Incidence Of Skin Tumors Research Articles

Solid-State and Solution Characterization of Myricetin.

Myricetin (MYR) is a natural compound that has been investigated as a chemopreventative agent. MYR has been shown to suppresses ultraviolet B (UVB)-induced cyclooxygenase-2 (COX-2) protein expression and reduce the incidence of UVB-induced skin tumors in mice. Despite MYR's promise as a therapeutic agent, minimal information is available to guide the progression of formulations designed for future drug development. Here, data is presented describing the solid-state and solution characterization of MYR. Investigation into the solid-state properties of MYR identified four different crystal forms, two hydrates (MYR I and MYR II) and two metastable forms (MYR IA and MYR IIA). From solubility studies, it was evident that all forms are very insoluble (<5 μg/ml) in pure water. MYR I was found to be the most stable form at 23, 35, and 56°C. Stability determination indicated that MYR undergoes rapid apparent first-order degradation under basic pH conditions, and that degradation was influenced by buffer species. Apparent first-order degradation was also seen when MYR was introduced to an oxidizing solution. Improved stability was achieved after introducing 0.1% antioxidants to the solution. MYR was found to have good stability following exposure to ultraviolet radiation (UVR), which is a consideration for topical applications. Finally, a partitioning study indicated that MYR possess a log P of 2.94 which, along with its solid-state properties, contributes to its poor aqueous solubility. Both the solid-state properties and solution stability of MYR are important to consider when developing future formulations.

Incidence, risk factors and outcome ofde novotumors in liver transplant recipients focusing on alcoholic cirrhosis

Orthotopic liver transplantation (OLT) is an established life-saving procedure for alcoholic cirrhotic (AC) patients, but the incidence of de novo tumors ranges between 2.6% and 15.7% and is significantly increased in comparison with patients who undergo OLT for other etiologies. Tobacco, a known carcinogen, has been reported to be between 52% and 83.3% in AC patients before OLT. Other risk factors that contribute to the development of malignancies are dose-dependent immunosuppression, advanced age, viral infections, sun exposure, and premalignant lesions (inflammatory bowel disease, Barrett's esophagus). A significantly more frequent incidence of upper aerodigestive (UAD) tract, lung, skin, and kidney-bladder tumors has been found in OLT recipients for AC in comparison with other etiologies. Liver transplant recipients who develop de novo non-skin tumors have a decreased long-term survival rate compared with controls. This significantly lower survival rate is more evident in AC recipients who develop UAD tract or lung tumors after OLT mainly because the diagnosis is usually performed at an advanced stage. All transplant candidates, especially AC patients, should be encouraged to cease smoking and alcohol consumption in the pre- and post-OLT periods, use skin protection, avoid sun exposure and over-immunosuppression, and have a yearly otopharyngolaryngeal exploration and chest computed tomography scan in order to prevent or reduce the incidence of de novo malignancies. Although still under investigation, substitution of calcineurin inhibitors for sirolimus or everolimus may reduce the incidence of de novo tumors after OLT.

Inhibitory Effects of Dietary Spirulina platensis on UVB-Induced Skin Inflammatory Responses and Carcinogenesis

Reactive oxygen species produced in response to UVR are important in skin tumor development. We have previously reported that deficiency of the Ogg1 gene, encoding the repair enzyme for 8-oxo-7,8-dihydroguanine (8-oxoG), increases skin tumor incidence in mice upon repetitive UVB exposure and modulation of UVB-induced inflammatory response. Spirulina platensis is used as a human food supplement because it contains abundant nutritional and antioxidant components. Therefore, we investigated the inhibitory effects of S. platensis on UVB-induced skin tumor development in Ogg1 knockout-(KO) mice and the wild-type (WT) counterpart. Dietary S. platensis suppressed tumor induction and development in both genotypes compared with our previous data without S. platensis. Induction of erythema and ear swelling, one of the hallmarks of UVB-induced inflammatory responses, was suppressed in the skin of Ogg1-KO mice and albino hairless mice fed with dietary S. platensis. Compared with untreated mice, S. platensis-administered mice showed significantly reduced 8-oxoG formation in the skin after UVB exposure. Moreover, we found that S. platensis effectively downregulated the signal proteins p38 mitogen-activated protein kinase, stress-activated protein kinase/c-Jun N-terminal kinase, and extracellular signal-regulated kinase after UVB exposure especially in Ogg1-KO mice. Our results suggest that S. platensis exerts antitumor effects against UVB irradiation in the skin through its anti-inflammatory and antioxidant effects.

