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PubMed1988

Retroviral protein P15E and tumorigenesis. Expression is neither required nor sufficient for tumor development.

Murine tumor cells frequently express retroviral protein p15E, a protein with antiinflammatory activity. This has led to the hypothesis that p15E expression allows nascent tumor cells to escape host immunologic defenses. To evaluate the role of p15E expression in tumorigenesis, NIH3T3 cells transformed by various oncogenes and BALB/c lines transformed by carcinogens or SV40 were examined for p15E expression and tumorigenicity. All of the NIH3T3 transformants and most of the BALB/c transformants did not express p15E, indicating that transformation per se does not inevitably induce the expression of p15E. Although not expressing p15E, some of these transformants were capable of forming tumors in immune competent hosts, indicating that p15E is not universally required for tumor growth. Four of the transformed cell lines negative for p15E expression and deficient in tumor-forming capacity were transfected with a gene coding for Moloney retroviral p15E. Despite the expression of p15E, there was no augmentation of their tumorigenic capacity, showing that p15E is not sufficient to ensure tumor formation by a transformed cell. These results argue against a general role for retroviral p15E expression in tumorigenesis.

Animals↗
PubMed1989

Relationship between in utero development of the mouse liver and tumor development following transplacental exposure to ethylnitrosourea.

Pregnant C3HeB/FeJ mice were treated with ethylnitrosourea (ENU) on one of gestation Days 10, 13, or 15 to determine if ENU treatment at different stages of gestation would result in morphological or quantitative differences in liver tumors induced in the offspring. Liver tumors were counted and measured 6 mo after treatment with ENU. Foci of cellular alteration were identified histologically and counted. Liver tumor number and foci of cellular alteration increased as a function of increasing dose and age at the time of ENU treatment. An inverse relationship between age at the time of treatment and the size of liver tumors was found. The mean tumor volume of male mice exposed on Day 10 of gestation was 123-fold larger than for spontaneous tumors observed in controls. The differences between mean liver tumor volume in mice which had been exposed to ENU on Days 10, 13, or 15 of gestation appeared to be associated with the exponential growth of the fetus during this period of gestation. Unique, large, multinodular foci of cellular alteration were found in mice treated on Day 10 of gestation. The relationship between the stage of gestation and the size of chemically induced liver tumors in these mice is similar to previous observations with transplacentally induced lung tumors in C3HeB/FeJ mice. This indicates that developmentally regulated cell proliferation occurring at the time of carcinogen exposure may affect the subsequent extent of tumor development in both the liver and lung. Therefore, cells transformed during early development may result in tumors that pose a greater biological hazard than those transformed in later development.

Animals↗
PubMed1996

Potential role of the inactivated X chromosome in ovarian epithelial tumor development.

BACKGROUND: Ovarian epithelial tumors can be divided into subcategories often regarded as different stages of neoplastic transformation. Cystadenomas belong to the least aggressive subgroup and are noninvasive and nonmetastatic. Ovarian tumors of low malignant potential (LMP) are intermediate between cystadenomas and carcinomas and show markedly reduced invasive and metastatic abilities. Invasion and metastasis are the hallmarks of carcinomas, which constitute the most aggressive subgroup and can be further subdivided into different grades. PURPOSE: We performed comparative allelotype analyses of ovarian cystadenomas, LMP tumors, and carcinomas, reasoning that such analyses could provide clues about the molecular determinants of their phenotypic differences. Because we realized that allelic losses involving the X chromosome might be associated with LMP tumor development, we determined whether such losses were interstitial and whether they involved the active or the inactive X chromosome. METHODS: Frequencies of loss of heterozygosity (LOH) at specific loci in every chromosomal arm were determined in 16 ovarian cystadenomas, 23 ovarian LMP tumors, 15 low-grade ovarian carcinomas, and 35 high-grade ovarian carcinomas by use of either the polymerase chain reaction (PCR) or Southern blot analyses. We took advantage of the fact that DNA methylation is an important mechanism of X-chromosome inactivation to determine whether losses involving the X chromosome were in the active or the inactive copy. We analyzed the methylation status of retained alleles on the X chromosome by determining whether they could be amplified by PCR after digestion with the methylation-sensitive restriction endonuclease Hpa II. RESULTS: High-grade carcinomas contained frequent(>50%) LOH in four autosomal chromosome arms, i.e., 6q, 13q, 17p, and 17q. Except for 13q, these same chromosomal arms showed frequent LOH in low-grade carcinomas. LOH in autosomal chromosomes was comparatively rare in LMP tumors and was absent in cystadenomas. In contrast, half (eight of 16) of LMP tumors informative for a locus in the proximal portion of chromosome Xq showed LOH at that locus. These losses were the result of interstitial deletions in six of the eight cases and involved the inactive copy of the X chromosome exclusively. Similar losses in the X chromosome were not seen in either cystadenomas or low-grade carcinomas. CONCLUSIONS AND IMPLICATIONS: LOH at multiple loci is associated with the development of ovarian carcinomas but not with the development of cystadenomas and LMP tumors. However, the integrity of a locus in chromosome Xq that possibly escapes X-chromosome inactivation is important for the control of LMP tumor development. The fact that this locus does not appear to be involved in the genesis of low-grade carcinomas suggests that LMP tumors are not precursors of such carcinomas.

