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PubMed1987

Appearance of serum antibodies to rat yolk-sac carcinomas during the latent period prior to primary tumor development.

Rat yolk-sac tumors were induced by intraperitoneal (i.p.) displacement of the visceral yolk sac in fetectomized W/Fu rats. Serum was obtained from each female rat prior to the pregnancy preceding the tumor-inducing procedure and then once a month during the induction period. The sera were analyzed for the presence of antibodies binding to cultured cells of one of the yolk-sac tumors. Sera were also assayed for complement-dependent cytotoxic antibodies on tumor cells. In rats that developed tumors, antibodies reacting specifically with the target tumor cells could be detected in all of 10 rats. Antibodies appeared before tumor detection in all animals but one, and in 6 rats as early as 11 to 25 weeks prior to tumor detection. Nine rats developed antibodies demonstrable in the binding assay and in 6 of those the antibodies appeared 8 to 25 weeks before the tumor became palpable. Analysis of the isotypes of the Ig that bound to tumor cells showed that IgG1 and IgG2b were most frequently present. In one rat IgG2a antibodies appeared one month before tumor detection followed by IgG1 and IgG2b antibodies detectable 4 weeks later. IgG2c and IgM antibodies were not detected in any of the rats. At dilution 1/10, sera of all 10 rats showed specific cytotoxicity to the tumor cells in the presence of added rabbit complement. In 9 of these animals antibodies were demonstrated 1 to 4 months prior to tumor detection.

Animals↗

PubMed1986

Inhibition of mouse lung tumor development by hyperoxia.

The hypothesis was tested that continuous hyperoxia would enhance the development of lung tumors in mice. In strain A/J mice treated with a single dose of urethan (1000 mg/kg) and exposed to 70% O2 for 16 wk, an average of 5 tumors per lung developed, whereas in animals kept in air, an average of 20 tumors per lung was found. When the animals were returned to air after oxygen exposure, it was found that a difference of 15 tumors per lung between the two groups persisted up to 1 yr later, indicating that O2 was tumoricidal. The shortest duration of O2 exposure to be effective was 4 wk, and delay of O2 exposure up to 12 wk after urethan still was effective in reducing the number of developing tumors. Histopathology showed that continued exposure to 70% O2 produced some hyperplasia of the bronchiolar epithelium and only very discrete changes in the pulmonary parenchyma. Analysis of cell proliferation patterns with a continuous [3H]thymidine labeling technique showed a persistent high cell labeling in the bronchiolar epithelium and a temporary increase in alveolar wall cell labeling. Chronic hyperoxia failed to alter the activities of pulmonary superoxide dismutase or glucose-6-phosphate dehydrogenase. Ornithine decarboxylase, on the other hand, was increased as long as the animals remained exposed to oxygen. It was concluded that hyperoxia kills developing tumor cells in mouse lung.

Animals↗

PubMed1990

Effects of dietary fat and protein on DMH-induced tumor development and immune responses.

Although in three different mouse tumor systems with corn oil as dietary fat we previously found that milk protein decreased tumor development compared with beef, the results were reversed in 1,2-dimethylhydrazine (DMH)-injected mice. The purpose of this study was to determine if the latter result was due to the protein source. BALB/c mice (n = 280) were divided into five diet groups and injected 10 times at weekly intervals with DMH (20 mg/kg wt) or saline. Four diets contained 11% protein (casein, milk, or beef) and 5% fat (corn oil or beef tallow), and the AIN-76A diet was used as a control diet. The source of fat was a significant modulator of tumor development. Corn oil markedly increased total tumor volume and the number of tumors per mouse compared with beef tallow. Its tumor-enhancing effects were evident when it was combined with milk but not with casein. In addition, significantly lower lymphoproliferation and T-cell cytotoxicity against colon tumor cell targets was associated with corn oil consumption, whereas nonfat milk as the protein source was related to normal oxidative burst capacity of phagocytes. These results demonstrate that the source of dietary fat, in addition to the protein source, has a profound effect on both tumor development and immune responsiveness in this animal tumor system.

1,2-Dimethylhydrazine↗

PubMed1979

Effect of thymectomy on tumor development and on T and B lymphocytes in tumor-bearing rats.

