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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to determine whether a dry bean (Phaseolus vulgaris, L.) containing diet exerts an inhibitory effect on mammary carcinogenesis in a well-characterized rodent model for breast cancer. Twenty-one-d-old female Sprague Dawley rats were given an intraperitoneal injection of 1-methyl-1-nitrosourea and 7 d after carcinogen injection were randomized to 1 of 5 groups fed a modification of the AIN-93G diet formulation containing 0, 7.5, 15, 30, or 60% (wt:wt) small red dry bean incorporated as cooked, freeze-dried, and milled powder. All experimental diets had the same macronutrient content based on proximate analysis. Compared with the control group, dry bean consumption resulted in dose-dependent reductions in mammary cancer incidence (P = 0.046), cancer multiplicity (P = 0.001), and tumor burden (P = 0.01). Dry bean consumption was associated with dose-dependent reductions in plasma concentrations of glucose, insulin, insulin-like growth factor-1, C-reactive protein, and interleukin-6 in food-deprived rats. Analysis of mammary adenocarcinomas indicated that a dominant mechanism accounting for reduced tumor burden was the induction of apoptosis. B cell lymphoma 2 and X-linked inhibitor of apoptosis protein levels decreased and BCL-2-associated X protein increased with increasing dry bean consumption, findings consistent with the induction of apoptosis via the mitochondrial pathway. These data demonstrate that a legume without noteworthy content of isoflavones inhibits the development of mammary carcinogenesis and are consistent with a recent report from the Nurses Health Study that bean or lentil intake is associated with a lower risk for breast cancer.
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PMID:Mechanisms associated with dose-dependent inhibition of rat mammary carcinogenesis by dry bean (Phaseolus vulgaris, L.). 1893 3

The prevalence of obesity, an established epidemiologic risk factor for many cancers, has risen steadily for the past several decades in the US. The increasing rates of obesity among children are especially alarming and suggest continuing increases in the rates of obesity-related cancers for many years to come. Unfortunately, the mechanisms underlying the association between obesity and cancer are not well understood. In particular, the effects on the carcinogenesis process and mechanistic targets of interventions that modulate energy balance, such as reduced-calorie diets and physical activity, have not been well characterized. The purpose of this review is to provide a strong foundation for the translation of mechanism-based research in this area by describing key animal and human studies of energy balance modulations involving diet or physical activity and by focusing on the interrelated pathways affected by alterations in energy balance. Particular attention is placed on signaling through the insulin and insulin-like growth factor-1 receptors, including components of the Akt and mammalian target of rapamycin (mTOR) signaling pathways downstream of these growth factor receptors. These pathways have emerged as potential targets for disrupting the obesity-cancer link. The ultimate goal of this work is to provide the missing mechanistic information necessary to identify targets for the prevention and control of cancers related to or caused by excess body weight.
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PMID:Reducing the weight of cancer: mechanistic targets for breaking the obesity-carcinogenesis link. 1897 Nov 25

Obesity is rapidly becoming a global phenomenon. This is more than a cosmetic issue as obesity is associated with several life-threatening diseases, including colon cancer. Insulin resistance and inflammation, underlying factors in obesity-related diseases, promote colonocyte proliferation and suppress programmed cell death, or apoptosis, by activating the insulin-like growth factor (IGF) and prostaglandin pathways. These pathways converge on the Wnt pathway, which is implicated in colon carcinogenesis. Despite tremendous advances in our understanding of the molecular mechanisms involved in colon carcinogenesis, mortality due to colon cancer world-wide is unacceptably high. Even though conventional therapies can prolong a patient's life-span a few years, they cause serious side effects. Thus, there is growing interest in functional foods and dietary bioactive compounds with chemopreventive properties. This search is fueled by the epidemiological studies indicating that plant-based diets are protective against several types of cancers. This review provides a brief summary of the IGF and prostaglandin pathways, which are implicated in obesity-enhanced colon cancer, and some of the functional foods/dietary compounds that target these pathways. It is essential to understand the molecular mechanisms involved in chemoprevention before providing appropriate science-based dietary recommendations to prevent colon cancer in both obese and non-obese individuals.
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PMID:Obesity-enhanced colon cancer: functional food compounds and their mechanisms of action. 1899 70

