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PubMed2000

Cooperative effects of Mycobacterium tuberculosis Ag38 gene transduction and interleukin 12 in vaccination against spontaneous tumor development in proto-neu transgenic mice.

An approach to stimulating an immune response against tumors is to transduce tumor cells with bacterial genes, which represent a "danger signal" and can induce a wide immune response. Mycobacterium tuberculosis genes and their encoded proteins play a pivotal role in linking innate and cell-mediated adaptive immunity and represent ideal candidates as immune adjuvants for tumor vaccines. The efficacy of a cancer vaccine, obtained by transduction of a mammary tumor cell line with the M. tuberculosis Ag38 gene, was investigated in female mice transgenically expressing the rat HER-2/neu proto-oncogene. These mice spontaneously develop stochastic mammary tumors after a long latency period. The onset of spontaneous mammary tumors was significantly delayed in mice vaccinated with Ag38-transduced cells but not in mice vaccinated with nontransduced cells as compared with untreated mice. Protection from spontaneous tumor development was increased when mice were vaccinated with the mycobacterium gene-transduced vaccine plus a systemic administration of interleukin 12 (IL-12) at a low dose. Mice vaccinated with nontransduced cells plus IL-12 developed tumors, with only a slight delay in tumor appearance as compared with the control group. Lymphocytes obtained from lymph nodes of mice vaccinated with transduced cells secreted high levels of IFN-gamma. CD3+CD8+ spleen cells derived from these mice responded to the tumor with IFN-gamma production. These data indicate the efficacy of a short-term protocol of vaccinations exploiting the adjuvant potency of a M. tuberculosis gene and low doses of IL-12 in a model of stochastic development of mammary tumors. This adjuvant approach may represent a promising immunotherapeutic strategy for cancer immunization.

Adjuvants, Immunologic↗
PubMed1985

Immune monitoring of tumor development after renal transplantation.

A series of immune parameters were available covering the period before, during, and after tumor appearance in ten patients who developed tumors after renal transplantation. Results were obtained using monoclonal antibodies OKT3, OKT4, OKT8, and the ratio OKT4/OKT8, and surface membrane fluorescence microscopy (SMIg) for B-lymphocytes, E-rosetting and blast transformation. A much lower immune responder state was indicated at the time of transplantation in patients who later developed a tumor, as compared to a control group, and a much lower immune responder state was seen before than after tumor appearance. A low OKT4/OKT8 ratio was found before the diagnosis of Hodgkin's disease in one patient, and an increase in the immune responder state was seen after treatment of a patient developing spinocellular carcinoma at the site of a former herpes labialis. Using a monoclonal antibody against Hodgkin and Sternberg-Reed cells (Ki-1), it was possible to demonstrate that these were present before transplantation, with an increase before the appearance of the first clinical symptoms and, perhaps activated by the transplantation and the following immunosuppression, in the patient who developed Hodgkin's disease.

Adult↗
PubMed1998

Skin tumor development and keratin expression in different experimental models. Relation to inducing agent and target tissue structure.

The applicability of the experimental skin carcinogenesis model for studies of tumor development was examined by exposing the skin of various mouse strains to different chemical carcinogens and UV radiation regimens, in order to analyze the development and progression of the neoplastic process and the role of differentiation markers such as keratins. In tumor-sensitive hairy NMRI mouse skin, the chemical carcinogen, 7,12-dimethylbenz(a)-anthracene (DMBA) induced an abnormal epidermal cell differentiation and structural irregularities associated with an altered keratin expression, as well as numerous papillomas and squamous cell carcinomas. A suboptimal dose of UVB irradiation increased the number of DMBA-induced benign squamous neoplasms. Low doses of benzo(a)pyrene resulted in mild epidermal alterations, but only in one tumor. High doses of UVB induced a large number of undifferentiated spindle cell tumors with few keratinpositive cells in NMRI mice, similar though fewer tumors in hairy, heavily pigmented C57BL/6 mice, numerous papillomas and squamous cell carcinomas in hairless hr/hr mice but only two papillomas in hairy, moderately pigmented DBA/2 mice while UVA exposure produced only two papillomas in hairless SKH-1 mice. In conclusion, the extent and type of skin tumor development depended upon the induction regimen: physical, chemical, dose and duration, as well as on the skin structure: pigmentation and adnexal development, all of which have to be taken into account when relating experimental results to human conditions.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2006

Verapamil-sensitive Ca2+ channel regulation of Th1-type proliferation of splenic lymphocytes induced by Walker 256 tumor development in rats.