Abstract 1323: Lack of cyclin D3 enhances the CDK6-dependent skin tumor susceptibility to malignant progression

Abstract The Cyclin-Dependent Kinases (CDKs) are a family of essential serine-threonine kinases that are cell cycle regulated by association with cyclins at specific time-points of the cell cycle. Specifically, D-type cyclins form complexes and activate CDK6 and CDK4. We have previously established that transgenic expression of CDK6 in mouse epidermis (K5CDK6 mice) alter an early stage of tumorigenesis leading to strong reduction of the multiplicity and incidence of skin tumors. Our previous results have shown that CDK6 preferentially binds to cyclin D3, which overexpression also decreases tumor development in mouse epidermis. Thus, we hypothesized that the association of CDK6/cyclin D3 and its enzymatic activity negatively impacts tumor development. To test this idea, we developed K5CDK6/Cyclin D3-/- mutant mice and subjected them to the two-stage carcinogenesis protocol. Contrary to our hypothesis, lack of cyclin D3 expression does not affect the tumor repression activity of CDK6 since both, K5CDK6 and K5CDK6/cyclin D3-/- mice, exhibit a severe reduction in the multiplicity and incidence of skin tumors compared to wild-type siblings. However, histopathological analysis of skin tumors revealed that 60% of the skin tumors in K5CDK6/cyclin D3-/- mice were classified as squamous-cell carcinomas I (SCC) with a variable degree of squamous differentiation; whereas wild type, K5CDK6 and cyclin D3-/- siblings exhibit benign tumors with no significant changes in the rate of malignant progression. Consistent with the malignant nature of the K5CDK6/cyclin D3-/- tumors, lack or reduction of cyclin D3 levels within the context of CDK6 overexpression (K5CDK6/D3-/- and K5CDK6/cyclin D3+/-) lead to 7-fold increase in tumor size compared to K5CDK6, cyclin D3-/- and wild-type tumors. Biochemical analysis of epidermal tumors shows that cyclin D3 ablation results in a rise of cyclin D1 protein levels. These data suggest that though cyclin D3 expression does not alter the tumor suppressive role of CDK6 at early stages of tumorigenesis, it does affect the expression of cyclin D1 resulting in the increased rate of malignant progression. Consistent with these studies, we have shown that elevated activity of CDK4/cyclin D1 complex results in an elevated number of SCC. We conclude that CDK6 activity can prevent tumor formation during the initial stages of tumorigenesis in a cyclin D3-independent manner and likely Rb-independent as well (Kollman et al, 2013). However, variations in the expression of cyclin D3 affects cyclin D2 (Rojas et al, 2007) and/or cyclin D1 levels, directly altering the susceptibility of CDK6 expressing tumors to malignant conversion. Therefore, therapies directed to reduce D-type cyclins expression should be considered within the context of the expression level of CDK6 and CDK4 to define the potential effect in the malignant progression of skin tumors. Supported by NIH grant CA116328. Note: This abstract was not presented at the meeting. Citation Format: Sung Hyun Lee, Xian Wang, Marcelo L. Rodriguez-Puebla. Lack of cyclin D3 enhances the CDK6-dependent skin tumor susceptibility to malignant progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1323. doi:10.1158/1538-7445.AM2014-1323

