Mechanisms in tumor promotion: guidance for risk assessment and cancer chemoprevention

Marks, Friedrich; Fürstenberger, Gerhard; Heinzelmann, T.; Müller‐Decker, Karin

doi:10.1016/0378-4274(95)03529-x

Cited by 19 publications

(8 citation statements)

References 37 publications

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“…These pleiotropic tissue responses are induced after TPA treatment and also occur during wound response. A close relationship between tumour promotion, tissue irritation and damage is well known68 and repeated wounding has been found to exert a powerful tumour‐promoting effect in initiated mouse skin 69. Under such conditions, a variety of mitogenic and anti‐mitogenic signals including pro‐inflammatory mediators are locally released and provide signals for both wound repair and clonal expansion of initiated cells.…”

Section: Discussionmentioning

confidence: 99%

Profile of gene expression induced by the tumour promotor TPA in murine epithelial cells

Schlingemann

Heß

Wrobel

et al. 2003

Intl Journal of Cancer

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Malignant transformation of mouse skin by chemical carcinogens and tumour promoters, such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), is a multistage process that leads to squamous cell carcinoma (SCC) formation. In an effort to identify tumour-associated genes, we studied the influence of short-term TPA-treatment on the gene expression profile of murine skin. A comprehensive microarray with some 5,000 murine gene specific cDNA fragments was established and hybridised with pooled RNA derived from control and TPA-treated dorsal skin samples. Of these genes, 54 were up-and 35 were down-regulated upon TPA application. Additionally, we performed suppression subtractive hybridisation (SSH) with respective RNA pools to generate and analyse a cDNA library enriched for TPA-inducible genes. Expression data of selected genes were confirmed by quantitative real-time PCR and Northern blot analysis. Comparison of microarray and SSH data revealed that 26% of up-regulated genes identified by expression profiling matched with those present in the SSH library. Besides numerous known genes, we identified a large set of unknown cDNAs that represent previously unrecognised TPA-regulated genes in murine skin with potential function in tumour promotion. Additionally, some TPA-induced genes, such as Sprr1A, Saa3, JunB, Il4r␣, Gp38, RalGDS and Slpi exhibit high basal level in advanced stages of skin carcinogenesis, suggesting that at least a subgroup of the identified TPA-regulated genes may contribute to tumour progression and metastasis.

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Section: Discussionmentioning

confidence: 99%

Profile of gene expression induced by the tumour promotor TPA in murine epithelial cells

Schlingemann

Heß

Wrobel

et al. 2003

Intl Journal of Cancer

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“…A proinflammatory cytokine, TNF-α (37), is an important agent in some processes of tumor development through its induction of the biosynthesis of matrix metalloproteinase and plasminogen activator (38), by expressing COX-2 (39) and iNOS (40), along with an association with tumor promotion (41). In fact, accumulating evidence from rodent and human studies demonstrates that COX-2 expression and TNF-α-release are the key steps in multi-step carcinogenic processes in a wide range of target organs (42)(43)(44)(45)(46)(47)(48)(49)(50). Further, it should be pointed out that the biological efficacy of ZER to suppress free radical generation, iNOS/COX-2 induction, and TNF-α-release is conspicuous among the food phytochemicals we have so far reported, including 1'-acetoxychaviaol acetate (29), auraptene (30), and AL-1 (31), as well as resveratrol and nobiletin (12).…”

Section: Discussionmentioning

confidence: 99%

Zerumbone, a Southeast Asian ginger sesquiterpene, markedly suppresses free radical generation, proinflammatory protein production, and cancer cell proliferation accompanied by apoptosis: the alpha,beta-unsaturated carbonyl group is a prerequisite