Recently, we demonstrated that verapamil, an L-type Ca2+ channel blocker, inhibits the activation of splenic lymphocytes during Walker 256 ascitic tumor development in adult rats. In the present study we have analyzed the changes in spleen size, splenic lymphocyte proliferation, white pulp organization and relative size as well as food intake, and levels of blood haemoglobin in Walker 256 tumor bearing rats. These rats displayed a spleen enlargement associated with a significant increase in white pulp area and TCD8+ lymphocyte proliferation. Levels of interferon-gamma, but not of interleukin-10, were elevated in tumor bearing rats, indicating a Th1-type immune response. These manifestations were accompanied by reduced food intake and anaemia. Treatment of tumor bearing rats with verapamil avoided spleen enlargement and increased expression of cytokines, as well as the splenic TCD8+ lymphocyte proliferation. In addition, verapamil treatment promoted an exacerbation of the anorexia and anaemia caused by Walker tumor development. No such effect was observed in control rats treated with verapamil. Taken together, these findings suggest that verapamil inhibits the immune response to cancer, resulting in an increase of the systemic effects induced by Walker 256 tumor.

Animals↗
PubMed2002

Stage-specific alterations of cyclin expression during UVB-induced murine skin tumor development.

We have evaluated the in vivo correlation between the expression of cell cycle markers and skin tumor development in SKH-1 hairless mice in a complete photocarcinogenesis protocol. Irradiated mice developed an average of 16 tumors per animal by week 23 with the average number of carcinomas per mouse being 2.1. The expression of p53 and cyclins A and D1 was confined initially to sporadic single cells and gradually developed into foci of patchy intense staining in the basal and granular layers of UVB-exposed epidermis. p53 was expressed in all the papilloma sections examined, whereas cyclins D1 and A were expressed in 68 and 71% of these lesions, respectively. In UVB-induced squamous cell carcinomas (SCC), p53 was expressed in >90% of the tumors, whereas cyclin D1 was detected in 55% of the lesions, and cyclin A staining was limited to 27%. These immunohistochemical observations were confirmed by Western blotting and protein kinase assays. We observed an early wave of cyclin A overexpression and cyclin A protein kinase activity preceding the appearance of detectable tumors. Cyclin D1 and p53 overexpression were coupled with the development of tumors, and these changes are likely to be relevant to the pathogenesis of these lesions.

Animals↗
PubMed2005

Chemopreventive effects of dietary flaxseed oil on colon tumor development.

Fatty acid composition of dietary fat, primarily the levels of omega-3 and omega-6 polyunsaturated fatty acids, has shown profound effect on colon tumor development in animal studies. Fats containing omega-6 fatty acids (for example, corn oil) enhanced and omega-3 fatty acids (for example, fish oil and mustard oil) reduced chemically induced colon tumors in rats. The purpose of this study was to investigate the effects of dietary flaxseed oil (containing alpha-linolenic acid, an omega-3 polyunsaturated fatty acid) on azoxymethane-induced colon tumor in rats and how it compared with the dietary corn oil-treated group. Male Fischer rats, separated into 2 groups of 30, were assigned to the AIN-93M diet, which was supplemented with either 15% corn oil or 15% flaxseed oil. Carcinogenesis was initiated with subcutaneous injections of azoxymethane (15 mg/kg) once a week for three consecutive weeks. Thirty-five weeks after initiation, the rats were sacrificed under ether anesthesia. Blood was collected by cardiac puncture. The gastrointestinal tract was isolated and flushed with ice-cold normal saline. The site, size, and number of tumors were recorded. The incidence and multiplicity of the tumors in the colon were determined. The fatty acid composition in the serum, colon, and tumors was estimated by using gas chromatography-flame ionization detection. Colon tumor incidence was found to be 100% and 54%, whereas multiplicity was found to be 3.1 and 0.7 tumors per rat in corn oil- and flaxseed oil-treated groups, respectively. Tumor size was significantly larger in the corn oil-treated group than in the flaxseed oil group. Colon and serum samples of the corn oil group showed an increase in the omega-6 fatty acid levels, whereas the flaxseed oil group exhibited an increase in the omega-3 fatty acid levels. The results indicate that dietary flaxseed oil, containing high levels of omega-3 fatty acids, is effective in preventing colon tumor development when compared with dietary corn oil containing omega-6 fatty acids in rats.

Animals↗
PubMed1996

Effects of two dietary fat levels and four dietary linoleic acid levels on mammary tumor development in Balb/c-MMTV mice under ad libitum feeding conditions.

