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Angiogenesis is a process of new blood vessel formation from pre-existing ones. The most important steps in angiogenesis include detachment, proliferation, migration, homing and differentiation of vascular wall cells, which are mainly endothelial cells and their progenitors. The study focused on the effect of beta-carotene (BC) supplementation (12,000 mg/kg) in the diet on angiogenesis in Balb/c mice. Female Balb/c mice were fed for 5 weeks with two different diets: with BC or without BC supplementation. After 4 weeks of feeding, Balb/c mice were injected subcutaneously with two matrigel plugs with or without basic fibroblast growth factor (bFGF). Six days later, the animals were killed, and the matrigel plugs were used for immunohistochemical staining with CD31 antibody and for gene expression analysis. Microarray and Real-Time PCR data showed down-regulation of genes involved in proliferation and up-regulation of genes encoding inhibitors of apoptosis, proteins regulating cell adhesion, matrix-degrading enzymes and proteins involved in the VEGF pathway. The results of this study demonstrated that BC proangiogenic activity (with or without bFGF) in vivo seemed to be more significantly associated with cells’ protection from apoptosis and their stimulation of chemotaxis/homing than cell proliferation. [ABSTRACT FROM AUTHOR]

Epidemiological evidence links lycopene consumption with decreased prostate cancer risk. Several signaling pathways have been identified as players in prostate cancer development. Chronic prostatitis, for example, due to infections, is a suggested risk factor for prostate cancer. Endogenous production of reactive oxygen species during inflammation may lead to oxidative DNA damage, which can be mutagenic, if unrepaired. Androgen signaling, cytokine (IL-6, IL-4) and growth factor signaling (e.g., IGF, Wnt/β-catenin) cross-talk via PI3K/Akt, MAPK, and Jak/STAT pathways have been identified as major controllers of prostate growth. During disease progression, and after androgen ablation therapy, the remaining operational pathways are upregulated to compensate for the lost growth signal, finally resulting in androgen-independent prostate cancer. Lycopene modulates several of the aforementioned pathways, providing a promising rationale for prostate cancer risk reduction by lycopene: In many experimental setups, lycopene reduced inflammatory signals, prevented oxidative DNA damage, modulated the expression or activity of IGF axis members, of Wnt/β-catenin and androgen signalling, and enhanced gap junctional communication. Lycopene's influence on these pathways likely contributes to the observed cell growth inhibition and apoptosis induction by lycopene. A substantial part of the lycopene effects can be explained by its antioxidant action, but other mechanisms might also be involved. [ABSTRACT FROM AUTHOR]

Abstract: A number of epidemiological studies have reported associations of β-carotene plasma levels or intake with decreased lung cancer risk. However, intervention studies in smokers reported increased lung tumor rates after high long-term β-carotene supplementation. For insight into these conflicting results, we studied the influence of β-carotene on tobacco smoke carcinogen-induced lung cancer development in the A/J-mouse using 4-(N-Methyl-N-nitro samino)-1-(3-pyridyl)-1-butanone (NNK) as the initiator and lung adenoma multiplicity as the functional endpoint. Gene regulation of the putative tumor suppressor RARβ in mouse lung was analyzed by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for its relevance in predicting the endpoint of lung cancer. A/J-mice achieved plasma β-carotene levels of up to 3 μmol/L within 4 wk and up to 6 μmol/L after 6 mo of supplementation on a diet modified to enhance β-carotene absorption. Despite high lung β-carotene concentrations of up to 6 μmol/kg, tumor multiplicity was not significantly affected by the β-carotene treatment, either in carcinogen-initiated or non-initiated mice, and was unrelated to β-carotene dose and the time point of treatment during cancer formation. Tumor multiplicity did not correlate with β-carotene plasma levels in NNK-treated animals. All RARβ isoforms were significantly suppressed in the lungs of NNK- and NNK plus high dose β-carotene-treated animals. However, the number of tumors per mouse did not correlate with the RARβ-isoform expression levels. β-carotene alone after 3 mo of supplementation mildly but significantly increased levels of RARβ1, β2, and β4. This increase persisted for 6 mo for RARβ2 and β4. In summary, we found no effect of β-carotene on tumor formation in the NNK-initiated A/J-mouse lung cancer model with respect to dose or time point of treatment. β-Carotene-induced changes in RARβ isoform gene expression levels were not predictive for the number of lung tumors but were indicative of intact β-carotene metabolism and persistent sensitivity to retinoic acid in the mice. Down-regulation of RARβ in NNK-induced adenoma-bearing lungs was similar to that observed in human lung cancer and further confirms the A/J-mouse as a valuable model for lung carcinogenesis. [ABSTRACT FROM AUTHOR]