et al. 2002

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Zerumbone (ZER), a sesquiterpene from the edible plantZingiber zerumbet Smith, has recently been found to suppress tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Epstein-Barr virus activation in a potent manner. In the present study, we evaluated the antiinflammatory and chemopreventive potentials of ZER in a variety of cell culture experiments. ZER effectively suppressed TPA-induced superoxide anion generation from both NADPH oxidase in dimethylsulfoxide-differentiated HL-60 human acute promyelocytic leukemia cells and xanthine oxidase in AS52 Chinese hamster ovary cells. The combined lipopolysaccharide-and interferon-γ-stimulated protein expressions of inducible nitric oxide synthase and cyclooxygenase (COX)-2, together with the release of tumor necrosis factor-α, in RAW 264.7 mouse macrophages were also markedly diminished. These suppressive events were accompanied with a combined decrease in the medium concentrations of nitrite and prostaglandin E 2 , while the expression level of COX-1 was unchanged. ZER inhibited the proliferation of human colonic adenocarcinoma cell lines (LS174T, LS180, COLO205, and COLO320DM) in a dose-dependent manner, while the growth of normal human dermal (2F0-C25) and colon (CCD-18 Co) fibroblasts was less affected. It also induced apoptosis in COLO205 cells, as detected by dysfunction of the mitochondria transmembrane, Annexin V-detected translocation of phosphatidylserine, and chromatin condensation. Intriguingly, α-humulene, a structural analog lacking only the carbonyl Abbreviations: AP, allopurinol; COX, cyclooxygenase; DMEM, Dulbecco's modified Eagle medium; DMSO, dimethylsulfoxide; DPI, diphenyleneiodonium; EBV, Epstein-Barr virus; FBS, fetal bovine serum; FITC, fluorescence isothiocyanate; HUM, α-humulene; IFN, interferon; iNOS, inducible NO; synthase; IR, inhibitory rate; LPS, lipopolysaccharide; MEM, minimum essential medium; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NF-ΦB, nuclear factor-kappaB; NO, nitric oxide; NO 2 -, nitrite; O 2 -, superoxide anion; PBS, phosphate-buffered saline; PG, prostaglandin; PI, propiodium iodide; PS, phosphatidylserine; TNF, tumor necrosis factor; TPA, 12-O-tetradecanoylphorbol-13-acetate; XO, xanthine oxidase; ZER, zerumbone.© Oxford University Press 795 group in ZER, was virtually inactive in all experiments conducted, indicating that the α,β-unsaturated carbonyl group in ZER may play some pivotal roles in interactions with unidentified target molecule(s). Taken together, our results indicate that ZER is a food phytochemical that has distinct potentials for use in anti-inflammation, chemoprevention, and chemotherapy strategies.

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“…The genetic instability underlying the progression towards malignancy appears to be an intrinsic property of papilloma cells. It may result from deregulation of endogenous signaling pathways that are thought to control cell survival and propagation or from generation of endogenous genotoxic metabolites and perhaps impairment of DNA repair [7].…”

Section: Introductionmentioning

confidence: 99%

“…Mechanistic studies of multistage carcinogenesis may be used for guidance for cancer prevention [7]. The molecular events involved in tumor promotion in particular are attractive targets for chemoprevention.…”

Section: Introductionmentioning

confidence: 99%

Localization of prostaglandin H synthase isoenzymes in murine epidermal tumors: Suppression of skin tumor promotion by inhibition of prostaglandin H synthase-2

et al. 1998

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The growth factor- and phorbol ester-inducible prostaglandin H synthase (PGHS)-2 has been found to be constitutively overexpressed in epidermal tumors generated by the initiation-promotion protocol in murine skin, whereas the expression of PGHS-1 does not change under these conditions. In this paper we report the intra-tumor distribution of the aberrantly expressed PGHS-2 and the cancer chemopreventive activity of a specific PGHS-2 inhibitor. By immunohistochemical methods using isoenzyme-specific antibodies, we found that the PGHS-1 protein was expressed in keratinocytes and Langerhans cells dispersed throughout the epithelial part of papillomas and squamous cell carcinomas and in inflammatory infiltrates occasionally seen in these tumors. A uniform pattern of PGHS-2 expression was observed in the basal keratinocytes of papillomas and in the follicular keratinocytes of carcinomas. In addition, Langerhans cells as well as tumor-associated inflammatory infiltrates exhibited PGHS-2-specific immunoreactivity. PGHS-2-catalyzed prostaglandin synthesis stimulated by the phorbol ester 12-O-tetradecanoylphorbol-13 acetate (TPA) in mouse epidermis in vivo was dose-dependently suppressed by topical administration of SC-58125, a specific PGHS-2 inhibitor. TPA-induced edema formation, epidermal DNA synthesis, and mitotic activity were not impaired by SC-58125 applied at a dose that inhibited TPA-induced prostaglandin E2 synthesis. However, the repetitive epicutaneous administration of SC-58125 substantially and significantly suppressed papilloma development. Malignant progression of papillomas was slightly retarded by the drug. These results indicate that aberrant expression of PGHS-2 in epidermal tumors may be a relevant target for prevention of epidermal cancer development in experimental animals and that the PGHS-2-specific inhibitor SC-58125, which is a potent inhibitor of tumor promotion in mouse skin, may be important for cancer chemoprevention in humans as well.

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Mechanisms in tumor promotion: guidance for risk assessment and cancer chemoprevention

Cited by 19 publications

References 37 publications

Profile of gene expression induced by the tumour promotor TPA in murine epithelial cells

Profile of gene expression induced by the tumour promotor TPA in murine epithelial cells

Zerumbone, a Southeast Asian ginger sesquiterpene, markedly suppresses free radical generation, proinflammatory protein production, and cancer cell proliferation accompanied by apoptosis: the alpha,beta-unsaturated carbonyl group is a prerequisite

Localization of prostaglandin H synthase isoenzymes in murine epidermal tumors: Suppression of skin tumor promotion by inhibition of prostaglandin H synthase-2

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