The relationship between dietary fat intake (level and type) and the development of breast cancer in humans is a matter of concern in Western society. A high fat intake is associated with a greater mammary cancer risk in humans and in animal models. Higher intake of polyunsaturated fatty acids in humans shows little or no association with mammary tumor development in epidemiologic surveys. From literature data, it appears that a higher intake of polyunsaturated fatty acids (linoleic acid) is related to an increase in mammary tumorigenesis in animal studies in which chemical carcinogens like dimethylbenz[a]anthracene are used as tumor initiator. Mostly the latency period of these chemically induced models in rather short. In this study, the Bald/c-MMTV (mouse mammary tumor virus) mouse strain was chosen as an animal model: MMTV leads to tumor initiation, and dietary factors influence tumor promotion over a relatively long latency period. The mice were fed diets with two fat concentrations: a high [36% of energy (en%)] or low (16 en%) fat level; fat was isocalorically replaced by carbohydrates (cornstarch). At both dietary fat levels, linoleic acid was given at four levels: 2, 3, 6, and 10 en%. Linoleic acid-rich fat was isocalorically replaced by oleic acid-rich fat. The diets were consumed ad libitum over a lifetime. Animals were euthanized as soon as mammary tumor diameter was > or = 1 cm or when the animals were in a poor clinical condition. The incidence of mammary tumors at 18 months was significantly higher in one group only: 36 en% fat and 2 en% linoleic acid. This group also showed the shortest mean latency period for mammary tumor development. Mean mammary tumor incidence was higher and mean onset time shorter in the four high-fat groups than in the low-fat groups. No (linear) dose-response relationship between dietary linoleic acid concentration and mammary tumor incidence and latency period was observed. This indicates that a higher dietary linoleic acid intake does not increase the incidence or shorten the latency period of breast cancer in the Balb/c-MMTV mouse strain at two different dietary fat levels.

Animals↗
PubMed1984

Effect of immunosuppression on neonatally diethylstilbestrol-induced genital tract lesion and tumor development in female mice.

Neonatal treatment of female rodents with the synthetic estrogen diethylstilbestrol [(DES) CAS: 56-53-1; alpha, alpha'-diethyl-4,4'-dimethoxystilbene] results in immunodeficiency that persists into adulthood, along with progressive development of genital tract lesions. DES-induced immunosuppression was examined as a possible promoter of genital tract lesion and tumor development in BALB/cCrgl female mice. Secondary suppression of T-cell immunity after neonatal DES treatment failed to increase lesion incidence or to promote genital tract tumor development in 8-month-old mice. Although hyperplastic lesions were present in 70% of the genital tracts from DES-treated mice at 8 months of age, apparently few neoplastic cells are present at this time, since transplantation of genital tracts from these animals into syngeneic hosts did not yield tumors. To reduce the possibility that potential tumors were too immunogenic to survive in the syngeneic hosts, genital tract pieces from 12-month-old DES-treated female mice were transplanted into immunosuppressed hosts; only 1 tumor resulted. The tumor was a mixed adenocarcinoma, squamous cell carcinoma, and sarcoma and was immunogenic. These results suggest that immunosurveillance by T-cells is relatively unimportant in DES-induced genital tract lesion development.

Animals↗
PubMed1990

Suppression of mouse mammary tumor proviral DNA and protooncogene expression: association with nutritional regulation of mammary tumor development.

Chronic energy intake restriction (CEIR) reduces mouse mammary tumor virus (MMTV)-induced mammary tumors in C3H/Ou mice. Fewer than 10% of C3H/Ou mice developed mammary tumors during 88 wk of study when subjected to CEIR regardless of calorie source (fat vs. carbohydrate). By contrast, 100% of mice fed ad libitum diets relatively high in fat or carbohydrate or a commercial diet developed tumors by 35-40 wk. MMTV proviral DNA transcription was shown to be activated in spleen, liver, lung, kidney, small intestine, and mammary gland of mice consuming these diets ad libitum. By contrast, these messages were suppressed by CEIR in all tissues analyzed except spleen. MMTV proviral messages in liver and mammary gland increased with age in full-fed mice and were suppressed by CEIR. These findings suggest that the nutritional regulation of MMTV proviral DNA expression is tissue-specific. In CEIR mice the suppressed MMTV proviral DNA transcripts in mammary gland and liver increased with time in association with the delayed onset of mammary tumors. Mammary tumorigenesis in C3H mice is associated with integration of MMTV proviral DNA, which appears to activate a putative mammary tumor protooncogene, int-1. CEIR apparently decreases the frequency of viral reintegration adjacent to the int-1 gene and thus inhibits expression of int-1 and probably an initiation step in mammary tumorigenesis. Expression of other putative protooncogenes, int-2 and ras, in liver tissue was also reduced by CEIR. These findings indicate that both initiation and promotion of mammary tumorigenesis are influenced by CEIR in C3H/Ou mice.

