Angiogenesis is an early event in the development of chemically induced skin tumors

Bolontrade, Marcela F.; Stern, Mariana C.; Binder, Robert L.; Zenklusen, Jean C.; Gimenez-Conti, Irma; Conti, Claudio J.

doi:10.1093/carcin/19.12.2107

Cited by 64 publications

(63 citation statements)

References 37 publications

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“…The causal role of angiogenesis in cancer has been assessed in vivo using animal models, including both traditional tumor transplants and mouse models of multistage carcinogenesis. From the latter, it is thought that neovascularization is first activated by an 'angiogenic switch' during premalignant phases of carcinogenesis, before tumors emerge (Folkman et al, 1989;Hanahan and Folkman, 1996;Bolontrade et al, 1998;Huss et al, 2001). Using the 3LL transplantation model, we found that S-Eng þ mice exhibit a deficient angiogenic phenotype leading to retardation of tumor growth.…”

Section: Discussionmentioning

confidence: 87%

Characterization of murine S-endoglin isoform and its effects on tumor development

et al. 2005

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Endoglin is a transmembrane glycoprotein that acts as an auxiliary receptor for transforming growth factor-b (TGF-b) and modulates cellular responses to this pleiotropic cytokine. Endoglin is strongly expressed in endothelial cells, where it appears to exert a crucial role in vascular development and angiogenesis. Two endoglin isoforms (L and S), differing in their cytoplasmic domains, have been previously characterized in human tissues. We now demonstrate the existence of similar L-and Sendoglin variants in murine tissues with 47 and 35 amino acids, respectively, in their cytoplasmic tail. RT-PCR analysis showed that L is the predominant endoglin isoform expressed in mouse tissues, although S-endoglin mRNA is significantly expressed in liver and lung, as well as in endothelial cell lines. Furthermore, a protein of size equivalent to recombinant S-endoglin expressed in mammalian cells was detected in mouse endothelial cells by Western blot analysis. L-and S-endoglin isoforms can form disulfide-linked heterodimers, as demonstrated by cotransfection of L-and S-endoglin constructs. To address the role of S-endoglin in vivo, an S-Eng þ transgenic mouse model that targets S-endoglin expression to the endothelium was generated. The lethal phenotype of endoglin-null (Eng À/À ) mice was not rescued by breeding S-Eng þ transgenic mice into the endoglin-null background. S-Eng þ mice exhibited reduced tumor growth and neovascularization after transplantation of Lewis lung carcinoma cells. In addition, S-Eng þ mice showed a drastic inhibition of benign papilloma formation when subjected to two-stage chemical skin carcinogenesis. These results point to S-endoglin as an antiangiogenic molecule, in contrast to L-endoglin which is proangiogenic.

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Section: Discussionmentioning

confidence: 87%

Characterization of murine S-endoglin isoform and its effects on tumor development

et al. 2005

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“…Moreover, studies have suggested that cyclin D1 can be induced by growth factors and TPA through activation of various signaling pathways including Ras/MAPKs, PI3K/Akt, AP-1, CREB, and NF-nB (62,63). Similarly, reports suggest that VEGF is a potent regulator of angiogenesis and Ha-rasmediated EGFR activation and Akt signaling are involved in the regulation of skin angiogenesis (64,65). In skin carcinogenesis, angiogenesis occurs very early in papilloma development, establishing blood vessel networks as tumors progress (65).…”

Section: Pge 2 Can Induce Cyclin D1 and Vegf In Vivomentioning

confidence: 99%

Multiple Signaling Pathways Are Responsible for Prostaglandin E2–Induced Murine Keratinocyte Proliferation

