Mouse Skin Carcinogenesis Research Articles

Peracetylated (−)-epigallocatechin-3-gallate (AcEGCG) potently prevents skin carcinogenesis by suppressing the PKD1-dependent signaling pathway in CD34 + skin stem cells and skin tumors

During the process of skin tumor promotion, expression of the cutaneous cancer stem cell (CSC) marker CD34(+) is required for stem cell activation and tumor formation. A previous study has shown that activation of protein kinase D1 (PKD1) is involved in epidermal tumor promotion; however, the signals that regulate CSCs in skin carcinogenesis have not been characterized. This study was designed to investigate the chemopreventive potential of peracetylated (-)-epigallocatechin-3-gallate (AcEGCG) on 7,12-dimethylbenz[a]-anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumorigenesis in ICR mice and to elucidate the possible mechanisms involved in the inhibitory action of PKD1 on CSCs. We demonstrated that topical application of AcEGCG before TPA treatment can be more effective than EGCG in reducing DMBA/TPA-induced tumor incidence and multiplicity. Notably, AcEGCG not only inhibited the expression of p53, p21, c-Myc, cyclin B, p-CDK1 and Cdc25A but also restored the activation of extracellular signal-regulated kinase 1/2 (ERK1/2), which decreased DMBA/TPA-induced increases in tumor proliferation and mitotic index. To clarify the role of PKD1 in cell proliferation and tumorigenesis, we studied the expression and activation of PKD1 in CD34(+) skin stem cells and skin tumors. We found that PKD1 was strongly expressed in CD34(+) cells and that pretreatment with AcEGCG markedly inhibited PKD1 activation and CD34(+) expression. More importantly, pretreatment with AcEGCG remarkably suppressed nuclear factor-kappaB, cyclic adenosine 3',5'-monophosphate-responsive element-binding protein (CREB) and CCAAT-enhancer-binding protein (C/EBPs) activation by inhibiting the phosphorylation of c-Jun-N-terminal kinase 1/2, p38 and phosphatidylinositol 3-kinase (PI3K)/Akt and by attenuating downstream target gene expression, including inducible nitric oxide synthase, cyclooxygenase-2, ornithine decarboxylase and vascular endothelial growth factor. Moreover, this is the first study to demonstrate that AcEGCG is a CD34(+) and PKD1 inhibitor in the multistage mouse skin carcinogenesis model. Overall, our results powerfully suggest that AcEGCG could be developed into a novel chemopreventive agent and that PKD1 may be a preventive and therapeutic target for skin cancer in clinical settings.

Enhanced UV-Induced Skin Carcinogenesis in Transgenic Mice Overexpressing Proprotein Convertases

The proprotein convertases (PCs) furin and PACE4 process numerous substrates involved in tumor growth, invasion, and metastasis. We have previously shown that PCs increase the susceptibility to chemical skin carcinogenesis. Because of the human relevancy of UV radiation in the etiopathogenesis of human skin cancer, we investigated whether or not transgenic mice overexpressing either furin alone or both furin and PACE4 show increased susceptibility to UV carcinogenesis. After backcrossing our previously described furin and PACE4 transgenic lines, targeted to the epidermis, into a SKH-1 background, we exposed both single and double transgenic mice to UV radiation for 34 weeks. The results showed an increase in squamous cell carcinoma (SCC) multiplicity of approximately 70% in the single furin transgenic mouse line SF47 (P < .002) and a 30% increase in the other single transgenic line SF49 when compared to wild-type (WT) SKH-1 mice. Interestingly, there was also an increase in the percentage of high histologic grade SCCs in the transgenic lines compared to the WT mice, i.e., WT = 9%, SF47 = 15%, and SF49 = 26% (P < .02). Targeting both furin and PACE4 to the epidermis in double transgenic mice did not have an additive effect on tumor incidence/multiplicity but did enhance the tumor histopathologic grade, i.e., a significant increase in higher grade SCCs was seen in the bigenic mouse line SPF47 (P < .02). Thus, we observed an increased susceptibility to UV in single furin transgenic mice that was not substantially enhanced in the double furin/PACE4 transgenic mice.