Alleles↗
PubMed2005

Sustained low-level expression of interferon-gamma promotes tumor development: potential insights in tumor prevention and tumor immunotherapy.

Although the proinflammatory cytokine interferon-gamma (IFN-gamma) has been generally thought to enhance antitumor immune responses and be involved in antitumor mechanisms of many other immunotherapy molecules, it has also been reported that IFN-gamma could promote tumor immune evasion. In this report, by using an ideal mouse model that expresses IFN-gamma locally in muscle, we demonstrate that sustained low-level expression of IFN-gamma promotes the development of several types of tumor including H22 hepatoma, MA782/5S mammary adenocarcinoma and B16 melanoma. However, transitory expression of IFN-gamma does not have such an effect. On the other hand, sustained high-level expression of IFN-gamma mediates significant antitumor effect on H22 hepatoma. Low level of IFN-gamma upregulates expression of PD-L1, PD-L2, CTLA-4 and Foxp3, which may partly account for the tumor immune evasion promoted by IFN-gamma. Furthermore, blockade of PD-L inhibits IFN-gamma's tumor-promoting effect. Our findings provide a mechanistic link between chronic inflammation and cancer and would have potential implications for cancer prevention and also for the design of cytokine-based cancer immunotherapy.

Adenocarcinoma↗
PubMed1996

Gonadotropins are essential modifier factors for gonadal tumor development in inhibin-deficient mice.

We previously demonstrated that mice deficient in inhibin develop gonadal sex cord-stromal tumors with nearly 100% penetrance. These ovarian and testicular tumors develop as early as 4 weeks of age and eventually cause cachexia-like symptoms and death in the inhibin-deficient mice. Gonadectomized inhibin-deficient mice initially do not develop this wasting syndrome, but eventually will develop adrenal cortical tumors with similar penetrance. These studies have demonstrated that inhibin is a secreted type of tumor suppressor in the gonads and adrenal glands. Gonadotropins are implicated to influence gonadal tumor development in humans as well as experimental animals, and in inhibin-deficient mice, serum FSH levels are elevated. To determine whether gonadotropins influence the development and/or progression of the tumors in the inhibin-deficient mice, we took advantage of a naturally occurring mutant mouse, hypogonadal (hpg); hpg/hpg mice lack a functional GnRH gene and, therefore, have suppressed FSH and LH levels. Heterozygous hpg/+mice were crossed to heterozygous inhibin mutant mice to generate compound homozygous mutant mice that lack both inhibin and GnRH. These compound homozygous mutant mice do not develop a wasting syndrome, do not exhibit gonadal or adrenal tumors, and can survive for more than 1 yr. These results demonstrate that gonadotropins are essential modifier factors for tumor development in inhibin-deficient mice.

Animals↗
PubMed1988

Increased hepatic androgen receptor expression in female rats during diethylnitrosamine liver carcinogenesis. A possible correlation with liver tumor development.

