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PubMed2005

Levels of 4-aminobiphenyl-induced somatic H-ras mutation in mouse liver DNA correlate with potential for liver tumor development.

The utility of liver H-ras codon 61 CAA to AAA mutant fraction as a biomarker of liver tumor development was investigated using neonatal male mice treated with 4-aminobiphenyl (4-ABP). Treatment with 0.1, 0.3, or 1.0 mumol 4-ABP produced dose-dependent increases in liver DNA adducts in B6C3F(1) and C57BL/6N mice. Eight months after treatment with 0.3 mumol 4-ABP or the DMSO vehicle, H-ras codon 61 CAA to AAA mutant fraction was measured in liver DNA samples (n = 12) by allele-specific competitive blocker-polymerase chain reaction (ACB-PCR). A significant increase in average mutant fraction was found in DNA of 4-ABP-treated mice, with an increase from 1.3 x 10(-5) (control) to 44.9 x 10(-5) (treated) in B6C3F(1) mice and from 1.4 x 10(-5) to 7.0 x 10(-5) in C57BL/6N mice. Compared with C57BL/6N mutant fractions, B6C3F(1) mutant fractions were more variable and included some particularly high mutant fractions, consistent with the more rapid development of liver foci expected in B6C3F(1) mouse liver. Twelve months after treatment, liver tumors developed in 79.2% of 4-ABP-treated and 22.2% of control B6C3F(1) mice; thus measurement of H-ras mutant fraction correlated with subsequent tumor development. This study demonstrates that ACB-PCR can directly measure background levels of somatic oncogene mutation and detect a carcinogen-induced increase in such mutation.

Aminobiphenyl Compounds↗
PubMed2002

Suppression of the renin-angiotensin system attenuates vascular endothelial growth factor-mediated tumor development and angiogenesis in murine hepatocellular carcinoma cells.

Angiotensin-II (AT-II), which is produced mainly by the renin-angiotensin system (RAS), has been shown to stimulate neovascularization. AT-II induces vascular endothelial growth factor (VEGF), which plays a pivotal role in tumor angiogenesis. The role of AT-II, however, in VEGF-mediated tumor development has not yet been elucidated. We examined the effect of RAS inhibition by angiotensin-I converting enzyme (ACE) inhibitor on VEGF-mediated tumor development and angiogenesis in a murine experimental model 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 an allograft study, the ACE inhibitor, perindopril (PE) significantly attenuated VEGF-mediated tumor development accompanying the suppression of neovascularization in the tumor at a clinically comparable low dose. In vitro study showed that perindoprilat, which is an active form of PE, inhibited VEGF-induced endothelial cell migration. These results suggested that RAS played an important role in VEGF-mediated tumor development and angiogenesis.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Identification of a specific marker chromosome early in tumor development in gamma-irradiated C57BL/6J mice.

Chromosomal changes such as aneuploidies, translocations, and gene amplification occur in many murine tumors. In this study, we have analyzed the changes in chromosomes at different stages of tumor development in C57BL/6J mice treated with gamma-irradiation or the chemical carcinogen, N-methylnitrosourea. Trisomy 15 occurred in both groups of mice regardless of inducing agent. The frequency of this event differed significantly in radiation-treated animals between stage I and stage II of the disease. A specific marker chromosome occurred only in the gamma-irradiated mice and not in the mice treated with N-methylnitrosourea. This marker consists of a translocation between chromosomes 1 and 5. It occurred in 43% of the gamma-irradiated animals at stage 1 of the disease and did not vary markedly during tumor development. In contrast, trisomy 15 increased in frequency between stages I and II of the disease in the same animals. These results suggest that the translocation event may be an early event in tumor development, whereas trisomy 15 may contribute to tumor progression.

Animals↗
PubMed2003

A continuous delivery system of IL-1 receptor antagonist reduces angiogenesis and inhibits tumor development.