Weight control and cancer preventive mechanisms: Role of insulin growth factor-1-mediated signaling pathways

Overweight and obese not only increase the risk of cardiovascular disease and type-2 diabetes mellitus, but are also now known risk factors for a variety of cancers. Weight control, via dietary calorie restriction and/or exercise, has been demonstrated to be beneficial for cancer prevention in various experimental models, but the underlying mechanisms are still not well defined. Recent studies conducted in a mouse skin carcinogenesis model show that weight loss induced a significant reduction of the circulating levels of insulin growth factor (IGF)-1 and other hormones, including insulin and leptin, resulting in reduced IGF-1-dependent signaling pathways, i.e. Ras-MAPK proliferation and protein kinase B-phosphoinositide 3-kinase (Akt-PI3K) antiapoptosis. Selective targeting IGF-1 to Akt/mammalian target of rapamycin and AMP-activated protein kinase pathways, via negative energy balance, might inactivate cell cycle progression and ultimately suppress tumor development. This review highlights the current studies focused on the major role of reducing IGF-1-activated signaling via weight control as a potential cancer preventive mechanism.

In Vivo SILAC-Based Proteomics Reveals Phosphoproteome Changes during Mouse Skin Carcinogenesis

Cancer progresses through distinct stages, and mouse models recapitulating traits of this progression are frequently used to explore genetic, morphological, and pharmacological aspects of tumor development. To complement genomic investigations of this process, we here quantify phosphoproteomic changes in skin cancer development using the SILAC mouse technology coupled to high-resolution mass spectrometry. We distill protein expression signatures from our data that distinguish between skin cancer stages. A distinct phosphoproteome of the two stages of cancer progression is identified that correlates with perturbed cell growth and implicates cell adhesion as a major driver of malignancy. Importantly, integrated analysis of phosphoproteomic data and prediction of kinase activity revealed PAK4-PKC/SRC network to be highly deregulated in SCC but not in papilloma. This detailed molecular picture, both at the proteome and phosphoproteome level, will prove useful for the study of mechanisms of tumor progression.

Extraction optimization of Tinospora cordifolia and assessment of the anticancer activity of its alkaloid palmatine.

Objective. To optimize the conditions for the extraction of alkaloid palmatine from Tinospora cordifolia by using response surface methodology (RSM) and study its anticancerous property against 7,12-dimethylbenz(a)anthracene (DMBA) induced skin carcinogenesis in Swiss albino mice. Methods. The effect of three independent variables, namely, extraction temperature, time, and cycles was investigated by using central composite design. A single topical application of DMBA (100 μg/100 μL of acetone), followed 2 weeks later by repeated application of croton oil (1% in acetone three times a week) for 16 weeks, exhibited 100 percent tumor incidence (Group 2). Results. The highest yield of alkaloid from Tinospora cordifolia could be achieved at 16 hours of extraction time under 40°C with 4 extraction cycles. Alkaloid administration significantly decreases tumor size, number, and the activity of serum enzyme when compared with the control (Group 2). In addition, depleted levels of reduced glutathione (GSH), superoxide dismutase (SOD), and catalase and increased DNA damage were restored in palmatine treated groups. Conclusion. The data of the present study clearly indicate the anticancer potential of palmatine alkaloid in DMBA induced skin cancer model in mice.

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.

Mouse Models of the Skin: Models to Define Mechanisms of Skin Carcinogenesis

Mouse Models of the Skin: Models to Define Mechanisms of Skin Carcinogenesis

Non-melanoma skin cancer in mouse and man

As a frontier organ, skin is exposed to different environmental and/or occupational chemicals which cause cutaneous cancers in experimental animals. In mice, 7,12-dimethylbenz[a]anthrancene (DMBA) and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) are frequently used as skin model tumor initiator and promoter, respectively. The sequential administration of DMBA and TPA leads to the appearance of a large number of benign papillomas, of which some convert later into invasive squamous cell carcinomas (SCC). At the molecular level, initiation of carcinogenesis in mouse skin consists in the mutational activation of the Ha-ras oncoprotein. HA-RAS mutations are rare in human SCC, but HA-RAS-mutated tumors appear in melanoma patients treated with B-raf inhibitors, indicating that initiated, HA-RAS-mutated stem cells also reside in human skin. Similarly, UV-induced human SCC show footprint mutations in the tumor suppressor gene TP53 which are also observed in UV-induced mouse SCC. Strong species differences exist with respect to phorbol ester-mediated tumor promotion. While certain mouse strains are very susceptible, other rodent species are much less sensitive. Likewise, humans appear to be much more resistant to phorbol ester-mediated skin toxicity. Papilloma formation as a result of a chemical insult is uncommon in men, questioning the relevance of this preneoplastic lesion for humans. However, skin tumorigenesis in the experimental situation and in humans appears to follow common molecular mechanisms, even though there are species differences in the morphological correlates to the preneoplastic state. Therefore, we recommend not simply labeling them as irrelevant for human risk assessment.