This study investigated the relationship between liver tumor development and androgen-receptor expression in diethylnitrosamine hepatocarcinogenesis in Wistar rats (SUAH substrain). Random liver samples were assayed by an isoelectric focusing method, with [3H]mibolerone as androgenic radioligand. After 16 wk of oral diethylnitrosamine treatment there was a greater than 20-fold increase in hepatic androgen receptor concentration in female rats (control group 0.3 +/- 0.07 fmol/mg cytosol protein; test group 8.36 +/- 0.96 fmol/mg cytosol protein; p less than 0.001, unpaired Student's t-test). This coincided with, and may be related to, an accelerated development of neoplastic nodules or hepatocellular carcinoma, or both. Male rats showed slower tumor development and no change in androgen receptor concentrations. This model is the first to demonstrate significantly increased androgen sensitivity in experimental hepatic carcinogenesis analogous to increased androgen receptor expression in human hepatocellular carcinoma. It may provide insight into steroid hormone sensitivity in developing tumors, and a means of testing potential therapeutic use of hormonal manipulation in human liver cancer.

Animals↗
PubMed1999

Vaccination with the extracellular domain of p185neu prevents mammary tumor development in neu transgenic mice.

The HER2/neu oncogene product, p185(HER2/neu), is overexpressed on the surface of many human breast cancers. Strains of transgenic mice have been developed that express the rat neu oncogene in mammary epithelial cells and develop spontaneous mammary tumors that overexpress p185neu. This model provides an ideal system for testing interventions to prevent tumor development. In this study, we immunized neu-transgenic mice with a vaccine consisting of the extracellular domain of p185neu (NeuECD). Immunized mice developed Neu-specific humoral immune responses, as measured by circulating anti-Neu antibodies in their sera, and cellular immune responses, as measured by lymphocyte proliferation to NeuECD in vitro. In addition, the subsequent development of mammary tumors was significantly lower in immunized mice than in controls and vaccine treatment was associated with a significant increase in median survival.

3T3 Cells↗
PubMed2002

Cdk4 deficiency inhibits skin tumor development but does not affect normal keratinocyte proliferation.

Most human tumors have mutations that result in deregulation of the cdk4/cyclin-Ink4-Rb pathway. Overexpression of D-type cyclins or cdk4 and inactivation of Ink4 inhibitors are common in human tumors. Conversely, lack of cyclin D1 expression results in significant reduction in mouse skin and mammary tumor development. However, complete elimination of tumor development was not observed in these models, suggesting that other cyclin/cdk complexes play an important role in tumorigenesis. Here we described the effects of cdk4 deficiency on mouse skin proliferation and tumor development. Cdk4 deficiency resulted in a 98% reduction in the number of tumors generated through the two-stage carcinogenesis model. The absence of cdk4 did not affect normal keratinocyte proliferation and both wild-type and cdk4 knockout epidermis are equally affected after topical treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), resulting in epidermal hyperplasia. In similar fashion, cdk4 knockout keratinocytes proliferated well in an in vivo model of wound-induced proliferation. Biochemical studies in mouse epidermis showed that cdk6 activity increased twofold in cdk4-deficient mice compared to wild-type siblings. These results suggest that therapeutic approaches to inhibit cdk4 activity could provide a target to inhibit tumor development with minimal or no effect in normal tissue.

Animals↗
PubMed1992

Platelet-derived growth factor receptor-beta is induced during tumor development and upregulated during tumor progression in endothelial cells in human gliomas.

BACKGROUND: Endothelial cells proliferate during brain development, are quiescent in normal adult brain but proliferate again under pathologic conditions such as glioma growth. The vascular phenotype of low grade glioma is comparable to normal brain, however high grade gliomas are focally highly vascularized and there is associated prominent endothelial cell proliferation. The mechanisms of this change in vascular phenotype are unknown but there is evidence that growth factors play an important role in this process as well as in normal angiogenesis and vascular differentiation. EXPERIMENTAL DESIGN: To investigate whether endothelial cells become activated during tumorigenesis and progression of human gliomas by a platelet-derived growth factor (PDGF) dependent pathway, we analyzed platelet-derived growth factor receptor-beta (PDGFR-beta) expression by in situ hybridization and immunocytochemistry in normal human brain, astrocytoma (grade II), anaplastic oligo-astrocytoma (grade III), and glioblastoma multiforme (grade IV). RESULTS: PDGFR-beta mRNA was not detectable in the vessels of normal human brain, but was expressed in the vasculature of low and high grade gliomas, particularly in endothelial cell proliferations in glioblastomas. The expression of the receptor in the tumor microvessels, was confirmed by double immunofluorescence in which the staining appeared to be in the endothelial cells. Primary cultures of endothelial cells derived from glioblastoma multiforme maintained receptor expression for 2 days in vitro, whereas it was not detectable in vitro in endothelial cells derived from normal brain. Tumor cells in all grades of glioma expressed very little PDGFR-beta mRNA in situ. CONCLUSIONS: Our results indicate that the malignant phenotype in human glial tumors is associated with an upregulation of the PDGFR-beta on endothelial cells of vessels which vascularize the tumor. These findings may contribute to our understanding of the mechanisms that regulate vessel growth and differentiation in normal and pathologic states.