The involvement of interleukin-1 (IL-1) in inflammation, tumor growth, and metastasis makes it an attractive target for therapeutic intervention. Here, we show that a continuous delivery of a low, but steady-state level of the naturally occurring IL-1 receptor antagonist (IL-1Ra) reduced inflammatory responses and inhibited tumor development in mice, phenomena that are induced by IL-1, mainly secretable IL-1beta. The IL-1Ra was delivered from microencapsulated genetically engineered cells, which overexpress and secrete this mediator. For a tumor model, we used fibrosarcoma cell line, which secretes high levels of IL-1beta; when injected s.c. into mice, the cells developed into large tumors characterized by very active angiogenic patterns. The proangiogenic features of IL-1beta were manifested at low levels of the cytokine, and release of 25 ng per day of the IL-1Ra was needed to oppose its effects and inhibit tumor development. The continuous delivery of the IL-1Ra contributed to improved biocompatibility of the microencapsulated cell systems; the fibrotic sac surrounding the systems was much thinner with significantly less blood capillaries and inflammatory cells. Not only do our findings point to the antiangiogenic properties of IL-1Ra in inflammation and tumor growth, but they also provide a more efficient and convenient way for treating diseases involving IL-1.

Animals↗
PubMed2001

Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1.

Dysregulation of imprinted genes on human chromosome 11p15 has been implicated in Beckwith-Wiedemann syndrome (BWS), an overgrowth syndrome associated with congenital malformations and tumor predisposition. The molecular basis of BWS is complex and heterogeneous. The syndrome is associated with alterations in two distinct imprinting domains on 11p15: a telomeric domain containing the H19 and IGF2 genes and a centromeric domain including the KCNQ1OT1 and CDKNIC genes. It has been postulated that disorders of imprinting in the telomeric domain are associated with overgrowth and cancer predisposition, whereas those in the centromeric domain involve malformations but not tumor development. In this study of 125 BWS cases, we confirm the association of tumors with constitutional defects in the 11p15 telomeric domain; six of 21 BWS cases with uniparental disomy (UPD) of 11p15 developed tumors and one of three of the rare BWS subtype with hypermethylation of the H19 gene developed tumors. Most importantly, we find that five of 32 individuals with BWS and imprinting defects in the centromeric domain developed embryonal tumors. Furthermore, the type of tumors observed in BWS cases with telomeric defects are different from those seen in BWS cases with defects limited to the centromeric domain. Whereas Wilms' tumor was the most frequent tumor seen in BWS cases with UPD for 11p15 or H19 hypermethylation, none of the embryonal tumors with imprinting defects at KCNQ1OT1 was a Wilms' tumor. This suggests that distinct tumor predisposition profiles result from dysregulation of the telomeric domain versus the centromeric domain and that these imprinting defects activate distinct genetic pathways for embryonal tumorigenesis.

Beckwith-Wiedemann Syndrome↗
PubMed1993

Cloning of tumor suppressor genes involved in solid tumor development.

OBJECTIVE: The homozygous inactivation of tumor suppressor genes is a common event in the multistep process of tumorigenesis. The identification of most tumor suppressor genes known to date has come from the study of individuals with a defective copy of such a gene that increases their predisposition to malignancy. Although much is still to be learned about the function of these genes, they all seem to play a role in cell growth regulation. Karyotypic and molecular studies of several solid tumors suggest the presence of at least three tumor suppressor genes on the short arm of human chromosome 3. We present an overview on the progress made in the identification of tumor suppressor genes involved in solid tumor development. CONCLUSION: The explosive effort to map the human genome fueled by the Human Genome Project will facilitate the identification of tumor suppressor genes on chromosome 3 and on other chromosomes within the next 2 to 3 years. This information will not only provide a better understanding in cell cycle regulation and differentiation but also new insights in the design of new therapies for the treatment of human cancer.

Chromosome Deletion↗
PubMed1997

Genomic instability, as measured by microsatellite alterations, is not associated with liver tumor development in the genetically susceptible B6C3F1 mouse.