Atrial natriuretic peptide (ANP) inhibits DMBA/croton oil induced skin tumor growth by modulating NF-κB, MMPs, and infiltrating mast cells in swiss albino mice

Cardiac hormone atrial natriuretic peptide (ANP) and its receptor, natriuretic peptide receptor-A (NPR-A) are implicated as a vital regulator of cancer cell growth and tumor progression. However, the underlying mechanism by which ANP opposes the cancer growth in in-vivo remains unknown. Herein, we investigated the anti-cancer activity of ANP on 7, 12-dimethyl benzanthracence (DMBA)/Croton oil- induced two-step skin carcinogenic mouse model. Skin tumor incidence and tumor volume were recorded during the experimental period of 16 weeks. ANP (1μg/kg body weight/alternate days for 4weeks) was injected subcutaneously from the 13th week of DMBA/Croton oil induction. ANP treatment markedly inhibited the skin tumor growth (P<0.001). A significant reduction in the level of NF-κB activation (P<0.001), infiltrating mast cell count (P<0.01) and MMP-2/-9 (P<0.001, respectively) were noticed in the ANP treated mice skin tissue. Further, ANP treatment revert back the altered levels of serum LDH-4, C-reactive protein (CRP), and enzymatic antioxidants (SOD and CAT activities) to near normal level. Taken together, the results of this study suggest that ANP opposes the skin carcinogenesis by suppressing the inflammatory response and MMPs.

Pharmacologically Antagonizing the CXCR4-CXCL12 Chemokine Pathway with AMD3100 Inhibits Sunlight-Induced Skin Cancer

One way sunlight causes skin cancer is by suppressing anti-tumor immunity. A major mechanism involves altering mast cell migration via the C-X-C motif chemokine receptor 4-C-X-C motif chemokine ligand 12 (CXCR4-CXCL12) chemokine pathway. We have discovered that pharmacologically blocking this pathway with the CXCR4 antagonist AMD3100 prevents both UV radiation-induced immune suppression and skin cancer. The majority of control mice receiving UV-only developed histopathologically confirmed squamous cell carcinomas. In contrast, skin tumor incidence and burden was significantly lower in AMD3100-treated mice. Perhaps most striking was that AMD3100 completely prevented the outgrowth of latent tumors that occurred once UV irradiation ceased. AMD3100 protection from UV immunosuppression and skin cancer was associated with reduced mast cell infiltration into the skin, draining lymph nodes, and the tumor itself. Thus a major target of CXCR4 antagonism was the mast cell. Our results indicate that interfering with UV-induced CXCL12 by antagonizing CXCR4 significantly inhibits skin tumor development by blocking UV-induced effects on mast cells. Hence, the CXCR4-CXCL12 chemokine pathway is a novel therapeutic target in the prevention of UV-induced skin cancer.

Topical application of Gallic acid suppresses the 7,12-DMBA/Croton oil induced two-step skin carcinogenesis by modulating anti-oxidants and MMP-2/MMP-9 in Swiss albino mice

Gallic acid (GA – 3,4,5-trihydroxybenzoic acid), a dietary anti-oxidant has been shown to inhibit cancer cell growth in in vitro. Herein, we investigated the in vivo chemo preventive activity of GA on 7,12-Dimethylbenz[a]anthracene (DMBA)/Croton oil induced two-step skin carcinogenesis in Swiss albino mice. Skin tumor incidence and tumor volume were recorded during the 16weeks of experimental period. In addition, LDH-isozyme shift, skin collagen content, activities of matrix metalloproteinases (MMP-2/MMP-9) enzymes and enzymatic and non-enzymatic antioxidant were studied in the skin and serum of experimental mice. Tumor incidence was significantly increased in the DMBA/Croton oil induced mice (100%; p<0.001) when compared to GA co-treated mice (60%; p<0.01) and 5-FU treated mice (50%; p<0.01). Skin collagen content, MMPs activities, LDH-isoenzymes and MMP-2/-9 expressions were increased in DMBA/Croton oil induced skin while decreased levels of enzymatic (GST, SOD, CAT & GPx) and non-enzymatic anti-oxidant (GSH) were noticed. On the other hand, GA co-treatment exhibited a significant protection by reverting back the altered levels of LDH-isoenzymes, antioxidants, collagen and MMP-2/MMP-9 activities. The results of this study indicate that topical application of GA inhibits DMBA/Croton oil induced two-stage skin carcinogenic process by modulating the antioxidants and MMPs (-2 & -9) in the mouse skin.