The article provides information on a study that examines lycopene effects on rat normal prostate and prostate tumor tissue. Epidemiological evidence links tomato consumption with reduced risk of prostate cancer. Prostate cancer remains a severe health problem throughout the Western world, and the success in treating advanced prostate cancer remains poor. Therefore, the importance of prevention through dietary measures is growing. Lycopene, a non-provitamin A carotenoid and the red pigment of tomatoes, is considered the major active compound in tomatoes. The health function of lycopene has been mainly linked to its potent antioxidant effects resulting in protection against oxidative DNA damage in vitro and in vivo. Lycopene also inhibits cell proliferation, at least in part due to its interference with insulin-like growth factor-I. In this study, to obtain insight into the in vivo mechanisms by which lycopene and/or vitamin E contribute to prostate cancer risk reduction, researchers used the MatLyLu Dunning prostate cancer model. In this model, thirty male Copenhagen rats were randomly assigned to 5 groups. The 2 control groups were non-supplemented controls and placebo-supplemented controls.

Focuses on a study which investigated the effect of lycopene on gene regulation in normal rat prostate. Uptake of lycopene in prostate tissue; Noninterference of lycopene with normal prostate growth; Activity of lycopene in normal prostate.

Deals with a study which tested the efficacy of lycopene and vitamin E in the treatment of Dunning prostate cancer. Methodology of the study; Accumulation of lycopene and vitamin E in tumor tissues; Role of lycopene in the reduction of 5-α-reductase and insulin-like growth factor-I.

High dose beta-carotene supplementation of smokers was associated with increased lung cancer risk in two intervention trials. It was proposed that generation of apocarotenals in smoke-exposed lungs impaired retinoic acid (RA) signaling, leading to squamous metaplasia and cell proliferation. To test this, we compared RA target gene regulation by retinoids, apocarotenals or beta-carotene by transcriptomics in BEAS-2B cells cultured to promote squamous differentiation. Retinoids, beta-carotene as well as apocarotenals induced known RA target genes. Retinoids upregulated involucrin, indicating that retinoids did not rescue BEAS-2B cells from squamous differentiation. Muc5AC, a marker for mucous differentiation, was transiently induced. beta-Carotene and apocarotenals less strongly induced involucrin and did not induce muc5AC. In summary, apocarotenals or beta-carotene upregulated RA target genes suggesting promotion, not inhibition, of RA signaling in BEAS-2B cells. Furthermore, apocarotenals and beta-carotene regulated gene expression independently of RA signaling. Squamous differentiation is not unequivocally linked to RA deficiency in BEAS-2B cells.

Objectives: Endothelial cells and their progenitors play an important role in angiogenesis that is essential for organogenesis and tissue remodelling, as well as for inflammatory responses and carcinogenesis in all periods of life. In the present study, the authors concentrated on the direct effect of beta-carotene (BC) on human umbilical cord-originated endothelial progenitor cells and human umbilical vein endothelial cells., Methods: BC uptake was measured using high-performance liquid chromatography. The effect on cell proliferation was measured based on bromodeoxyuridine incorporation. Chemotaxis was performed in a Boyden chamber. The influence on tubular-like structure formation was investigated using a three-dimensional assay in Matrigel (Becton Dickinson, USA) both in an in vitro and in vivo model. Changes in gene expression were analyzed using the microarray hybridization method. Quantitative gene expression was estimated using the real-time polymerase chain reaction method., Results: It was shown that BC, in the physiological range of concentrations found in human blood, is a potent activator of chemotaxis of endothelial cells. Microarray data analysis revealed that the genes involved in cell-cell and cell-matrix adhesion, matrix reorganization and activation of chemotaxis were the most affected by BC genes in human umbilical vein endothelial cells and endothelial progenitor cells. These results were also confirmed in an in vivo angiogenesis model., Conclusion: BC, in the range of physiological concentrations, stimulates early steps of angiogenic activity of endothelial cells by activation of cellular migration, as well as by matrix reorganization and a decrease in cellular adhesion.

A number of epidemiological studies have reported associations of beta-carotene plasma levels or intake with decreased lung cancer risk. However, intervention studies in smokers reported increased lung tumor rates after high long-term beta-carotene supplementation. For insight into these conflicting results, we studied the influence of beta-carotene on tobacco smoke carcinogen-induced lung cancer development in the A/J-mouse using 4-(N-Methyl-N-nitro samino)-1-(3-pyridyl)-1-butanone (NNK) as the initiator and lung adenoma multiplicity as the functional endpoint. Gene regulation of the putative tumor suppressor RARbeta in mouse lung was analyzed by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for its relevance in predicting the endpoint of lung cancer. A/J-mice achieved plasma beta-carotene levels of up to 3 micromol/L within 4 wk and up to 6 micromol/L after 6 mo of supplementation on a diet modified to enhance beta-carotene absorption. Despite high lung beta-carotene concentrations of up to 6 micromol/kg, tumor multiplicity was not significantly affected by the beta-carotene treatment, either in carcinogen-initiated or non-initiated mice, and was unrelated to beta-carotene dose and the time point of treatment during cancer formation. Tumor multiplicity did not correlate with beta-carotene plasma levels in NNK-treated animals. All RARbeta isoforms were significantly suppressed in the lungs of NNK- and NNK plus high dose beta-carotene-treated animals. However, the number of tumors per mouse did not correlate with the RARbeta-isoform expression levels. beta-carotene alone after 3 mo of supplementation mildly but significantly increased levels of RARbeta1, beta2, and beta4. This increase persisted for 6 mo for RARbeta2 and beta4. In summary, we found no effect of beta-carotene on tumor formation in the NNK-initiated A/J-mouse lung cancer model with respect to dose or time point of treatment. beta-Carotene-induced changes in RARbeta isoform gene expression levels were not predictive for the number of lung tumors but were indicative of intact beta-carotene metabolism and persistent sensitivity to retinoic acid in the mice. Down-regulation of RARbeta in NNK-induced adenoma-bearing lungs was similar to that observed in human lung cancer and further confirms the A/J-mouse as a valuable model for lung carcinogenesis.