Certain human heritable forms of colon cancer have characteristically high frequencies of microsatellite alterations. These microsatellite changes are markers of genomic instability and the direct consequence of mutations in genes involved with DNA mismatch repair processes, which are in part responsible for maintaining the sequence integrity of the genome. Given that the B6C3F1 mouse is genetically predisposed to develop liver tumors we were interested in determining whether tumors derived in this strain of mouse may contain alterations in microsatellite sequences. The analysis of 48 tumors at 24 different microsatellite loci revealed that microsatellite alterations were detected in 12 of 48 tumors (25%). Although this frequency is relatively high, 11 of the 12 tumors exhibited only a single alteration and in 10 of those tumors this change was at the same microsatellite locus. Microsatellite alterations were also detected in the DNA isolated from 6 of 22 (27%) normal liver tissues with 4 of the 6 occurring at the same locus where the majority of changes were observed in the tumors. Based on these results, we conclude that the microsatellite alterations present in the mouse liver tumor tissue are most likely the result of spontaneous mutational events. Consequently, the genomic instability operational in a particular type of hereditary human colon cancer does not appear to be operational in the genetically predisposed B6C3F1 mouse liver. In addition, we demonstrated that the activation of the H-ras gene, which causes some forms of genetic instability in vitro, does not contribute to genetic instability within liver tumors as measured by microsatellite alterations.

Animals↗
PubMed2001

Progression of infection and tumor development in damselfish.

The bicolor damselfish (Stegastes partitus) is a tropical marine teleost naturally affected by multiple neurofibromas and chromatophoromas on South Florida reefs. Damselfish neurofibromatosis is a transmissible disease caused by a subcellular agent. Development of tumors is associated with the appearance of a series of extrachromosomal DNAs ranging in size from 1.2 to 7 kb that appear to be the genome of a small virus-like agent which we termed the damselfish virus-like agent (DVLA). This DNA was found at high copy number in most spontaneous and experimentally induced tumors. An essentially identical pattern of DNA, but with lower copy numbers, was observed in non-tumor-bearing tissue from diseased fish. Copy numbers of DVLA DNA in tumors and nontumorous tissues increased as the disease progressed from early to late stages. In healthy fish in which DVLA DNA was detected, the quantities were much lower than those in diseased fish. Healthy fish from populations with a high prevalence of disease exhibited more infected tissues than fish from populations with low levels.

Journal Article↗
PubMed1999

Bcl-2 expression delays mammary tumor development in dimethylbenz(a)anthracene-treated transgenic mice.

Bcl-2 is known to have dual antiproliferative and antiapoptotic roles. Overexpression of Bcl-2 in the mammary gland using a whey acidic protein (WAP) promoter-driven Bcl-2 transgene inhibits apoptosis in the mammary gland during pregnancy, lactation, and involution, and also counteracts apoptosis induced by overexpression of a mutant p53 transgene (WAP-p53 172 R-L). WAP-Bcl-2 mice and nontransgenic controls were treated with the carcinogen dimethylbenz(a)anthracene (DMBA). Surprisingly, the nontransgenic mice developed mammary tumors with decreased latency. Tumors arising in WAP-Bcl-2 mice displayed substantially reduced levels of proliferation relative to those seen in nontransgenic mice (P < 0.015), perhaps resulting in the observed increase in tumor latency following carcinogen treatment. This WAP-Bcl-2 mouse tumor model reflects the situation seen in some human breast cancers overexpressing Bcl-2, where expression of Bcl-2 has been shown to correlate with a lower proliferative index in tumors.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2005

MCP-1 overexpressed in tuberous sclerosis lesions acts as a paracrine factor for tumor development.