Histology of melanoma and nonmelanoma skin cancer.

Incidence of skin tumors is increasing among elderly patients, and the multi-morbidities which occur in the elderly are a great challenge for dermatologists. Basis of every treatment of skin cancer patients is a reliable diagnosis. Therefore, histopathology serves as the gold standard in clinical dermatooncology and dermatologic surgery. This chapter provides a comprehensive review on the main types of melanoma and nonmelanoma skin cancers, including precursor lesions.

Malignant skin tumors in benin city, South-South, Nigeria.

Malignant skin tumors rank amongst the most common forms of cancer worldwide and constitute a major challenge in dermatopathology and oncology research. This study aims to determine the frequency and patterns of malignant skin tumors at the University of Benin Teaching Hospital, Benin City, Nigeria. A 25-year (1982-2007) retrospective study of surgical day books and slides of all patients presenting with skin lesions was conducted at the Surgical and Pathology Departments of University of Benin Teaching Hospital. A total of 694 skin biopsies were seen at the department during the study period; of these, 187 cases were malignant constituting 27% of all skin lesions. The majority of the malignant skin tumors (48%) occurred between the third and fifth decades with a male to female ratio of 1.4:1 and a mean age of 47 ± 29 years. Malignant melanoma was the most common skin malignancy, accounting for (n=61; 33%). Kaposi sarcoma constituted the second majority of the cases (n=56; 30%), with a markedly increased incidence between 2000 and 2008. This was consecutively followed by squamous cell carcinoma (n=45; 24%), basal cell carcinoma (n=18; 10%) and dermatofibrosarcoma protuberans (n=7; 4%). The leg and foot were the most common sites for malignant skin tumors. Malignant melanoma was the most common skin malignancy in this study. However, an increasing incidence of all malignant skin tumors was observed. This was particularly noticeable with Kaposi sarcoma, which may be attributed to the increasing prevalence of HIV/AIDS in Nigeria.

Abstract 4860: Chemopreventive effects of α-santalol on ultraviolet B induced skin tumorigenesis by modulating cell cycle regulators.

Abstract Previous studies from our laboratory have shown chemopreventive effects of 5% α-santalol, a sequiterpene isolated from the sandalwood oil in ultraviolet-B induced skin tumor multiplicity in SKH-1 hairless mice. However, this dosage did not have significant effect on tumor incidence. The objective of this study was to investigate the effects of α-santalol (10%, w/v in acetone) on UVB-induced skin tumor incidence in SKH-1 hairless mouse model and to identify the molecular targets in α-santalol mediated protection. Tumor initiation and promotion were carried out by UVB radiation (30 mJ/cm2/day for 5 days a week up to 30 week) that is in the range of human exposure to sunlight that can cause skin cancer. Topical treatment of mice with α-santalol causes a significant reduction in tumor multiplicity, tumor volume and tumor incidence, and also delayed tumor development. Histopathological analysis of hematoxylin-eosin stained skin sections showed that α-santalol pretreatment strongly inhibited UVB-induced epidermal hyperplasia and total thickness of the epidermis. The proliferation potential of skin and tumor tissue sections from UVB-induced carcinogenesis protocol was evaluated by immunohistochemical expression of proliferation marker PCNA. Both intensity of brown staining as well as the number of positively stained nuclei were reduced in skin tumors and adjacent skin tissues from α-santalol treated group when compared to control group. Western blot analysis of skin lysates showed that α-santalol decreases the level of different cyclin-dependent kinases and associated cyclins, Cdc25 phosphatases (Cdc25B and Cdc25C) together with an up-regulation of CDK inhibitor Cip1/p21. However, the level of Kip1/p27 and p53 did not show a significant difference. Our data suggested that α-santalol (10%, topical) is a safer and promising skin cancer chemopreventive agent through targeting different cell cycle regulators. (This work is supported by a Translational Cancer Center Research Grant, funded by the State of South Dakota). Citation Format: Sreevidya Santha, Chandradhar Dwivedi. Chemopreventive effects of α-santalol on ultraviolet B induced skin tumorigenesis by modulating cell cycle regulators. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4860. doi:10.1158/1538-7445.AM2013-4860