We studied the influence of beta-carotene on the tobacco smoke carcinogen 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumor development in the A/J-mouse model. The normally low beta-carotene absorption was facilitated with a diet enriched in fat and bile salt, resulting in plasma and lung tissue levels similar to humans. beta-Carotene enhanced NNK-induced early bronchial cell proliferation, however, this effect was not predictive for later tumor development. Tumor multiplicity was not significantly affected by beta-carotene, neither in carcinogen-initiated nor in uninitiated mice, and regardless of dose and time point of supplementation during tumor development. RARbeta isoform and CYP26 gene expression levels analyzed by quantitative RT-PCR were weakly, but significantly, inversely correlated and showed evidence for altered retinoid signaling and catabolism in the lungs of NNK-initiated, beta-carotene supplemented mice. However, this interaction did not translate into enhanced tumor multiplicity. These results indicate that impaired retinoid signaling is not likely a key factor in lung tumorigenesis in this mouse model.

Ultraviolet light A (UVA) exposure is thought to cause skin aging mainly by singlet oxygen ((1)O(2))-dependent pathways. Using microarrays, we assessed whether pre-treatment with the (1)O(2) quencher beta-carotene (betaC; 1.5 microM) prevents UVA-induced gene regulation in HaCaT human keratinocytes. Downregulation of growth factor signaling, moderate induction of proinflammatory genes, upregulation of immediate early genes including apoptotic regulators and suppression of cell cycle genes were hallmarks of the UVA effect. Of the 568 UVA-regulated genes, betaC reduced the UVA effect for 143, enhanced it for 180, and did not interact with UVA for 245 genes. The different interaction modes imply that betaC/UVA interaction involved multiple mechanisms. In unirradiated keratinocytes, gene regulations suggest that betaC reduced stress signals and extracellular matrix (ECM) degradation, and promoted keratinocyte differentiation. In irradiated cells, expression profiles indicate that betaC inhibited UVA-induced ECM degradation, and enhanced UVA induction of tanning-associated protease-activated receptor 2. Combination of betaC-promoted keratinocyte differentiation with the cellular "UV response" caused synergistic induction of cell cycle arrest and apoptosis. In conclusion, betaC at physiological concentrations interacted with UVA effects in keratinocytes by mechanisms that included, but were not restricted to (1)O(2) quenching. The retinoid effect of betaC was minor, indicating that the betaC effects reported here were predominantly mediated through vitamin A-independent pathways.

UVA exposure causes skin photoaging by singlet oxygen (1)O(2)-mediated induction of, e.g., matrix metalloproteases (MMPs). We assessed whether pretreatment with beta-carotene, a (1)O(2) quencher and retinoic acid (RA) precursor, interferes with UVA-induced gene regulation. HaCaT keratinocytes were precultured with beta-carotene at physiological concentrations (0.5, 1.5, and 3.0 microM) prior to exposure to UVA from a Hönle solar simulator (270 kJ/m(2)). HaCaT cells accumulated beta-carotene in a time- and dose-dependent manner. UVA irradiation massively reduced the cellular beta-carotene content. Beta-carotene suppressed UVA-induction of MMP-1, MMP-3, and MMP-10, three major matrix metalloproteases involved in photoaging. We show that regulation by not only MMP-1, but also MMP-10, involves (1)O(2)-dependent mechanisms. Beta-carotene dose-dependently quenched (1)O(2)-mediated induction of MMP-1 and MMP-10. Thus, as in chemical solvent systems, beta-carotene quenches (1)O(2) also in living cells. Vitamin E did not cooperate with beta-carotene to further inhibit MMP induction. HaCaT cells produced weak retinoid activity from beta-carotene, as demonstrated by mild upregulation of RAR beta and activation of an RARE-dependent reporter gene. Beta-carotene did not regulate the genes encoding other RARs, RXRs, or the two beta-carotene cleavage enzymes. These results demonstrate that beta-carotene acts photoprotectively, and that this effect is mediated by (1)O(2) quenching.