Azadirachta indica acts as a pro‐oxidant and modulates cell cycle associated proteins during DMBA/TPA induced skin carcinogenesis in mice

The present study was designed to determine the modulatory effect of aqueous Azadirachta indica leaf extract (AAILE) on cell cycle-associated proteins during two-stage skin carcinogenesis in mice. Considering the dual role of reactive oxygen species in cancer and its chemoprevention, the levels of lipid peroxidation (index of peroxidative damage) were also determined. Skin tumours were induced by topical application of 7,12-dimethylbenz(a)anthracene (DMBA) as a carcinogen followed by the repetitive application of 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. Skin tumours obtained in the DMBA/TPA group exhibited enhanced expression of proliferating cell nuclear antigen (PCNA, index of proliferation), p21 and cyclin D1, with no alterations in p53 expression in comparison to the control group. Tumours in AAILE + DMBA/TPA group exhibited low PCNA and cyclin D1 expression and enhanced expression of p53 and p21 in comparison to the DMBA/TPA group. The skin tumours obtained in the AAILE + DMBA/TPA group exhibited high lipid peroxidation levels in comparison to the tumours obtained in the DMBA/TPA group. The observations of the present study suggest that AAILE behaves as a pro-oxidant in the tumours, thereby rendering them susceptible to damage, which eventually culminates into its anti-neoplastic action. Also, cell cycle regulatory proteins may be modulated by AAILE and could affect the progression of cells through the cell cycle.

Inhibitory Effects of Opuntia humifusa on 7, 12-Dimethyl-benz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate Induced Two-stage Skin Carcinogenesis

Opuntia humifusa, member of the Cactaceae family, was previously demonstrated to have radical scavenging, anti-inflammatory and anti-proliferative effects in in vitro models. It was suggested that O. humifusa could function in the prevention of carcinogenesis. To investigate the in vivo chemopreventive effect of O. humifusa, mice were fed a diet containing either 1% or 3% following 7, 12-dimethylbenz[a] anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) induction of skin carcinogenesis. Significant decrease in the numbers of papilloma and epidermal hyperplasia were observed in mice fed with O. humifusa, compared to the control group. O. humifusa also upregulated high total antioxidant capacity and level of phase II detoxifying enzyme such as superoxide dismutase and glutathione S-transferase activity in the skin. Lipid peroxidation activity level was measured in skin cytosol and significantly inhibited in 3% OH fed group compared to the control group. These results suggest that O. humifusa exerts chemopreventive effects on chemical carcinogenesis in mouse skin and that prevention effects are associated with reduction of oxidative stress via the modulation of cutaneous lipid peroxidation, enhancing of total antioxidant capacity especially in phase II detoxifying enzyme system and partial apoptotic influence.

Focal adhesion kinase is required for β-catenin-induced mobilization of epidermal stem cells

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that integrates signals downstream of integrin and growth factor activation. Previously, we have shown that skin-specific loss of fak prevents chemically induced skin carcinogenesis in mice following phorbol ester treatment. In this study, we show that skin-specific deletion of fak prevents mobilization of stem cells within the bulge region of the hair follicle, which are the precursors of papillomas following phorbol ester treatment. We also show that phorbol ester treatment results in activation of-catenin within the skin and that FAK is required for β-catenin-induced stem cell mobilization. In addition, inhibition of Src kinase activity, a major binding partner of FAK also prevents stem cell mobilization. We show that FAK is required for the nuclear localization of β-catenin in the skin following phorbol ester treatment and the transcriptional activation of the β-catenin target gene c-Myc. This provides the first evidence of cross-talk between integrin and Wnt signalling pathways in the control of epidermal stem cells and the early events associated with skin carcinogenesis.