Improved patient‐centered care with effective use of Integra® in dermatologic reconstructive surgery

The incidence of skin tumors is increasing among elderly patients, and the multi-morbidities which occur in the elderly are a great challenge for dermatologic surgeons. The currently required safety margins for different types of melanomas and non-melanoma skin cancers lead to extensive and profound wounds. To investigate the usefulness of a dermal substitute (Integra®) for routine use in surgery for dermatologic tumors. In this retrospective study 20 patients underwent sequential surgeries for skin cancer. Wound closures were performed using Integra® (single layer) and immediate split-thickness skin graft. Twenty-two tumors (6 malignant melanomas, 10 squamous cell carcinomas, 2 pleomorphic sarcomas, 1 basal cell carcinoma, 2 Merkel cell carcinomas, and 1 trichoblastic carcinoma) were resected. The mean defect size was 41.4 cm(2) . All transplants were (65-100 %) vital; however, defects in the midface (cheek and infra-orbital area) often healed with esthetically disturbing, dense, pillow-like scars. With the use of Integra®, the duration of hospitalization was decreased, patients with multi-morbidities were effectively treated, and functionally- and esthetically-satisfactory outcomes were achieved. On the basis of these observations, we discuss points of handling those patients who require rapid and effective surgery and undergo dermatologic surgery using dermal substitutes.

New Molecular and Cellular Targets for Chemoprevention and Treatment of Skin Tumors by Plant Polyphenols: A Critical Review

As the incidence of skin tumors has been steadily growing, there is an urgent need for the preventive measures as well as the improved therapeutic approaches. In the last two decades, natural plant derived polyphenols (PPs, resveratrol, silibinin, green tea polyphenols, flavonoids, anthocyanins, etc.) have been drawing particular interest as emerging active substances in dermatological/cosmeceutical compositions for the prevention, slowing, or reversion of skin tumorigenesis (chemoprevention). When chronically applied to the skin, they supposedly would not damage normal skin cells or negatively affect their functions while they would suppress tumorigenic cell transformation, inhibit tumor cell proliferation, and activate tumor cell apoptosis. PPs are also reported to synergize with conventional anti-cancer therapies. The major aim of this critical review is to provide recent updates on the molecular and cellular targets for the prevention and therapy of skin tumors with a special focus on the crossroad between inflammation and carcinogenesis as the most promising approach to chemoprevention. Novel therapeutic targets as different as epidermal stem cells, cellular senescence, epigenetic enzymes involved in carcinogenesis, epidermal growth factor and aryl hydrocarbon receptors, and metabolic CYP1 subfamily enzymes are highlighted. The mechanisms of PPs interaction with these molecular and cellular targets are reviewed. The feasibility of PPs to prevent/ cure specific cutaneous toxicity connected to anti-EGFR therapy and to reduce multidrug resistance of skin tumors is also discussed.