Tumor growth and changes in T and B lymphocyte ratio in spleen, draining lymph node and peripheral blood of thymectomized, irradiated rats, reconstituted with syngeneic bone marrow transplanted at various time intervals with MC-1 fibrosarcoma cells were followed. Control nonthymectomized or "sham" operated rats were transplanted an equal dose of tumor cells. Thymectomy and irradiation reduced the numbers of T lymphocytes in all lymphoid organs, while the enhanced numbers of B cells are probably related to reconstitution with cells of syngeneic bone marrow. The time interval between thymectomy, irradiation and transplantation of tumor cells proved to be a limiting factor for tumor growth and changes in T and B cell ratio. Early transplantation of tumor cells (7 days after irradiation) resulted in an enhanced resistance to tumor development, a reduced tumor growth rate and a progressing decline in the number of T cells. If the interval between thymectomy and tumor cell transplantation lasted 4 weeks, the T cell population became partially regenerated, and tumors grew progressively in correlation with a continuing T lymphocyte depletion. The results are discussed in terms of the role of various T cell subpopulations and the significance of residual, thymectomy- and irradiation-resistant T lymphocyte population, vital for a preservation of T cell immunological functions.

Animals↗

PubMed1986

Effects of four antioxidants on N-methyl-N'-nitro-N-nitrosoguanidine initiated gastric tumor development in rats.

The effects of antioxidant administration during the post initiation phase of gastric tumor development were investigated in male Wistar rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Animals (20/group) were given MNNG in the drinking water (100 mg/l) for 8 weeks, and for the duration of this treatment were also fed on diet supplemented with 10% sodium chloride. Thereafter, they were divided into 6 groups and were maintained on diet containing either 2% butylated hydroxyanisole (BHA), 1% BHA, 1% butylated hydroxytoluene (BHT), 1% ethoxyquin (EQ) or 1% DL-alpha-tocopherol (alpha-TP) for 32 weeks. A carcinogen control group was fed the basal diet without antioxidant supplementation. The experiment was terminated 40 weeks after the beginning of administration of MNNG and development of gastroduodenal tumors was determined histopathologically. EQ significantly increased the incidence of tumors in the glandular stomach. No modification of tumor development in this region of the organ were observed with 2% BHA, 1% BHA, 1% BHT or 1% alpha-TP, although both 2% BHA and 1% BHA induced and/or promoted tumor development in the forestomach. In addition, nephrocalcinosis was identified only in the kidneys of rats given EQ after MNNG treatment.

Animals↗

PubMed2002

Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development.

Natural killer (NK) cells and interferon (IFN)-gamma have been implicated in immune surveillance against tumor development. Here we show that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plays a critical role in the NK cell-mediated and IFN-gamma-dependent tumor surveillance. Administration of neutralizing monoclonal antibody against TRAIL promoted tumor development in mice subcutaneously inoculated with a chemical carcinogen methylcholanthrene (MCA). This protective effect of TRAIL was at least partly mediated by NK cells and totally dependent on IFN-gamma. In the absence of TRAIL, NK cells, or IFN-gamma, TRAIL-sensitive sarcomas preferentially emerged in MCA-inoculated mice. Moreover, development of spontaneous tumors in p53(+/-) mice was also promoted by neutralization of TRAIL. These results indicated a substantial role of TRAIL as an effector molecule that eliminates developing tumors.

Animals↗

PubMed1984

Butylated hydroxyanisole and lung tumor development in A/J mice.

A diet containing 0.75% butylated hydroxyanisole (BHA) did not enhance the development of lung tumors in A/J mice if fed for 8 weeks after administration of urethan, benzo[a]pyrene (B[a]P), or dimethylnitrosamine (DMN). Prefeeding animals with BHA partially protected animals against the tumorigenic effect of urethan and B[a]P. Partial protection was also seen in animals given B[a]P and then exposed to BHA in the diet. The two isomers of BHA (3-tert.-butyl-4-hydroxyanisole and 2-tert.-butyl-4-hydroxyanisole) were synthesized and injected ip. They failed to enhance lung tumor development. It is concluded that BHA is not a promoting agent as is butylated hydroxytoluene (BHT) for lung tumors in mice. One possible explanation is that BHA in the diet does not produce the extensive cell proliferation seen in the lungs of mice fed BHT.

Animals↗

PubMed1987

The influence of dietary medium chain triglycerides on rat mammary tumor development.