Interactions between wild-type and mutant Ras genes in lung and skin carcinogenesis

Ras oncogenes (Hras, Kras, and Nras) are important drivers of carcinogenesis. However, tumors with Ras mutations often show loss of the corresponding wildtype (WT) allele, suggesting that proto-oncogenic forms of Ras can function as a suppressor of carcinogenesis. In vitro studies also suggest that WT Ras proteins can suppress the tumorigenic properties of alternate mutant Ras family members, but in vivo evidence for these heterologous interactions is lacking. We have investigated the genetic interactions between different combinations of mutant and WT Ras alleles in vivo using carcinogen-induced lung and skin carcinogenesis in mice with targeted deletion of different Ras family members. The major suppressor effect of WT Kras is observed only in mutant Kras-driven lung carcinogenesis, where loss of one Kras allele led to increased tumor number and size. Deletion of one Hras allele dramatically reduced the number of skin papillomas with Hras mutations, consistent with Hras as the major target of mutation in these tumors. However, skin carcinoma numbers were very similar, suggesting that WT Hras functions as a suppressor of progression from papillomas to invasive squamous carcinomas. In the skin, the Kras proto-oncogene functions cooperatively with mutant Hras to promote papilloma development, although the effect is relatively small. In contrast, the Hras proto-oncogene attenuated the activity of mutant Kras in lung carcinogenesis. Interestingly, loss of Nras increased the number of mutant Kras-induced lung tumors but decreased the number of mutant Hras-induced skin papillomas. These results show that the strongest suppressor effects of WT Ras are only seen in the context of mutation of the cognate Ras protein, and only relatively weak effects are detected on tumor development induced by mutations in alternative family members. The data also underscore the complex and context-dependent nature of interactions between proto-oncogenic and oncogenic forms of different Ras family members during tumor development.

Progression of mouse skin carcinogenesis is associated with increased ERα levels and is repressed by a dominant negative form of ERα.

Estrogen receptors (ER), namely ERα and ERβ, are hormone-activated transcription factors with an important role in carcinogenesis. In the present study, we aimed at elucidating the implication of ERα in skin cancer, using chemically-induced mouse skin tumours, as well as cell lines representing distinct stages of mouse skin oncogenesis. First, using immunohistochemical staining we showed that ERα is markedly increased in aggressive mouse skin tumours in vivo as compared to the papilloma tumours, whereas ERβ levels are low and become even lower in the aggressive spindle tumours of carcinogen-treated mice. Then, using the multistage mouse skin carcinogenesis model, we showed that ERα gradually increases during promotion and progression stages of mouse skin carcinogenesis, peaking at the most aggressive stage, whereas ERβ levels only slightly change throughout skin carcinogenesis. Stable transfection of the aggressive, spindle CarB cells with a dominant negative form of ERα (dnERα) resulted in reduced ERα levels and reduced binding to estrogen responsive elements (ERE)-containing sequences. We characterized two highly conserved EREs on the mouse ERα promoter through which dnERα decreased endogenous ERα levels. The dnERα-transfected CarB cells presented altered protein levels of cytoskeletal and cell adhesion molecules, slower growth rate and impaired anchorage-independent growth in vitro, whereas they gave smaller tumours with extended latency period of tumour onset in vivo. Our findings suggest an implication of ERα in the aggressiveness of spindle mouse skin cancer cells, possibly through regulation of genes affecting cell shape and adhesion, and they also provide hints for the effective targeting of spindle cancer cells by dnERα.

Ei24-deficiency attenuates protein kinase Cα signaling and skin carcinogenesis in mice

Etoposide-induced gene 24 (Ei24) is a p53 target gene that inhibits growth, induces apoptosis and autophagy, as well as suppresses breast cancer. To evaluate the role of Ei24 in in vivo tumorigenesis, we generated an Ei24-deficient mouse model. Here, we report that, although Ei24 homozygous knockout mice are embryonic lethal, Ei24 heterozygous null mice are attenuated to DMBA/TPA-induced carcinogenesis with regard to the number and size of tumors but not the incidence. Ei24 contains a functional consensus motif, named as an R motif that is highly analogous to amino acids 105–110 of RINCK1, an E3 ligase for protein kinase C (PKC) proteins. We found that Ei24 stabilizes PKCαvia RINCK degradation and competition with RINCK for binding with the C1a domain of PKCα. We also found that Ei24 contributes to PKCα-mediated transactivation of EGFR by promoting PKCα membrane localization and interaction with EGFR. Finally, using Oncomine database we show that Ei24 and EGFR are upregulated in some subsets of human HNSCC. These results suggest that Ei24 is a regulator of the RINCK1-PKCα-EGFR signaling pathway in the development of skin-cancer.