Ansari

Rundhaug

Fischer

2008

Molecular Cancer Research

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Although prostaglandin E 2 (PGE 2 ) has been shown by pharmacologic and genetic studies to be important in skin cancer, the molecular mechanism(s) by which it contributes to tumor growth is not well understood. In this study, we investigated the mechanisms by which PGE 2 stimulates murine keratinocyte proliferation using in vitro and in vivo models. In primary mouse keratinocyte cultures, PGE 2 activated the epidermal growth factor receptor (EGFR) and its downstream signaling pathways as well as increased cyclic AMP (cAMP) production and activated the cAMP response element binding protein (CREB). EGFR activation was not significantly inhibited by pretreatment with a c-src inhibitor (PP2), nor by a protein kinase A inhibitor (H-89). However, PGE 2 -stimulated extracellularly regulated kinase 1/2 (ERK1/2) activation was completely blocked by EGFR, ERK1/2, and phosphatidylinositol 3-kinase (PI3K) pathway inhibitors. In addition, these inhibitors attenuated the PGE 2 -induced proliferation, nuclear factor-KB, activator protein-1 (AP-1), and CREB binding to the promoter regions of the cyclin D1 and vascular endothelial growth factor (VEGF) genes and expression of cyclin D1 and VEGF in primary mouse keratinocytes. Similarly, in vivo, we found that WT mice treated with PGE 2 and untreated cyclooxygenase-2 -overexpressing transgenic mice had higher levels of cell proliferation and expression of cyclin D1 and VEGF, as well as higher levels of activated EGFR, nuclear factor-KB, AP-1, and CREB, than vehicle-treated WT mice. Our findings provide evidence for a link between cyclooxygenase-2 overexpression and EGFR-, ERK-, PI3K-, cAMP-mediated cell proliferation, and the tumor-promoting activity of PGE 2 in mouse skin.

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“…2D). Angiogenesis has been described in benign papillomas induced with 7,12-dimethylbenz[a]anthracene (tumor initiator) and 12-Otetradecanoylphorbol-13-acetate (tumor promoter) in mice (Bolontrade et al, 1998).…”

Section: Beckwith Et Almentioning

confidence: 99%

Ethylnitrosourea Induces Neoplasia in Zebrafish (Danio rerio)

Beckwith

Moore

Tsao-Wu

et al. 2000

Laboratory Investigation

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SUMMARY:The zebrafish (Danio rerio) has been successfully used to discover hundreds of genes involved in development and organogenesis. To address the potential of zebrafish as a cancer model, it is important to determine the susceptibility of zebrafish to tumors. Germ line mutations are most commonly induced for zebrafish mutant screens by exposing adult male zebrafish to the alkylating agent, ethylnitrosourea (ENU). To determine whether ENU induces tumors, we compared the incidence of tumors in ENU-treated fish with untreated controls. Interestingly, 18 of 18 (100%) fish mutagenized with either 2.5 or 3.0 mM ENU developed epidermal papillomas, which numbered 1 to 22 per fish, within 1 year of treatment. The induced epidermal lesions included epidermal hyperplasia, flat papillomas (0.2 to 1.2 mm), and pedunculated papillomas (1.2 to 8 mm in greatest dimension), but no skin cancers. Angiogenesis was evident in papillomas larger than approximately 1 mm. All but two papillomas contained the three cell types (keratinocytes, club, and mucous cells) of normal zebrafish epidermis; histologic variants lacked either club cells or mucous cells. Two cavernous hemangiomas and a single malignant peripheral nerve sheath tumor were also found in the treated fish. None of five untreated controls developed tumors. These studies establish the feasibility of the zebrafish as an experimental model for the study of skin tumors. (Lab Invest 2000, 80:379-385).

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Angiogenesis is an early event in the development of chemically induced skin tumors

Cited by 64 publications

References 37 publications

Characterization of murine S-endoglin isoform and its effects on tumor development

Characterization of murine S-endoglin isoform and its effects on tumor development

Multiple Signaling Pathways Are Responsible for Prostaglandin E2–Induced Murine Keratinocyte Proliferation

Ethylnitrosourea Induces Neoplasia in Zebrafish (Danio rerio)

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