Skin Cancer After Solid Organ Transplantation

Sir, We read the article by Belloni-Fortina et al. (1) with great interest. This retrospective study focused on the incidence of, and risk factors for, skin complications among liver transplant patients. They concluded that in these recipients the risk of premalignant and malignant skin lesions was lower than that of other solid organ transplants. Although organ transplant recipients are predisposed to the development of skin cancers, the epidemiology of skin tumours following organ transplantation varies geographically (2, 3); therefore, the lower rate of skin cancer in the study of Belloni-Fortina et al. (1) may reflect geographical differences. We have previously reported on the low rate of skin tumours among Iranian kidney transplant patients (2, 3). The overall incidence of skin tumors in 11,255 kidney transplant recipients was 1.14%, representing half of all post-transplant malignancies (128 out of 245 cases) (2). Kaposi’s sarcoma was the most common tumour type (2, 3); the incidence of Kaposi’s sarcoma is greatly increased among transplant patients in the Middle East countries (4, 5). Belloni-Fortina et al. (1) showed that male sex (maleto-female ratio of 6:1) and advanced age increased the risk of skin tumours after liver transplantation. In our study, male recipients also had more skin cancers (male:female ratio of 2.5:1), and individuals older than 45 years were at higher risk (odds ratio 3.8) (2). Although Belloni-Fortina et al. (1) found azathioprine as a second immunosuppressant was not a risk factor for the development of skin cancer, we observed that recipients who were on azathioprine were more likely to develop skin tumours when compared with those treated with mycophenolate mofetil (odds ratio 2.9) (2). In conclusion, the types of skin tumours following organ transplantation vary geographically, and the incidence and risk factors for these tumours appear to differ be tween countries.

Anticarcinogenic effect of quercetin by inhibition of insulin-like growth factor (IGF)-1 signaling in mouse skin cancer

It has been shown that dysregulation of IGF-1 signaling is associated with tumor incidence and progression, whereas blockade of the signaling can effectively inhibit carcinogenesis. Although several mechanisms of anticancer activity of quercetin were proposed, molecular targets of quercetin have not been identified yet. Hence, we assessed the effect of quercetin on IGF-1 signaling inhibition in BK5.IGF-1 transgenic (Tg) mice, which over-expresses IGF-1 in the skin epidermis. A quercetin diet (0.02% wt/wt) for 20 weeks remarkably delayed the incidence of skin tumor by 2 weeks and reduced tumor multiplicity by 35% in a 7,12-dimethylbenz(a)anthracene (DMBA)-tetradecanoyl phorbol-13-acetate (TPA) two stage mouse skin carcinogenesis protocol. Moreover, skin hyperplasia in Tg mice was significantly inhibited by a quercetin supplementation. Further analysis of the MT1/2 skin papilloma cell line showed that a quercetin treatment dose dependently suppressed IGF-1 induced phosphorylation of the IGF-1 receptor (IGF-1R), insulin receptor substrate (IRS)-1, Akt and S6K; however, had no effect on the phosphorylation of PTEN. Additionally, the quercetin treatment inhibited IGF-1 stimulated cell proliferation in a dose dependent manner. Taken together, these data suggest that quercetin has a potent anticancer activity through the inhibition of IGF-1 signaling.

The absence of Brm exacerbates photocarcinogenesis

Brm is an ATPase subunit of the SWI/SNF chromatin-remodelling complex. Previously, we identified a novel hotspot mutation in Brm in human skin cancer, which is caused by exposure to ultraviolet radiation (UVR). As SWI/SNF is involved in DNA repair, we investigated whether Brm-/- mice had enhanced photocarcinogenesis. P53+/- and Brm-/-p53+/- mice were also examined as the p53 tumor suppressor gene is mutated early during human skin carcinogenesis. Mice were exposed to a low-dose irradiation protocol that caused few skin tumors in wild-type mice. Brm-/- mice with both p53 alleles intact had an increased incidence of skin and ocular tumors compared to Brm+/+p53+/+ controls. Brm loss in p53+/- mice did not further enhance skin or ocular cancer incidence beyond the increased photocarcinogenesis in p53+/- mice. However, the skin tumors that arose early in Brm-/- p53+/- mice had a higher growth rate. Brm-/- did not prevent UVR-induced apoptotic sunburn cell formation, which is a protective response. Unexpectedly, Brm-/- inhibited UVR-induced immunosuppression, which would be predicted to reduce rather than enhance photocarcinogenesis. In conclusion, the absence of Brm increased skin and ocular photocarcinogenesis. Even when one allele of p53 is lost, Brm has additional tumor suppressing capability.