The N-nitrosomethylurea rat mammary tumor model was used to compare the tumor-promoting effects of a high-fat (HF) diet containing a 3:1 mixture of medium chain triglycerides (MCT) and corn oil with that of a HF and a low-fat (LF) corn oil diet. The serum and tumor lipid content and fatty acid (FA) composition were also determined in the three dietary groups. It was found that the MCT-containing diet failed to promote tumor development compared with the HF corn oil group. Tumor incidence in the HF-MCT group was similar to that of the LF corn oil group (5% fat, w/w), but significantly decreased compared to the HF corn oil group. Total serum cholesterol levels were significantly depressed in the HF corn oil group compared to the HF-MCT and LF corn oil groups. Analysis of serum and tumor FA profiles indicated that the HF corn oil group exhibited approximately twice the amount of linoleic acid (LA) as the other two treatment groups. Differences among the three groups in the major FA metabolite of LA, arachidonic acid, were minimal. These results are consistent with the hypothesis that tumor promotion by dietary fat is more a function of the type than the amount of fat ingested. In addition, they indicate that MCT, due at least in part to their unique structural and physiological properties, exert markedly different effects on mammary tumor development than conventional long chain unsaturated fatty acids.

Animals↗

PubMed2003

Identification and characterization of CRG-L2, a new marker for liver tumor development.

Liver cancer is very common worldwide and the rates of hepatocellular carcinoma (HCC) have increased by over 70% in the last 2 decades in the US. Late diagnosis, because of the lack of clinical symptoms, and decreased hepatic function, because of underlying hepatic disease, lead to the extremely high mortality rates associated with HCC. Clearly, the identification of markers that are expressed early in the development of HCC and that are easily detected in high-risk patients would aid in early diagnosis and increased survival. We present the cloning and characterization of a novel gene, CRG-L2 (Cancer related gene-Liver 2), which displays high expression in murine and human hepatocellular carcinomas. Using in situ hybridization, we show that CRG-L2 mRNA levels are increased early during the development of liver tumors in C3H/HeJ mice, and that in normal tissues CRG-L2 mRNA is restricted to the murine testis and human placenta. Its restricted expression in normal tissues and unique early upregulation during tumor development make CRG-L2 an excellent candidate as a new clinical marker of HCC.

Base Sequence↗

PubMed2005

Lack of expression of the EP2 but not EP3 receptor for prostaglandin E2 results in suppression of skin tumor development.

The EP2 receptor for prostaglandin E2 (PGE2) is a membrane receptor that mediates at least part of the action of PGE2. It has been shown that EP2 plays a critical role in tumorigenesis in mouse mammary gland and colon. However, the possibility that the EP2 receptor is involved in the development of skin tumors was unknown. The purpose of this study was to investigate the role of the EP2 receptor in mouse skin carcinogenesis. Unlike EP3 knockout mice, the EP2 knockout mice produced significantly fewer tumors and reduced tumor incidence compared with wild type (WT) mice in a 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) two-stage carcinogenesis protocol. EP2 knockout mice had significantly reduced cellular proliferation of mouse skin keratinocytes in vivo and in vitro compared with that in WT mice. In addition, the epidermis of EP2 knockout mice 48 hours after topical TPA treatment was significantly thinner compared with that of WT mice. The inflammatory response to TPA was reduced in EP2 knockout mice, based on a reduced number of macrophages in the dermis and a reduced level of interleukin-1alpha mRNA expression, compared with WT mice. EP2 knockout mice also had significantly reduced epidermal cyclic AMP levels after PGE2 treatment compared with WT mice. Tumors from WT mice produced more blood vessels and fewer apoptotic cells than those of EP2 knockout mice as determined by immunohistochemical staining. Our data suggest that the EP2 receptor plays a significant role in the protumorigenic action of PGE2 in skin tumor development.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1986

Relationship between circulating plasminogen activators and tumor development in mice.