The prevalence of obesity, an established epidemiologic risk factor for many chronic diseases including cancer, has been steadily increasing in the US over several decades. The mechanisms used to regulate energy balance and adiposity and the relationship of these factors to cancer are not completely understood. Here we have used knockout mice to examine the roles of the transcription factors CCAAT/enhancer-binding protein (C/EBP) beta and C/EBPdelta in regulating body composition and systemic levels of hormones such as insulin-like growth factor-1 (IGF-1), leptin and insulin that mediate energy balance. Dual-energy X-ray absorptiometry showed that C/EBPbeta, either directly or indirectly, modulated body weight, fat content and bone density in both males and females, while the effect of C/EBPdelta was minor and only affected adiposity and body weight in female animals. Levels of IGF-1, leptin and insulin in the serum were decreased in both male and female C/EBPbeta(-/-) mice, and C/EBPbeta was associated with their promoters in vivo. Moreover, colon adenocarcinoma cells displayed reduced tumorigenic potential when transplanted into C/EBPbeta-deficient animals, especially males. Thus, C/EBPbeta contributes to endocrine expression of IGF-1, leptin and insulin, which modulate energy balance and can contribute to cancer progression by creating a favorable environment for tumor cell proliferation and survival.
Carcinogenesis 2009 May
PMID:C/EBPbeta regulates body composition, energy balance-related hormones and tumor growth. 1905 28

The critical role played by stroma-epithelium crosstalk in carcinogenesis and progression of prostate cancer has been increasingly recognized. These interactions are mediated by a variety of paracrine factors secreted by cancer cells and/or stromal cells. In human prostate cancer, reactive stroma is characterized by an increase in myofibroblasts and a corresponding amplification of extracellular matrix production and angiogenesis. Permanent genetic mutations have been reported in stromal cells as well as in tumour cells. Transforming growth factor-beta, vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor signalling pathways are involved in the process of angiogenesis, whereas hepatocyte growth factor, insulin-like growth factor-1, epidermal growth factor, CXC12 and Interleukin-6 play active roles in the progression, androgen-independent conversion and distal metastasis of prostate cancer. Some soluble factors have reciprocal interactions with androgens and the androgen receptor (AR), and can even activate AR in the absence of the androgen ligand. In this article, we review the complex interactions between cancer cells and the surrounding microenvironment, and discuss the potential therapeutic targets in the stromal compartment of prostate cancer.
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PMID:Stroma-epithelium crosstalk in prostate cancer. 1909 34

This chapter posits that cancer is a complex and multifactorial process as demonstrated by the expression and production of key endocrine and steroid hormones that intermesh with lifestyle factors (physical activity, body size, and diet) in combination to heighten cancer risk. Excess weight has been associated with increased mortality from all cancers combined and for cancers of several specific sites. The prevalence of obesity has reached epidemic levels in many parts of the world; more than 1 billion adults are overweight with a body mass index (BMI) exceeding 25. Overweight and obesity are clinically defined indicators of a disease process characterized by the accumulation of body fat due to an excess of energy intake (nutritional intake) relative to energy expenditure (physical activity). When energy intake exceeds energy expenditure over a prolonged period of time, the result is a positive energy balance (PEB), which leads to the development of obesity. This physical state is ideal for intervention and can be modulated by changes in energy intake, expenditure, or both. Nutritional intake is a modifiable factor in the energy balance-cancer linkage primarily tested by caloric restriction studies in animals and the effect of energy availability. Restriction of calories by 10 to 40% has been shown to decrease cell proliferation, increasing apoptosis through anti-angiogenic processes. The potent anticancer effect of caloric restriction is clear, but caloric restriction alone is not generally considered to be a feasible strategy for cancer prevention in humans. Identification and development of preventive strategies that "mimic" the anticancer effects of low energy intake are desirable. The independent effect of energy intake on cancer risk has been difficult to estimate because body size and physical activity are strong determinants of total energy expenditure. The mechanisms that account for the inhibitory effects of physical activity on the carcinogenic process are reduction in fat stores, activity related changes in sex-hormone levels, altered immune function, effects in insulin and insulin-like growth factors, reduced free radical generation, and direct effect on the tumor. Epidemiologic evidence posits that the cascade of actions linking overweight and obesity to carcinogenesis are triggered by the endocrine and metabolic system. Perturbations to these systems result in the alterations in the levels of bioavailable growth factors, steroid hormones, and inflammatory markers. Elevated serum concentrations of insulin lead to a state of hyperinsulinemia. This physiological state causes a reduction in insulin-like growth factor-binding proteins and promotes the synthesis and biological activity of insulin-like growth factor (IGF)-I, which regulates cellular growth in response to available energy and nutrients from diet and body reserves. In vitro studies have clearly established that both insulin and IGF-I act as growth factors that promote cell proliferation and inhibit apoptosis. Insulin also affects on the synthesis and biological availability of the male and female sex steroids, including androgens, progesterone, and estrogens. Experimental and clinical evidence also indicates a central role of estrogens and progesterone in regulating cellular differentiation, proliferation, and apoptosis induction. Hyperinsulinemia is also associated with alterations in molecular systems such as endogenous hormones and adipokines that regulate inflammatory responses. Obesity-related dysregulation of adipokines has the ability to contribute to tumorigenesis and tumor invasion via metastatic potential. Given the substantial level of weight gain in industrialized countries in the last two decades, there is great interest in understanding all of the mechanisms by which obesity contributes to the carcinogenic process. Continued focus must be directed to understanding the various relationships between specific nutrients and dietary components and cancer cause and prevention. A reductionist approach is not sufficient for the basic biological mechanisms underlying the effect of diet and physical activity on cancer. The joint association between energy balance and cancer risk are hypothesized to share the same underlying mechanisms, the amplification of chemical mediators that modulate cancer risk depending on the responsiveness to those hormones to the target tissue of interest. Disentangling the connection between obesity, the insulin-IGF axis, endogenous hormones, inflammatory markers, and their molecular interaction is vital.
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PMID:Energy balance, physical activity, and cancer risk. 1910 29