Brain Neoplasms↗
PubMed2025

Single-cell RNA-seq of small-intestinal neuroendocrine tumors reveals the cell of origin and gene expression of early tumor development.

Patients with a hereditary form of small-intestinal neuroendocrine tumors (SI-NETs) present with multiple synchronous tumors and precursors at various stages. Using this germline trait, single-cell RNA sequencing is performed to define the cell-of-origin and gene-expression trajectory in early tumor development. A subset of CES1(+), LCN15(-) enterochromaffin (EC) cells, residing at +4 position and below in the crypts, distinct from EC cells migrating up the villi, emerges as the putative SI-NET origin. PRODH2 is identified as a key biomarker for precursor cells, revealing stage-specific gene expression linked to early tumor development. From precursor to fully developed tumors, notable changes include the up-regulation of UCHL1 and MBD3L2, as well as the significant down-regulation of cell-cycle inhibitory genes, CDKN1A, CDKN1C, and CDKN2B, which play roles in cell survival and tumorigenesis. The current study provides insight into SI-NET initiation and progression, offering potential advancements in diagnosis, prevention, and treatment.

Neuroendocrine Tumors↗
PubMed1999

Estrogen-induced pituitary tumor development in the ACI rat not inhibited by dietary energy restriction.

We have demonstrated that a 40% restriction of dietary energy consumption virtually abolishes the development of prolactin (PRL)-producing pituitary tumors in Fischer 344 (F344) rats treated chronically with estrogen, apparently by inhibiting the ability of estrogen to enhance survival within a rapidly proliferating lactotroph population. The purpose of the study reported here was to determine whether energy restriction exerts a similar antitumorigenic action in another rat strain, August x Copenhagen-Irish (ACI), in which PRL-producing pituitary tumors develop in response to estrogen treatment. Ovariectomized female ACI rats were either allowed to consume a control diet ad libitum or were fed a modified diet that restricted energy consumption by 40% relative to the amount of energy consumed by animals fed the control diet. We also examined the ability of 17beta-estradiol (E2) administered for 20 wk via subcutaneous Silastic implants to induce development of PRL-producing pituitary tumors. Treatment with E2 increased pituitary weight as well as the pituitary weight-to-body weight ratio and induced gross hyperprolactinemia to the same extent in ACI rats fed either the control or the energy-restricted diet. Moreover, dietary energy restriction did not affect the ability of E2 to induce pituitary cell proliferation or inhibit apoptosis, as evidenced by quantification of two surrogate markers. These data provide compelling evidence that a 40% restriction of energy consumption does not inhibit the ability of E2 to induce pituitary tumor development in the ACI rat. In conjunction with our published studies of the F344 rat strain, the data presented herein indicate that the inhibitory effects of dietary energy restriction on estrogen-induced pituitary tumor development are rat-strain specific and suggest that sensitivity to specific antitumorigenic actions of energy restriction is strongly affected by genetic background.

Animals↗
PubMed1984

Different stages of tumor development are unequally affected by pretreatment of tumor cells with a polysaccharide.

Pretreatment with the polysaccharide levan of Lewis lung carcinoma and AKR lymphoma cells affected unequally different stages of tumor development. While levan pretreatment sharply reduced the evolution of tumors from subcutaneously inoculated cells, no such inhibition was observed with pretreated cells inoculated intravenously. Since levan is known to affect the cell membrane, it is concluded that different cell membrane properties may be involved in the various stages of tumor progression.