Plasminogen activators (PAs) present in the plasma of BALB/c mice and produced in vitro by murine tumor cell cultures (B77-3T3, SR-BALB, AA6) have been characterized using electrophoretic-zymographic techniques. BALB/c mouse plasma contains a main PA activity with an approximate molecular weight of 88,000 and pI 6.3, inhibited by anti-human tissue-type plasminogen activator (t-PA) serum, here defined as murine t-PA. On the contrary, all tumor cells tested release a PA activity with a molecular weight of 44,500 and pI 9.2 characteristic of urokinase-type activator (murine u-PA). The injection s.c. of the different tumorigenic cells into BALB/c mice leads to tumor development and to a rapid increase of t-PA from the first day following the injection. This early enhancement of t-PA activity is not detectable in mice given injections of lethally irradiated B77-3T3 cells. Moreover the development of the tumor in the animals is related to the appearance of increasing levels of u-PA in the blood. This activity is detectable in the plasma of treated mice almost 2 wk before detection of a tumor 1 mm in diameter. During tumor development, the molecular weight of the u-PA and t-PA forms present in the plasma does not change, while there is a decrease of the isoelectric point of the u-PA leading to the appearance of distinct PA activities with pI 7.6 and 8.9. Syngenic and allogenic lymphocytes, injected in BALB/c mice, do not induce any modification in the pattern of the plasma PA. The injection of highly metastatic cells, as opposed to nonmetastatic or low-metastatic cells, does not give rise to detectable levels of u-PA in the plasma of treated mice. These data suggest that the lack of plasma u-PA activity facilitates the formation of metastates, while the increase of this activity is important in tumor development and is independent of the metastatic potential of the injected cells.

Animals↗

PubMed1999

Protein kinase C lies on the signaling pathway for vascular endothelial growth factor-mediated tumor development and angiogenesis.

The growth of any solid tumor depends on angiogenesis. Among the known angiogenic factors, vascular endothelial growth factor (VEGF) has been shown to play a pivotal role in tumor angiogenesis. However, to date, the signal transduction pathway initiated by VEGF is still not fully understood. It has been suggested that protein kinase C (PKC) plays an important role in the VEGF-induced signal transduction pathway in vitro, although the role of PKC in tumor angiogenesis in vivo still remains to be elucidated. By delivering the VEGF gene within the self-contained tetracycline-regulated retroviral vector (Retro-Tet) into hepatocellular carcinoma (HCC) cells, we manipulated VEGF expression by providing tetracycline in the drinking water to assess the tumor kinetics mediated exclusively by VEGF. In this study, we combined this Retro-tet system and LY333531, an inhibitor of the PKC-beta isoform, to elucidate the role of PKC-beta in tumor development and angiogenesis. Using a syngenic xenograft model, tumor augmentation induced by VEGF overexpression in HCC was markedly suppressed by oral administration of the PKC-beta inhibitor, with an accompanying reduction of neovascularization and p44/42 mitogen-activated protein kinase activation. This inhibitory effect was achieved even after the tumor was fully established. Immunohistochemical analysis revealed that apoptosis increased markedly in the tumor upon PKC-beta inhibitor treatment, whereas tumor cell proliferation itself did not change. Furthermore, with orthotopical transplantation, PKC-beta inhibition suppressed HCC tumor development in the liver. These results suggest that PKC-beta lies on the signal transduction pathway by which VEGF augments development and angiogenesis not only at the initial stage but also after the tumor is fully established.

Animals↗

PubMed2001

FHIT gene therapy prevents tumor development in Fhit-deficient mice.

The tumor suppressor gene FHIT spans a common fragile site and is highly susceptible to environmental carcinogens. FHIT inactivation and loss of expression is found in a large fraction of premaligant and malignant lesions. In this study, we were able to inhibit tumor development by oral gene transfer, using adenoviral or adenoassociated viral vectors expressing the human FHIT gene, in heterozygous Fhit(+/-) knockout mice, that are prone to tumor development after carcinogen exposure. We therefore suggest that FHIT gene therapy could be a novel clinical approach not only in treatment of early stages of cancer, but also in prevention of human cancer.

Acid Anhydride Hydrolases↗

PubMed2000

Efficient inhibition of in vivo human malignant glioma growth and angiogenesis by interferon-beta treatment at early stage of tumor development.