Chemopreventive effects of Lawsonia Inermis L. (Henna) leaf powder and its pigment artifact, lawsone on skin carcinogenesis in mice

The medicinal plant Lawsonia inermis L, commonly known as 'henna' and lawsone (2-hydroxy-1,4-naphthoquinone), the red-orange pigment artifact formed during the extraction or preparation of the dye from henna leaves, were evaluated for chemopreventive effects against skin carcinogenesis in three mouse models. In the two-stage mouse skin carcinogenesis model using UV-B radiation for initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) for tumor promotion, oral feeding of henna leaf powder (0.0025%) in drinking water ad libitum decreased tumor incidence by 66% and multiplicity by 40%. Similarly, in the above mouse model, orally fed lawsone (0.0025%) decreased tumor incidence by 72% and multiplicity by 50%. The tumor inhibitory trend continued throughout the 20-week test period. Similar antitumor activities were observed when henna leaf powder (0.5mg/ml) was applied topically on the back skin in the UV-B initiated, TPA promoted and peroxynitrite initiated, TPA promoted mouse skin carcinogenesis models. Topically applied lawsone (0.015mg/ml) also exhibited similar protection against tumor formation in the 7,12-dimtehylbenz(a)anthracene induced and TPA promoted skin cancer in mice. Also, there was a delay of 1 to 2 weeks in tumor appearance in both henna leaf powder and lawsone treated groups in all three test models. This study ascertains the skin cancer chemopreventive activity of henna leaf powder and lawsone when administered by either oral or topical routes. Further, the results suggest that lawsone, the pigment artifact is primarily responsible for the observed chemopreventive effect of henna leaf powder in the mouse skin carcinogenesis models used.

Anti‐Inflammatory and Anti‐Tumor‐Promoting Effects of 5‐Deprenyllupulonol C and Other Compounds from Hop (Humulus lupulus L.)

A new phloroglucinol derivative, 5-deprenyllupulonol C (1), along with four other phloroglucinol derivatives, 2-5, five chalcones, 6-10, four flavanones, 11-14, two flavonol glycosides, 15 and 16, and five triterpenoids, 17-21, were isolated from the female inflorescence pellet extracts of hop (Humulus lupulus L.). Upon evaluation of these compounds against the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) in Raji cells, twelve compounds, i.e., 1-4, 11-14, 17-19, and 21, showed potent inhibitory effects on EBV-EA induction, with IC₅₀ values in the range of 215-393 mol ratio/32 pmol TPA. In addition, eleven compounds, i.e., 1-4, 6, 11, 12, 14, 17, 18, and 20, were found to inhibit TPA-induced inflammation (1 μg/ear) in mice, with ID₅₀ values in the range of 0.13-1.06 μmol per ear. Further, lupulone C (2) and 6-prenylnaringenin (14) exhibited inhibitory effects on skin-tumor promotion in an in vivo two-stage mouse-skin carcinogenesis test based on 7,12-dimethylbenz[a]anthracene (DMBA) as initiator and with TPA as promoter.

Tamoxifen-loaded novel liposomal formulations: evaluation of anticancer activity on DMBA-TPA induced mouse skin carcinogenesis

Purpose: Tamoxifen (TAM) is a non-steroidal estrogen receptor modulator known for its anticancer activity. Apart from marked breast cancer activity, this drug has also shown potential in treating other types of cancers including skin cancers. TAM is reported to be associated with serious side effects primarily due to its systemic distribution. The localized delivery of this drug in this regard would be highly beneficial with respect to safety as well as efficacy.Methods: In the current studies, an endeavor has been made to investigate the efficacy of topically applied liposome-encapsulated TAM on skin cancer model. The drug was encapsulated in phospholipid-based vesicular systems viz. conventional liposomes and elastic liposomes. Incidence of papillomas and histopathological examination were employed to determine the efficacy of the tested formulations.Results: The results demonstrated carrier-dependent strong inhibition of skin carcinogenesis with encapsulated drug vis-à-vis drug in the solution form. The encouraging findings from the current work construe immense potential of the TAM-loaded liposomal systems in the management of skin cancer.