Patients with tuberous sclerosis complex (TSC) develop hamartomatous tumors showing loss of function of the tumor suppressor TSC1 (hamartin) or TSC2 (tuberin) and increased angiogenesis, fibrosis, and abundant mononuclear phagocytes. To identify soluble factors with potential roles in TSC tumorigenesis, we screened TSC skin tumor-derived cells for altered gene and protein expression. Fibroblast-like cells from 10 angiofibromas and five periungual fibromas produced higher levels of monocyte chemoattractant protein-1 (MCP-1) mRNA and protein than did fibroblasts from the same patient's normal skin. Conditioned medium from angiofibroma cells stimulated chemotaxis of a human monocytic cell line to a greater extent than conditioned medium from TSC fibroblasts, an effect blocked by neutralizing MCP-1-specific antibody. Overexpression of MCP-1 seems to be caused by loss of tuberin function because Eker rat embryonic fibroblasts null for Tsc2 (EEF Tsc2(-/-)) produced 28 times as much MCP-1 protein as did EEF Tsc2(+/+) cells; transient expression of WT but not mutant human TSC2 by EEF Tsc2(-/-) cells inhibited MCP-1 production; and pharmacological inhibition of the Rheb-mTOR pathway, which is hyperactivated after loss of TSC2, decreased MCP-1 production by EEF Tsc2(-/-) cells. Together these findings suggest that MCP-1 is an important paracrine factor for TSC tumorigenesis and may be a new therapeutic target.

Analysis of Variance↗
PubMed1994

[Murine leukemia virus Akv promotes bone tumor development in fos-transgenic mice].

Newborn hMT-fos-LTR transgenic C3H mice and their non-transgenic siblings were infected with Akv, derived from the ecotropic provirus of the AKR mouse. Bone sarcomas in non-infected transgenics were observed in 20% (3/15) of females at 448 +/- 25 days and in 8% (1/12) of males at 523 days. Akv-infected transgenics developed bone tumors with higher frequency and at younger age: Females in 69% (20/28) at 268 +/- 122 days, males in 83% (24/29) at 279 +/- 109 days. In the majority of the bone tumors of Akv-infected transgenics (70% in females, 59% in males) cellular atypia was lacking and the histological pattern resembled human parosteal osteosarcoma. Only 50% (12/24) of bone tumors in Akv-infected transgenics revealed newly integrated virus sequences by Southern analysis. PCR analysis detected Akv sequences in DNAs of all tumors. Obviously, the insertion of Akv in a few cells induced the considerably accelerated bone tumor growth.

Animals↗
PubMed1996

Somatic mutations of the RET proto-oncogene are not required for tumor development in multiple endocrine neoplasia type 2 (MEN 2) gene carriers.

Germ line mutations in one allele of the RET proto-oncogene predispose to the multiple endocrine neoplasia type 2 (MEN 2) syndromes. To investigate whether these inherited mutations alone can cause the development of tumors in vivo (oncogene model) or whether somatic mutations in the homologous RET allele are required for tumorigenesis (tumor suppressor gene model), we analyzed the entire coding region of both alleles of the RET gene in two MEN 2A and two MEN 2B tumors by reverse transcription-PCR and direct sequencing. No tumor-specific mutations could be detected in either allele of the RET gene in these tumors. Unlike the molecular mechanism in other hereditary tumor syndromes, somatic mutations in the homologous allele are apparently not required in MEN 2 tumorigenesis. Thus, RET genes with MEN 2-specific germ line mutations act as dominantly transforming oncogenes in vivo.

DNA, Complementary↗
PubMed2001

The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells.

Angiogenesis is now recognized as a crucial process in tumor development, including hepatocellular carcinoma (HCC). Since HCC is known as a hypervascular tumor, anti-angiogenesis is a promising approach to inhibit the HCC development. Trientine dihydrochloride (trientine) is used in clinical practice as an alternative copper (Cu)-chelating agent for patients with Wilson's disease of penicillamine intolerance. In our study, we examined the effect of Cu-chelating agents on tumor development and angiogenesis in the murine HCC xenograft model. Although both trientine and penicillamine in the drinking water suppressed the tumor development, trientine exerted a more potent inhibitory effect than penicillamine. In combination with a Cu-deficient diet, both trientine and penicillamine almost abolished the HCC development. Trientine treatment resulted in a marked suppression of neovascularization and increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. In vitro studies also exhibited that trientine is not cytotoxic for the tumor cells. On the other hand, it significantly suppressed the endothelial cell proliferation. These results suggested that Cu plays a pivotal role in tumor development and angiogenesis in the murine HCC cells, and Cu-chelators, especially trientine, could inhibit angiogenesis and enhance apoptosis in the tumor with consequent suppression of the tumor growth in vivo. Since trientine is already used in clinical practice without any serious side effects as compared to penicillamine, it may be an effective new strategy for future HCC therapy.