Malignant gliomas are highly angiogenic and aggressive tumors. IFN-beta has been used for the treatment of patients with malignant glioma; however, its antitumor mechanism in vivo remains unclear. To understand the in vivo antitumor effect and mechanism of recombinant human IFN-beta (rhIFN-beta) depending on the stages of tumor development or progression, we used orthotopic xenograft brain tumors generated by stereotactic intracerebral implantation of U-87 human glioma cells in nude mice. Mice bearing tumors 7 days (group 1) and 21 days (group 2) postimplant were treated with 2 x 10(5) IU/day of rhIFN-beta or saline i.p. for 15 days, respectively. Tumor growth was suppressed by 69.6% in group 1 and 10.8% in group 2 compared with tumors of each control group treated with saline. rhIFN-beta-treated group 1 animals showed 38% reduction in vascularization along with a 2.5-fold increase of the apoptotic index and no change in the proliferative index as compared with untreated tumors. The expression level of vascular endothelial cell growth factor and basic fibroblast growth factor was not affected by rhIFN-beta treatment. rhIFN-beta showed inhibitory activity on proliferation of U-87 cells, human umbilical vein endothelial cells, and PAM 212 murine keratinocytes in vitro. Our results indicate that the in vivo antitumor effect of rhIFN-beta on malignant gliomas may be mediated, at least in part, via angiogenesis inhibition rather than antiproliferative activity and that rhIFN-beta may be more effective for the treatment of malignant glioma patients at an early stage with minimal or microscopic tumor burdens rather than at an advanced stage of tumor development.

Angiogenesis Inhibitors↗

PubMed1995

Mice deficient in both p53 and Rb develop tumors primarily of endocrine origin.

To examine whether a cooperative role exists between inherited Rb and p53 deficiency in tumorigenesis, crosses were made between p53- and Rb-deficient mice and were monitored for subsequent tumor incidence and spectrum. Parental mice containing either Rb or p53 mutant alleles showed a predisposition for pituitary adenomas or lymphomas and sarcomas, respectively. Mice heterozygous for both Rb and p53 mutant alleles developed tumors of endocrine origin (medullary thyroid carcinomas, pancreatic islet cell carcinomas, and pituitary adenomas) in addition to lymphomas and sarcomas. Except for pituitary adenomas, these endocrine tumors were rarely seen in the parental p53 or Rb mutant mice. Mice deficient for both Rb and p53 showed a faster rate of tumor development than mice deficient only in Rb or p53. These results indicate that p53 and Rb do cooperate in the acceleration of tumorigenesis and in the development of endocrine tumor types.

Adenocarcinoma↗

PubMed1993

[Endogenous and exogenous factors in tumor development and cell differentiation in gastrointestinal tumors].

In recent years, epidemiological and molecular studies revealed very important new insights into the development of tumors in the gastrointestinal tract. Above all, certain forms of nutrition and molecular genetic features and events are responsible for tumor occurrence. This article tries to give a short review of the most important recent findings in this field of research.

Cell Division↗

PubMed1990

Dietary manipulation of mammary tumor development in adult C3H/Bi mice.

Chronic energy intake restriction (CEIR) in virgin female mice is one of the most effective ways of reducing significantly mammary adenocarcinoma in C3H/Bi mice, a strain which develops mammary adenocarcinoma associated with the murine mammary tumor virus spontaneously and at high incidence. In this study, the influence of chronic energy intake restriction imposed on fully mature (4- to 5-month-old), breeding female C3H/Bi mice was addressed, and the influence of energy intake where energy was derived largely from fat versus diets in which energy was derived largely from carbohydrates on tumor development and survival rate was investigated. The results show that chronic energy intake restriction can be delayed until full maturation and successful reproduction and still reduce significantly the incidence of mammary tumor development in this relatively short-lived strain of mice. Our findings demonstrate that the overriding dietary factor controlling mammary tumor development in these experiments in C3H/Bi mice was the level of energy intake, regardless of the primary source of energy (fat or carbohydrates).

Adenocarcinoma↗

PubMed2005

Tumor development: haploinsufficiency and local network assembly.

According to the current models, tumor development is a continuous process of mutation accumulation, leading to several intermediate phenotypes and final phases of autonomy, unlimited growth and metastasis. One of the most important events in that process is the initial destabilization of cellular pathways that subsequently allow mutations to accumulate. The mechanisms involved in that stage are not clear. In principle, the estimated very low mutation frequency in human or mouse cells would suggest that accumulating the required number of mutations for tumor development should be a statistically unlikely event. However, this theory is contradicted by the high incidence of cancers. Here we discuss the role of protein haploinsufficiency as a contributor to the initial phases of tumor development, and suggest possible mechanisms that might be involved in that process.

Animals↗