Animals↗
PubMed2002

Inhibition of Rel/Nuclear Factor-kappaB signaling in skin results in defective DNA damage-induced cell cycle arrest and Ha-ras- and p53-independent tumor development.

In recent years a growth inhibitory role in skin for the Rel/NF-kappaB transcription factors has been established, and the block of Rel/NF-kappaB signaling results in rapid development of spontaneous skin cancer. The molecular mechanism underlying tumor development is however unknown. In the present study, we show that inhibition of NF-kappaB signaling in mouse skin by targeted expression of degradation resistant IkappaB-alpha generates transgenic keratinocytes unable to arrest the cell cycle in response to DNA damage induced by gamma-radiation. The results indicate that transgenic keratinocytes have a defect at the G1-S checkpoint whereas the G2-M checkpoint response was found to be intact. However, transgenic keratinocytes still respond by induction of the cyclin dependent kinase inhibitor p21(Cip1/Waf) after exposure to gamma-radiation. In the spontaneous skin tumors that develop in transgenic mice no mutations were found in the Ha-ras or p53 gene, suggesting that inhibition of NF-kappaB signaling in skin can induce cancer development independently of initiating mutations in the Ha-ras gene or additional mutations in the p53 gene. These findings demonstrate an involvement of NF-kappaB signaling in the DNA damage response and cell cycle checkpoint control in the skin.

Animals↗
PubMed1989

Haemorheological study during the process of tumor development after subcutaneous transplantation of mouse forestomach carcinoma (FC) cells.

A metastatic tumor model of mouse forestomach carcinoma (FC) was used in this study. Tumor cells were subcutaneously transplanted into right costal region of inbred 615-strain mice. Animals were killed on the 3rd, 6th, 9th, 12th and 15th day. Histological and haemorheological examinations were performed. Based on the histological findings the development of the tumor was divided into 5 stages; i.e. latent stage, invasive stage, early stage of metastasis, middle stage of metastasis and late stage of metastasis, corresponding with 3rd, 6th, 9th, 12th and 15th day after transplantation of mouse forestomach carcinoma. Results of haemorheological studies indicated that plasma and blood viscosity elevated in the invasion and early metastatic stages and the increased viscosity of blood was able to promote metastasis during the early stage of tumor development, while the tumor developed in the middle and late metastatic stages when the values of plasma viscosity, blood viscosity, aggregation of red blood cells and haematocrit decreased but the rigidity of red blood cells increased in these periods.

Animals↗
PubMed2005

Effects of soy protein and soy phytochemicals on mammary tumor development in female transgenic mice overexpressing human pituitary growth hormone.

The objective of this study was to determine the effect of soy-based diets on mammary tumors in female cancer- prone mice. Transgenic virgin female mice expressing human pituitary growth hormone and their respective phenotypically normal littermates were fed a diet containing either casein (C), low-isoflavone soy protein (LIS), or high-isoflavone soy protein (HIS). Indices of tumor development were measured throughout the study. Both days from birth until death and days on diet until death were increased [by 20% (P = .01) and 19% (P = .02), respectively] in the LIS group when compared with the C group. Both intervals were increased also (by 16% and 17%, respectively; P < .05) in the HIS group when compared with the C group. Days from birth to first tumor were increased by 7% (P < .05), as was days on diet to first tumor by 5% (P < .05), in the LIS group when compared with the C group. First-onset number of tumors was decreased (P = .02) by 41% and 34% in the LIS and C groups, respectively, when compared with the HIS group. Final onset of tumors was decreased (P < .05) by 44% and 9% in the LIS and HIS groups, respectively, when compared with the C group. Total area of final tumors was decreased (P < .05) by 30% in the LIS group when compared with the C group. Taken cumulatively, these data suggest that a diet rich in soy protein may provide protective benefits regarding tumor development in female cancer-prone mice. Furthermore, some bioactive compounds in the HIS diet appeared to confound the soy protein-induced beneficial effects.

Animals↗
PubMed1987

Hereditary suppression of lethal (2) giant larvae malignant tumor development in Drosophila by gene transfer.