Animals↗
PubMed1984

Role of estrogen and prolactin in stimulation of carcinogen-induced mammary tumor development by a high-fat diet.

The role of estrogen and prolactin in high-fat (HF) dietary stimulation of carcinogen-induced mammary tumors was examined in female Sprague-Dawley rats. At 55 days of age, the rats were given injections i.v. of 5 mg of dimethylbenz(a)anthracene and, 5 days later, rats were sham- or bilaterally ovariectomized. Ten days after dimethylbenz(a)anthracene administration, the rats were placed on either a 20.0% HF diet or a 4.5% control fat (CF) diet and were then subjected to various drug and endocrine treatments to maintain uniform levels of circulating estrogen and prolactin. Sham-operated intact rats and bilaterally ovariectomized rats were given daily injections of haloperidol to increase prolactin secretion, bromocryptine to decrease prolactin secretion, and/or estradiol benzoate (EB). The intact rats fed the HF diet showed significant stimulation of all parameters of mammary tumor development when compared to similarly treated rats fed the CF diet. In ovariectomized rats fed either the HF or CF diet, there was nearly complete inhibition of mammary tumor development. When the HF diet was given to ovariectomized rats treated daily with either haloperidol or EB, or EB and bromocryptine, some parameters of mammary tumor development were enhanced by the HF diet. However, in all cases, mammary tumorigenesis was reduced when compared to sham-operated control rats. Ovariectomized rats fed the HF diet and given both EB and haloperidol exhibited significantly greater tumor number per rat, increased average tumor size, and reduced tumor latency period when compared to similarly treated rats fed the CF diet. However, these parameters of mammary tumorigenesis were still reduced when compared to those of sham-control rats fed the HF diet. These results indicate that a HF diet requires adequate circulating levels of estrogen and prolactin to maximally promote increased mammary tumorigenesis in dimethylbenz(a)anthracene-treated rats. Moreover, the enhancing effects of a HF diet on mammary tumorigenesis can be achieved in the presence of similar circulating levels of estrogen and/or prolactin, whether decreased or increased. These results suggest, therefore, that mechanisms independent of altered secretion of estrogens and/or prolactin are involved in promotion of mammary tumorigenesis by high levels of dietary fat.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2001

Results of hyperamplification of centrosomes in naturally developing tumors of dogs.

OBJECTIVE: To evaluate results of centrosome hyperamplification in naturally developing tumors of dogs. SAMPLE POPULATION: Tumor specimens from 9 dogs with tumors (rhabdomyosarcoma, osteosarcoma, chondrosarcoma, myxosarcoma, and mammary gland tumor) and 2 canine osteosarcoma cell lines. PROCEDURE: 3 antibodies for centrosome proteins (ie, anti-gamma-tubulin, anti-BRCA1, and anti-pericentrin) were used for immunohistochemical analysis. Double immunostaining for centrosomes was used to confirm the specificity of these antibodies for centrosomes. Mutational analysis of the canine p53 gene was carried out by polymerase chain reaction-single-strand conformation polymorphism analysis, and expression of canine MDM2 protein was evaluated by use of immunohistochemical analysis, using anti-MDM2 antibody. RESULTS: Immunohistochemical analysis of dog osteosarcoma cell lines with apparent aneuploidy revealed frequent hyperamplification of centrosomes in the osteosarcoma cell lines. Similar hyperamplified centrosomes were detected in the tumor tissues from all of the 9 tumors. The frequency of cells with hyperamplified centrosomes (3 to 20/cell) in each tumor tissue ranged from 9.50 to 48.1%, whereas centrosome hyperamplification was not observed in normal lymph nodes from these dogs. In 8 of the 9 tumors, mutation of p53 gene or overexpression of MDM2, or both, was detected. CONCLUSIONS AND CLINICAL RELEVANCE: Various types of naturally developing tumors in dogs often have hyperamplification of centrosomes associated with chromosome instability. Hyperamplification of centrosomes is a novel tumor marker for use in cytologic and histologic examinations of clinical specimens obtained from dogs.