On How Mammary Gland Reprogramming Metalloproteinases Couple Form with Function

On How Mammary Gland Reprogramming Metalloproteinases Couple Form with Function

Abstract 167: Myricetin suppresses UVB-induced photoaging, skin cancer, and angiogenesis by targeting multiple kinases

Abstract Chronic exposure to solar ultraviolet is a major cause of photoaging and skin carcinogenesis. In the present study, we investigated the effect of myricetin on UVB-induced photoaging, skin cancer, and angiogenesis in JB6 P+ cells and a mouse skin tumorigenesis model. Myricetin inhibited wrinkle formation induced by UVB irradiation (0.18 J/cm2, 3 days/week for 15 weeks) in mouse skin. Myricetin treatment reduced UVB-induced epidermal thickening of mouse skin and also suppressed UVB-induced matrix metalloproteinase-9 (MMP-9) protein expression and enzyme activity. In vitro and in vivo pull-down and kinase assays revealed that myricetin suppressed Raf activity by binding with Raf. Secondly, myricetin suppressed UVB-induced COX-2 expression and mitogen-activated protein kinases in JB6 P+ cells and mouse skin. Pull-down and kinase assay results showed that myricetin directly inhibited UVB-induced Fyn kinase activity by binding with Fyn in an ATP-competitive manner. Mouse skin tumorigenesis data clearly showed that pretreatment with myricetin significantly suppressed UVB-induced skin tumor incidence in a dose-dependent manner. Topical treatment with myricetin suppressed repetitive UVB-induced neovascularization in the SKH-1 hairless mouse skin. The induction of vascular endothelial growth factor, matrix metalloproteinase (MMP)-9 and MMP-13 expression by chronic UVB irradiation was substantially suppressed by myricetin treatment. Immunohistochemical and Western blot analyses revealed that myricetin attenuated UVB-induced hypoxia inducible factor-1alpha expression in mouse skin. In vivo kinase and pull down assay data revealed that myricetin suppressed UVB-induced phosphatidylinositol 3 (PI3)-kinase activity by direct binding with PI3-kinase. Overall, together these results suggest that the anti-photoaging, anti-skin carcinogenesis, and anti-angiogenesis effects of myricetin are due to mainly targeting Raf, Fyn, and PI3-K, respectively. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 167. doi:1538-7445.AM2012-167

Lack of promoting effect of titanium dioxide particles on chemically-induced skin carcinogenesis in rats and mice

Nano-sized titanium dioxide particles (TiO(2)) are widely used in cosmetics, sunscreens and food additives. We previously reported that topical application of non-coated rutile type TiO(2) did not exhibit a promoting effect on ultraviolet B-initiated skin carcinogenesis in rats, and that this was likely due to lack of penetration of TiO(2) into the epidermis. In the present study, we examined the promoting effect of silicone coated TiO(2 )(sTiO(2)) suspended in silicone oil and non-coated TiO(2 )(ncTiO(2)) suspended in Pentalan 408 on a two-stage skin chemical carcinogenesis model: sTiO(2) suspended in silicon oil forms smaller particles than ncTiO(2) suspended in Pentalan because of the smaller sizes of aggregates formed. The model used skin carcinogenesis-sensitive human c-Ha-ras proto-oncogene transgenic mice (rasH2) and rats (Hras128) and their wild-type counterparts and CD-1 mice to test the effects of topical application of TiO(2). Animals were initially treated with a single dose of 7,12-dimethylbenz[a]anthracene (DMBA) and then with 0, 10, or 20 mg sTiO(2) (mice) or 0, 50, or 100 mg ncTiO(2) (rats). The incidence and multiplicity of skin tumors (squamous cell papilloma and carcinoma) did not increase over DMBA alone controls in skin carcinogenesis-sensitive mice or rats or wild-type animals. Analysis of rat skin indicated that sTiO(2) and ncTiO(2) did not penetrate though either healthy or damaged skin. Furthermore sTiO(2) did not penetrate an in vitro human epidermis model. Our results indicate that treatment with sTiO(2) or ncTiO(2) did not promote skin carcinogenesis in mice or rats, probably due to lack of penetration through the epidermis.