Inotilone suppresses phorbol ester‐induced inflammation and tumor promotion in mouse skin

Chemoprevention is one of the most feasible approaches to reduce the risk of cancer. Over the past decades, scientists have realized that chronic inflammation is a critical component of cancer development. Inotilone, existing in Inonotus mushroom has been reported to exhibit anti-inflammatory properties in vitro. Hence, we investigated the effects of inotilone on 12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated acute inflammation and tumor promotion in mouse skin and the underlying molecular mechanisms. Inotilone was topically applied to mouse skin 30 min prior to TPA treatment. The results have shown that inotilone inhibited the production of inflammatory mediators by attenuating the activation of nuclear factor-κB (NF-κB) and the expression of CCAAT/enhancer binding protein β (C/EBPβ). Furthermore, the ability of inotilone to prevent tumorigenesis at promotion stage was evaluated using a classical two-stage mouse skin carcinogenesis model. After initiation of 7,12-dimethylbenz[a]anthracene (DMBA), applying inotilone topically before each TPA treatment was found to reduce the tumor incidence and tumor multiplicity of papillomas. Based on the results, we concluded that inotilone has potential to be developed into an effective chemopreventive agent for the treatment of a variety of inflammatory diseases, especially the prevention and treatment of epithelial skin cancer.

A small molecule inhibitor of the TGF β type I Receptor suppresses UVB-Induced mouse Skin Carcinogenesis (74.3)

Abstract Ultraviolet radiation is a key environmental mutagen and chronic exposure to UVB is the leading cause of Skin Cancer. Transforming Growth Factor (TGF-β) represents an important immunoregulatory cytokine in the skin microenvironment with context dependent role in modulating tumor formation and progression. The immune system plays a critical role in containing the toxic damage caused by UVB; TGF-β has been known to play a key role in the activation and survival of immune cells. However, the specific role of TGF-β signaling in UVB induced skin cancers is not clear. To study this interplay between UVB, TGF-β and the immune system, we performed a UVB carcinogenesis study in the presence or absence of SB431542, an inhibitor of TGF-β1 type I receptor. We observed a significant decrease in the number of papillomas with TGF-β1 pathway inhibition and a concomitant decrease in the tumor infiltration and activation status (IFNγ secretion) of CD4 and CD8 lymphocytes. In order to understand the mechanism of suppression of T cell response by SB431542, we analyzed antigen presentation by dermal dendritic cells and langerhans cells. Preliminary data suggests that inhibition of TGF-β1 pathway suppresses the migration of skin DC subsets to the lymph nodes in response to UV, in turn suppressing the T lymphocyte response. In summary, the TGF-β1 pathway is important for the activation of the inflammatory response to UVB irradiation of the skin, which maybe mediated through Dendritic cells.

마우스 피부암에 대한 장뇌삼과 인삼의 특이적 항암 효능

Mountain cultivated ginseng (MCG) is a type of Panax ginseng C. A. Mayer, grown in the mountains by artificial seeding. In general, it has been known that the biophysical activities of MCG is greater than that of ginseng. However, the in vivo efficacy of MCG on cancer has not been studied. In this study, we investigated the anti-carcinogenic effect of MCG and ginseng using the 7,12-dimethylbenz[a]anthracene (DMBA)-12-O-tetradecanoylphorbol- 13-acetate (TPA) two stage mouse skin carcinogenesis model. Six weeks of female ICR mice were divided into control, MCG, and ginseng diet groups and were subjected into two different experimental protocols. In the first study, each experimental diet was fed with TPA promotion for 24 weeks. The result showed that supplementation of MCG reduced tumor incidence, tumor multiplicity, and tumor size compared to those of the control and ginseng groups. In the second study, 3 groups of mice were supplied with each diet 4 weeks before DMBA tumor initiation, until the end of experiment. The result showed that tumor incidence, tumor multiplicity, and tumor size were reduced in the ginseng diet group compared to those of the control and MCG groups. TPA-induced BrdU incorporation was also significantly reduced in the ginseng diet group. Taken together, these results suggest that MCG is chemotherapeutic, whereas ginseng has a chemopreventative effect on mouse skin cancer.