Animals↗
PubMed1989

Life-span studies on spontaneous tumor development in the medaka (Oryzias latipes).

A total of 961 medaka, separated chronologically from the first to the fifth year of life, were examined for spontaneous tumor development. While no liver tumors were found in either male or female medaka under the age of 1 year and the incidence in 2-year-old fish was relatively low (males 1.9% and females 1.7%), they became more common with advancing age. The incidence was higher in females than in males from 3 to 5 years of age, reaching 7.1% in 5-year-old female stock. These liver tumors included a total of 12 adenomas and 9 hepatocellular carcinomas. The hepatocellular carcinomas were histologically well differentiated and were all observed in female medaka. Spontaneous tumors occurring in organs other than the liver were rare and sporadic. Four squamous cell carcinomas, 5 melanomas and 4 lymphosarcomas were observed with no sexual or pronounced age bias being evident. The squamous cell carcinomas developed in the surface epithelium with local invasion into the dermis. Melanomas occurred in the abdominal cavity and demonstrated systemic invasion into various parts of the body. Three out of the 4 lymphosarcomas arose from the inner part of the operculum suggesting that these tumors were of thymic origin. They also showed extensive invasion. The data indicate a particular susceptibility of older female medaka to liver but not other tumor development.

Adenoma↗