CXCR3 Enhances a T-Cell–Dependent Epidermal Proliferative Response and Promotes Skin Tumorigenesis

The chemokine receptor CXCR3 has been proposed to play a critical role in host antitumor responses. In this study, we defined CXCR3-expressing immune cell infiltration in human skin squamous cell carcinomas and then used CXCR3-deficient mice to assess the contribution of CXCR3 to skin tumorigenesis. Our studies employed two established protocols for chemical skin carcinogenesis [methylcholanthrene (MCA) or 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) models]. CXCR3 deletion did not affect tumor development in the MCA model; however, CXCR3 was important in the DMBA/TPA model where gene deletion reduced the incidence of skin tumors. This decreased incidence of skin tumors did not reflect differences in epidermal development but rather was associated with reduced epidermal thickness and proliferation in CXCR3(-/-) mice, implicating the CXCR3 pathway in DMBA/TPA-induced epidermal inflammation and proliferation. Notably, CXCR3 expressed in CD4(+) and CD8(+) T cells was found to be important for enhanced epidermal proliferation. Specifically, CXCR3-deficient mice reconstituted with T cells isolated from wild-type mice treated with DMBA/TPA restored wild-type levels of epidermal proliferation in the mutant mice. Taken together, our findings establish that CXCR3 promotes epidermal tumorigenesis likely through a T-cell-dependent induction of keratinocyte proliferation.

7,3′,4′-Trihydroxyisoflavone, a Metabolite of the Soy Isoflavone Daidzein, Suppresses Ultraviolet B-induced Skin Cancer by Targeting Cot and MKK4

Nonmelanoma skin cancer is one of the most frequently occurring cancers in the United States. Chronic exposure to UVB irradiation is a major cause of this cancer. Daidzein, along with genistein, is a major isoflavone found in soybeans; however, little is known about the chemopreventive effects of daidzein and its metabolites in UVB-induced skin cancer. Here, we found that 7,3',4'-trihydroxyisoflavone (THIF), a major metabolite of daidzein, effectively inhibits UVB-induced cyclooxygenase 2 (COX-2) expression through the inhibition of NF-κB transcription activity in mouse skin epidermal JB6 P+ cells. In contrast, daidzein had no effect on COX-2 expression levels. Data from Western blot and kinase assays showed that 7,3',4'-THIF inhibited Cot and MKK4 activity, thereby suppressing UVB-induced phosphorylation of mitogen-activated protein kinases. Pull-down assays indicated that 7,3',4'-THIF competed with ATP to inhibit Cot or MKK4 activity. Topical application of 7,3',4'-THIF clearly suppressed the incidence and multiplicity of UVB-induced tumors in hairless mouse skin. Hairless mouse skin results also showed that 7,3',4'-THIF inhibits Cot or MKK4 kinase activity directly, resulting in suppressed UVB-induced COX-2 expression. A docking study revealed that 7,3',4'-THIF, but not daidzein, easily docked to the ATP binding site of Cot and MKK4, which is located between the N- and C-lobes of the kinase domain. Collectively, these results provide insight into the biological actions of 7,3',4'-THIF, a potential skin cancer chemopreventive agent.