Obesity and diabetes mellitus are risk factors for colon cancer. The activation of the insulin-like growth factor (IGF)/IGF-IR axis plays a critical role in this carcinogenesis. (-)-Epigallocatechin gallate (EGCG), the major constituent of green tea, seems to have both antiobesity and antidiabetic effects. This study examined the effects of EGCG on the development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice, which are obese and develop diabetes mellitus. Male db/db mice were given four weekly s.c. injections of azoxymethane (15 mg/kg body weight) and then they received drinking water containing 0.01% or 0.1% EGCG for 7 weeks. At sacrifice, drinking water with EGCG caused a significant decrease in the number of total aberrant crypt foci, large aberrant crypt foci, and beta-catenin accumulated crypts in these mice, all of which are premalignant lesions of the colon. The colonic mucosa of db/db mice expressed high levels of the IGF-IR, phosphorylated form of IGF-IR (p-IGF-IR), p-GSK-3beta, beta-catenin, cyclooxygenase-2, and cyclin D1 proteins, and EGCG in drinking water caused a marked decrease in the expression of these proteins. Treating these mice with EGCG also caused an increase in the serum level of IGFBP-3 while conversely decreasing the serum levels of IGF-I, insulin, triglyceride, cholesterol, and leptin. EGCG overcomes the activation of the IGF/IGF-IR axis, thereby inhibiting the development of colonic premalignant lesions in an obesity-related colon cancer model, which was also associated with hyperlipidemia, hyperinsulinemia, and hyperleptinemia. EGCG may be, therefore, useful in the chemoprevention or treatment of obesity-related colorectal cancer.
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PMID:(-)-Epigallocatechin gallate suppresses azoxymethane-induced colonic premalignant lesions in male C57BL/KsJ-db/db mice. 1913 73

Colon cancer patients frequently show increased levels of serum insulin-like growth factor-binding protein-2 (IGFBP-2), however, the pathogenetic relevance of this phenomenon for colorectal cancer is unclear. Therefore, we have used IGFBP-2 transgenic animals which overexpress IGFBP-2 systemically and locally in the intestine to study its role in chemically induced colorectal carcinogenesis. Mice received intraperitoneal injections of 1,2-dimethylhydrazine (DMH) (40 mg/kg body weight) once a week for 6 weeks to selectively induce aberrant crypt foci (ACF) and tumors in the colon. While tumor incidence was comparable in transgenic and control mice, the volume of adenomas in IGFBP-2 transgenic mice was reduced more than 2-fold. Furthermore, serum IGFBP-2 levels negatively correlated with tumor volume in the IGFBP-2 transgenic group. Histological examination showed that IGFBP-2 transgenic mice developed significantly less dysplastic ACF with a high potential to progress to advanced stages. The reduced tumor volume in IGFBP-2 transgenic animals was due to significantly reduced proliferative capacity, evidenced by a lower proportion of cells positive for Ki67. Our results demonstrate for the first time in an experimental model that IGFBP-2 overabundance prior to the onset and during colorectal carcinogenesis reduces tumor growth by inhibition of cell proliferation.
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PMID:IGFBP-2 overexpression reduces the appearance of dysplastic aberrant crypt foci and inhibits growth of adenomas in chemically induced colorectal carcinogenesis. 1914 66