Homozygous mutations of the recessive oncogene lethal-(2) giant larvae (l(2)gl) of Drosophila melanogaster cause lethal neoplasms of the imaginal discs and the brain hemisphere. A 13-kb DNA segment spanning the l(2)gl+ locus has been inserted into P element vectors and used for P-mediated transformation. The P-l(2)gl+ transposons have been introduced into the germ line of heterozygous l(2)gl-/+ flies and were shown by backcrossing to fully rescue the homozygous l(2)gl deficient animals, which otherwise would have died of brain and imaginal disc neoplasms. Further genetic backcrossing with l(2)gl deficiencies characterized by deletions of increased sizes involving the left end of chromosome 2 indicated that a relatively large region of developmentally regulated DNA sequence adjacent to the l(2)gl gene is apparently not essential for the viability and fertility of the fly. These experiments indicate that all the genetic information specified by the l(2)gl+ gene is contained within this 13-kb DNA segment and demonstrates that the development of neuroblastomas and imaginal disc tumors results from the absence of l(2)gl function. When this function is restored, tumor development is completely suppressed.

Animals↗
PubMed1991

Organ-specific modification of tumor development by low-dose combinations of agents in a rat wide-spectrum carcinogenesis model.

The combined effects of low doses of various carcinogens and carcinogenesis modifiers on tumor development were investigated by using a wide-spectrum organ carcinogenesis model in F344 rats. These agents were administered as three groups: (1) a group of known hepatocarcinogens; (2) a group of nitroso compounds having various target organ specificities; and (3) a group of antioxidants having various inhibiting or enhancing activities depending on the target organ. Doses were used which were generally below the known effective level for the individual chemical. These groups of chemicals were administered with or without prior administration of N-diethylnitrosamine (100 mg/kg body wt., i.p.), N-methylnitrosourea (4 x 20 mg/kg body wt., i.p.) and dihydroxy-di-N-propylnitrosamine (0.1% in drinking water for 2 weeks). The hepatocarcinogen group in combination with various nitroso compounds increased the incidences of liver hyperplastic nodules and hepatocellular carcinomas. In contrast, incidences were clearly reduced when the hepatocarcinogens and/or the nitroso compounds were administered in combination with the antioxidants. For the urinary bladder, the combination with nitroso compounds and antioxidants enhanced cancer development, and the addition of hepatocarcinogens further increased tumorigenesis. For the glandular stomach, additive effects on the numbers of pepsinogen isozyme 1-altered pyloric glands, a putative preneoplastic lesion, were produced by the combination treatment of antioxidants and the nitroso compounds. No synergistic effects on tumor development were seen in other organs. The results of the present study demonstrated that combinations of various compounds at low doses can additively or synergistically exert either enhancing or inhibitory effects on the development of preneoplastic and neoplastic lesions in different organs in a single model having a wide spectrum of organ effects.

Animals↗
PubMed1982

Expression of the cellular immune response during tumor development in an animal model of bladder cancer.

Papillary and solid transitional cell cancers were induced in the bladders of Fischer rats by ingestion of the carcinogen N-[4-(5-nitro-furyl)-2-thiazolyl] formamide. At sequential regular intervals, purified splenic, peripheral blood, regional lymph node, and thymus lymphocytes were harvested from tumor-bearing and age-matched control animals and tested for cytotoxicity against a variety of cell lines. Lymphocytes were also tested in mixed lymphocyte cultures for blastogenesis. Tumor development was accompanied by decreased lymphocyte cytotoxicity against bladder tumor targets at each interval tested. This decrease was in addition to the age-related decrease in cytotoxicity expressed by lymphocytes from control animals. No corresponding differences were seen in lymphocyte subpopulations as determined by immunofluorescence or in lymphocyte blastogenesis. Suppressor cell activity in tumor-bearing animals could not be demonstrated, and no cause-effect relationship between cytotoxicity depression and tumor development in these experiments was apparent.

Animals↗
PubMed1987

The effect of inhibition of mitochondrial protein synthesis on the proliferation and phenotypic properties of a rat leukemia in different stages of in-vivo tumor development.

It has been shown before that prolonged treatment with doxycycline (DC), an inhibitor of mitochondrial protein synthesis, leads to proliferation arrest of a leukemia in the rat and, moreover, to eradication of this tumor. It has also been demonstrated that the period of treatment required to achieve this is shorter when DC administration is started in later stages of tumor progression. Therefore, the leukemic cells may have properties with regard to DC sensitivity which change with time during tumor progression. In the present study this hypothesis was tested by studying the permeability for DC, the presence of cell-surface molecules, and the mitochondrial content of the leukemic cells in various stages of tumor development in control and in DC-treated rats. Changes in DC permeability or antigenic phenotype were not observed, but the content of mitochondria decreases during tumor progression. DC treatment leads to an additional reduction of the content of functional mitochondria which results in proliferation arrest. The higher mitochondrial content of the leukemic cells during the earlier stages of tumor development explains thus why a longer period of DC treatment is needed to achieve growth arrest when treatment is started in these stages.

Animals↗