Animals↗
PubMed2002

Cyclooxygenase-2 overexpression in the skin of transgenic mice results in suppression of tumor development.

Significant evidence has accumulated suggesting that the inducible form of cyclooxygenase (COX-2), a central enzyme in the prostaglandin biosynthetic pathway, plays an important role in tumor development. To better understand the role of COX-2 in tumorigenesis, we generated transgenic mice that overexpress COX-2 under control of the human keratin 14 promoter, which allows for expression in the epidermis and some other epithelia. Transgenic mice, referred to as K14.COX2 mice, were readily distinguished from their nontransgenic littermates by the appearance of significant alopecia. Administration of a specific COX-2 inhibitor restored hair growth, indicating that the alopecia was attributable to elevated COX-2 enzymatic activity. Unexpectedly, COX-2 overexpression was found to protect, rather than sensitize, K14.COX2 mice to skin tumor development induced by an initiation/promotion protocol. K14.COX2 transgenics developed tumors at a much lower frequency than did their littermate controls (3.3% versus 93%, respectively, on a FVB background and approximately 25% versus 100%, respectively, on an ICR background) and presented with significantly reduced tumor burdens (average, 0.03 versus 12.7 tumors/mouse, respectively, on a FVB background and 0.5 versus 7.1 tumors/mouse, respectively, on an ICR background). Mice fed a COX-2 inhibitor in utero and as weanlings up to the time of promotion also showed a significant resistance to tumor development. These results clearly raise questions regarding the role of COX-2 and elevated prostaglandin levels in skin tumor development.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2002

The roles of IFN gamma in protection against tumor development and cancer immunoediting.

Interferon-gamma (IFN gamma) is a cytokine that plays physiologically important roles in promoting innate and adaptive immune responses. The absence of IFN gamma production or cellular responsiveness in humans and experimental animals significantly predisposes the host to microbial infection, a result that validates the physiologic importance of this cytokine in preventing infectious disease. Recently, an additional role for IFN gamma in preventing development of primary and transplanted tumors has been identified. Although there now appears to be a consensus that IFN gamma promotes host responses to tumors, the mechanisms by which this cytokine achieves its effects remain unclear. In this review, we briefly discuss key issues of the molecular cell biology of IFN gamma and its receptor that are most relevant to IFN gamma-dependent anti-tumor effects and then focus on the data implicating IFN gamma as a critical immune system component that regulates tumor development. Potential mechanisms underlying IFN gamma's anti-tumor effects are discussed and a preliminary integrative model of IFN gamma's actions on tumors is proposed. Finally, the capacity of IFN gamma and lymphocytes to not only provide protection against tumor development but also to sculpt the immunogenic phenotype of tumors that develop in an immunocompetent host is presented and introduced as a "cancer immunoediting" process.

Animals↗
PubMed1999

Factors affecting the risk of contralateral Wilms tumor development: a report from the National Wilms Tumor Study Group.

BACKGROUND: Approximately 1% of children with unilateral Wilms tumor develop contralateral disease. The authors assessed the demographic and histologic features associated with metachronous bilateral Wilms tumor (BWT). METHODS: Characteristics of all children registered on the first four National Wilms Tumor Studies (NWTS) were recorded. The primary endpoint for evaluation was the first appearance of Wilms tumor in the remaining kidney. The cumulative risk of contralateral disease as a function of time since initial presentation was calculated as 1 minus the Kaplan-Meier estimate of remaining free of contralateral disease. A matched case control study was conducted to determine whether the presence and type of nephrogenic rests (NRs) were associated with metachronous BWT. RESULTS: Fifty-eight of 4669 registered children developed metachronous BWT; 38 of 2445 females (expected, 30.2) versus 20 of 2224 males (expected, 27.8) (P = 0.04) developed BWT. The cumulative incidence of contralateral disease 6 years after initial diagnosis decreased from greater than 3% in the first NWTS to approximately 1.5% in the three subsequent studies (P = 0.08). Patients with NRs had a significantly increased risk of metachronous BWT. This was particularly true for young children (20 of 206 age < 12 months compared with 0 of 304 age > 12 months). Data from the matched case control study confirmed the increased relative risk associated with young age and the presence of NRs. CONCLUSIONS: Children younger than 12 months diagnosed with Wilms tumor who also have NRs, in particular perilobar NRs, have a markedly increased risk of developing contralateral disease and require frequent and regular surveillance for several years. Surveillance is also recommended for those with NRs who are diagnosed after the age of 12 months.