Consumption of cow's milk and cow's milk protein result in changes of the hormonal axis of insulin, growth hormone and insulin-like growth factor-1(IGF-1) in humans. Milk consumption raises IGF-1 serum levels in the perinatal period, adolescence and adulthood. During puberty with the physiological onset of increased secretion of growth hormone, IGF-1 serum levels increase and are further enhanced by milk consumption. IGF-1 is a potent mitogen; after binding to its receptor in various tissues, it induces cell proliferation and inhibits apoptosis. Keratinocytes and sebocytes, as well as the androgen-synthesizing adrenals and gonads, are stimulated by IGF-1. The epidemic incidence of adolescent acne in Western milk-consuming societies can be explained by the increased insulin- and IGF-1-stimulation of sebaceous glands mediated by milk consumption. Acne can be regarded as a model for chronic Western diseases with pathologically increased IGF-1-stimulation. Many other organs, such as the thymus, bones, all glands, and vascular smooth muscle cells as well as neurons are subject to this abnormally increased hormonal stimulation. The milk-induced change of the IGF-1-axis most likely contributes to the development of fetal macrosomia, induction of atopy, accelerated linear growth, atherosclerosis, carcinogenesis and neurodegenerative diseases. Observations of molecular biology are supported by epidemiologic data and unmask milk consumption as a promoter of chronic diseases of Western societies.
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PMID:Milk consumption: aggravating factor of acne and promoter of chronic diseases of Western societies. 1924 83

Endometrial serous carcinomas (ESC) constitute only approximately 10% of endometrial cancers, but have a substantially higher case-fatality rate than their more common endometrioid counterparts. The precise composite of factors driving endometrial serous carcinogenesis and progression remain largely unknown, but we attempt to review the current state of knowledge in this report. ESC probably do not evolve through a single pathway, and their underlying molecular events probably occur early in their evolution. TP53 gene mutations occur in 22.7 to 96% of cases, and p53 protein overexpression is seen in approximately 76%. By gene expression profiling, p16 is upregulated in ESC significantly above both normal endometrial cells and endometrioid carcinomas, and 92-100% of cases display diffuse expression of the p16 protein by immunohistochemistry (IHC). Together, these findings suggest dysregulation of both the p16(INKA)/Cyclin D-CDK/pRb-E2F and the ARF-MDM2-p53 cell cycle pathways in ESC. By IHC, HER2/neu is overexpressed (2+ or 3+) in approximately 32.1% of ESC, and approximately 54.5% of cases scored as 2+ or 3+ by IHC display c-erbB2 gene amplification as assessed by fluorescent in situ hybridization. Genetic instability, typically manifested as loss of heterozygosity in multiple chromosomes, is a common feature of ESC, and one study found loss of heterozygosity at 1p32-33 in 63% of cases. A subset of ESC display protein expression patterns that are characteristic of high grade endometrial carcinomas, including loss of the metastasis suppressor CD82 (KAI-1) and epithelial-to-mesenchymal transformation, the latter manifested as E-cadherin downregulation, P-cadherin upregulation, and expression of epithelial-to-mesenchymal transformation-related molecules such as zinc-finger E-box-binding homeobox 1 (ZEB1) and focal adhesion kinase. Preliminary data suggests differential patterns of expression in ESC of some isoforms of claudins, proteases, the tumor invasiveness and progression-associated oncofetal protein insulin-like growth factor II mRNA-binding protein 3 (IMP3), as well as a variety of other molecules. At the morphologic level, evidence that indicates that endometrial glandular dysplasia (EmGD) is the most likely morphologically recognizable precursor lesion to ESC is presented. We advocate use of the term endometrial intraepithelial carcinoma (EIC, or its other appellations) only as a morphologic descriptor and never as a diagnostic/pathologic statement of biologic potential. Given its potential for extrauterine extension, we consider the lesions described as EIC, when present in isolation, as examples of localized ESC, and patients should be managed as such. Morphologically normal, p53 immunoreactive endometrial cells (the so-called "p53 signatures"), show a statistically significant association with ESC, display p53 mutations in a significant subset, and form the start of a progression model, outlined herein, from p53 signatures to EmGD to localized ESC to the more conventionally invasive neoplasm. The identification of a morphologically-recognizable precursor holds the promise of early detection of ESC, with the attendant reduction in its overall associated mortality rate. Deciphering the molecular basis for endometrial serous carcinogenesis should uncover potential targets for diagnosis, therapy, and/or disease surveillance.
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PMID:Insights into endometrial serous carcinogenesis and progression. 1929 1


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