Animals↗
PubMed2002

Centrosome amplification drives chromosomal instability in breast tumor development.

Earlier studies of invasive breast tumors have shown that 60-80% are aneuploid and approximately 80% exhibit amplified centrosomes. In this study, we investigated the relationship of centrosome amplification with aneuploidy, chromosomal instability, p53 mutation, and loss of differentiation in human breast tumors. Twenty invasive breast tumors and seven normal breast tissues were analyzed by fluorescence in situ hybridization with centromeric probes to chromosomes 3, 7, and 17. We analyzed these tumors for both aneuploidy and unstable karyotypes as determined by chromosomal instability. The results were then tested for correlation with three measures of centrosome amplification: centrosome size, centrosome number, and centrosome microtubule nucleation capacity. Centrosome size and centrosome number both showed a positive, significant, linear correlation with aneuploidy and chromosomal instability. Microtubule nucleation capacity showed no such correlation, but did correlate significantly with loss of tissue differentiation. Centrosome amplification was detected in in situ ductal carcinomas, suggesting that centrosome amplification is an early event in these lesions. Centrosome amplification and chromosomal instability occurred independently of p53 mutation, whereas p53 mutation was associated with a significant increase in centrosome microtubule nucleation capacity. Together, these results demonstrate that independent aspects of centrosome amplification correlate with chromosomal instability and loss of tissue differentiation and may be involved in tumor development and progression. These results further suggest that aspects of centrosome amplification may have clinical diagnostic and/or prognostic value and that the centrosome may be a potential target for cancer therapy.

Aneuploidy↗
PubMed1998

Dietary lutein from marigold extract inhibits mammary tumor development in BALB/c mice.

High levels of dietary lutein can inhibit mammary tumor growth in mice. However, the antitumor effect of low levels of dietary lutein on mammary tumors is unavailable. Female BALB/c mice and the WAZ-2T (-SA) mammary tumor cell line were used in two experiments. A preliminary tumor cell dose titration study (Experiment 1) was designed to determine the inoculation dose to produce approximately 65% tumor incidence. Mice (n = 10/dose) were inoculated with 0 to 1 x 10(6) tumor cells in the right inguinal mammary fat pad. A tumor cell load of 2.5 x 10(3) cells/inoculation produced approximately 65% tumor incidence. This dose was used in a subsequent study (Experiment 2) of the efficacy of dietary lutein against mammary tumor development. Mice (n = 20/treatment) were fed a semisynthetic diet containing 0, 0.002, 0.02, 0.2 or 0.4% lutein from marigold extract. After 14 d, all mice were inoculated with 2.5 x 10(3) tumor cells, and tumor growth was measured daily for 70 d at which time blood, liver, spleen and tumors were obtained. Lutein + zeaxanthin uptake increased dose-dependently (P < 0.05) with dietary lutein levels from 0 to 0.02% (spleen) or 0.2% (plasma, liver and tumor). Low levels (0.002 and 0.02%) of dietary lutein lowered (P < 0.05) mammary tumor incidence, tumor growth and lipid peroxidation, and increased tumor latency, whereas higher dietary levels (0.2 or 0.4%) were less effective. Therefore, very low amounts of dietary lutein (0.002%) can efficiently decrease mammary tumor development and growth in mice.

Animals↗