Age Factors↗
PubMed1994

The molecular genetics of Wilms tumor: a paradigm of heterogeneity in tumor development.

The evidence that genes on chromosome 11 are involved in Wilms tumor development is convincing; however, it is also evident that the mechanisms of tumorigenesis are more complex than the two-mutation model originally proposed. Potentially several genetic loci participate in Wilms tumor development. This should not be too surprising considering the complexity of pathways regulating growth and differentiation in nephrogenesis. It is possible that these various genes act at different points in the differentiation pathway and disruption of their normal function contributes to tumorigenesis. In fact, these loci may interact with one another in tumor formation. Certain types of genetic alterations may be the rate-limiting steps, but other changes may also contribute or be necessary for tumor development. Homozygous inactivation of specific genes, combinations of mutated alleles, and relaxation of genetic imprinting, or even interactions between different mutated alleles may all be part of the process for individual tumors. It has been found that some patients with the WAGR syndrome who are hemizygous for WT1 at 11p13 have in addition loss of heterozygosity within 11p15, and a sporadic tumor has been shown to have a WT1 mutation and loss of heterozygosity at loci at both 11p15 and 11p13 (59,85). These observations suggest the potential for interaction among the various Wilms tumor loci. Not only are there likely to be a number of different genetic loci linked to Wilms tumor development, but the mechanisms underlying altered gene function may be more variable than originally believed. It is probably not correct to think of Wilms tumor as a homogeneous entity. Mutations at different loci or various combinations of genetic lesions could well be responsible for the different categories of Wilms tumors. This apparent genetic complexity of Wilms tumor development is a concept that can very likely be applied to many other types of neoplasms. A complete understanding of Wilms tumorigenesis awaits identification of all members of the Wilms tumor gene family and the functional significance of their alterations.

Chromosomes, Human, Pair 11↗
PubMed2006

Chemopreventive effects of dietary flaxseed on colon tumor development.

Fatty acid composition of dietary fat plays a vital role in colon tumor development in animal models. Fats containing omega-6 fatty acids (e.g., corn oil) enhanced and omega-3 fatty acids (e.g., flaxseed oil) reduced chemically induced colon tumor development in rats. Lignans have also been shown to prevent colon tumor development in experimental animals. The objective of this investigation is to study the effects of dietary flaxseed meal, a source of both omega-3 fatty acid and lignans, on colon tumor development and compare them with the effects of dietary corn meal. Male Fischer rats, two groups of 24 each, were assigned to the AIN-93M diet supplemented with either 15% corn meal or 15% flaxseed meal, respectively. Carcinogenesis was initiated with subcutaneous injections of azoxymethane (15 mg/kg) once a week for 3 consecutive wk. After 35 wk of initiation, rats were anesthetized with ether. Blood was collected by cardiac puncture, and rats were sacrificed. The gastrointestinal tract was isolated. The site, size, and number of tumors were recorded. The fatty acid analysis of the collected serum and colon samples was performed. Expression of cyclooxygenase (COX)-1 and COX-2 was performed by Western blot method. Lignan levels in serum and colon samples were assayed. Colon tumor incidence, multiplicity, and size were found to be 82.6% and 29.4%; 1.3 and 0.3; and 44.4 and 5.3 mm(2) in corn and flaxseed meal groups, respectively. Colon and serum samples of the corn meal group showed higher levels of omega-6 fatty acid levels whereas the flaxseed meal group exhibited higher levels of omega-3 fatty acids. COX-1 and COX-2 expression in the flaxseed group was significantly lower (P < 0.05) as compared to the corn group. Dietary flaxseed meal containing high levels of omega-3 fatty acids and lignans is effective in preventing colon tumor development when compared with dietary corn meal possibly by increasing omega-3 fatty acid levels and decreasing COX-1 and COX-2 levels.

Animals↗