Publications by authors named "Donna Kusewitt"

90 Publications

Pyrazole-Based Lactate Dehydrogenase Inhibitors with Optimized Cell Activity and Pharmacokinetic Properties.

J Med Chem 2020 10 27;63(19):10984-11011. Epub 2020 Sep 27.

National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation of reduced nicotinamide adenine dinucleotide as the final step in the glycolytic pathway. Glycolysis plays an important role in the metabolic plasticity of cancer cells and has long been recognized as a potential therapeutic target. Thus, potent, selective inhibitors of LDH represent an attractive therapeutic approach. However, to date, pharmacological agents have failed to achieve significant target engagement , possibly because the protein is present in cells at very high concentrations. We report herein a lead optimization campaign focused on a pyrazole-based series of compounds, using structure-based design concepts, coupled with optimization of cellular potency, drug-target residence times, and PK properties, to identify first-in-class inhibitors that demonstrate LDH inhibition . The lead compounds, named () and (), possess desirable attributes for further studying the effect of LDH inhibition.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830743PMC
October 2020

Dynamic Imaging of LDH Inhibition in Tumors Reveals Rapid In Vivo Metabolic Rewiring and Vulnerability to Combination Therapy.

Cell Rep 2020 02;30(6):1798-1810.e4

Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address:

The reliance of many cancers on aerobic glycolysis has stimulated efforts to develop lactate dehydrogenase (LDH) inhibitors. However, despite significant efforts, LDH inhibitors (LDHi) with sufficient specificity and in vivo activity to determine whether LDH is a feasible drug target are lacking. We describe an LDHi with potent, on-target, in vivo activity. Using hyperpolarized magnetic resonance spectroscopic imaging (HP-MRSI), we demonstrate in vivo LDH inhibition in two glycolytic cancer models, MIA PaCa-2 and HT29, and we correlate depth and duration of LDH inhibition with direct anti-tumor activity. HP-MRSI also reveals a metabolic rewiring that occurs in vivo within 30 min of LDH inhibition, wherein pyruvate in a tumor is redirected toward mitochondrial metabolism. Using HP-MRSI, we show that inhibition of mitochondrial complex 1 rapidly redirects tumor pyruvate toward lactate. Inhibition of both mitochondrial complex 1 and LDH suppresses metabolic plasticity, causing metabolic quiescence in vitro and tumor growth inhibition in vivo.
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http://dx.doi.org/10.1016/j.celrep.2020.01.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039685PMC
February 2020

DNA polymerase ζ deficiency causes impaired wound healing and stress-induced skin pigmentation.

Life Sci Alliance 2018 Jun 29;1(3). Epub 2018 Jun 29.

Department of Epigenetics & Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, and the Graduate School of Biomedical Sciences at Houston, Smithville, Texas, P.O. Box 389, Smithville, TX, 78957, USA.

DNA polymerase ζ (pol ζ) is a specialized enzyme important for DNA damage tolerance, facilitating synthesis past lesions caused by radiation or chemical damage. Here we report that disruption of (encoding the catalytic subunit of pol ζ) in mouse epidermis leads to a defect in proliferation that impairs cutaneous wound healing. A striking increase in epidermal skin pigmentation accompanied both wound healing and UV irradiation in these mice. This was a consequence of stress-induced migration of -proficient melanocytes to the -defective epidermis. This pigmentation corresponded with p53 activation in keratinocytes and was absent in p53-negative areas of the epidermis. Expression of the kit ligand () gene, a p53-controlled mediator of keratinocyte to melanocyte signaling, was enhanced during wound healing or following UV irradiation. This study extends the function of pol ζ to the process of proliferation during wound healing. -deficient epidermis may be a useful mouse model system for examining communication between damaged keratinocytes and melanocytes, including signaling relevant to human disease.
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http://dx.doi.org/10.26508/lsa.201800048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055517PMC
June 2018

Innate Sex Bias of Skin Infection Is Driven by α-Hemolysin.

J Immunol 2018 01 8;200(2):657-668. Epub 2017 Dec 8.

Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM 87131;

Numerous studies have reported sex bias in infectious diseases, with bias direction dependent on pathogen and site of infection. is the most common cause of skin and soft tissue infections (SSTIs), yet sex bias in susceptibility to SSTI has not been described. A search of electronic health records revealed an odds ratio of 2.4 for SSTI in males versus females. To investigate the physiological basis of this bias, we compared outcomes between male and female mice in a model of dermonecrosis. Consistent with the epidemiological data, female mice were better protected against SSTI, with reduced dermonecrosis followed later by increased bacterial clearance. Protection in females was disrupted by ovariectomy and restored by short-term estrogen administration. Importantly, this sex bias was mediated by a sex-specific response to the secreted virulence factor α-hemolysin (Hla). Infection with wild-type suppressed inflammatory cytokine production in the skin of female, but not male, mice when compared with infection with an isogenic deletion mutant. This differential response was conserved following injection with Hla alone, demonstrating a direct response to Hla independent of bacterial burden. Additionally, neutrophils, essential for clearing , demonstrated sex-specific bactericidal capacity ex vivo. This work suggests that sex-specific skin innate responsiveness to Hla and neutrophil bactericidal capacity play important roles in limiting SSTI in females. Understanding the molecular mechanisms controlling this sex bias may reveal novel targets to promote host innate defense against skin infection.
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http://dx.doi.org/10.4049/jimmunol.1700810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760295PMC
January 2018

The R-Enantiomer of Ketorolac Delays Mammary Tumor Development in Mouse Mammary Tumor Virus-Polyoma Middle T Antigen (MMTV-PyMT) Mice.

Am J Pathol 2018 02 21;188(2):515-524. Epub 2017 Nov 21.

Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico. Electronic address:

Epidemiologic studies report improved breast cancer survival in women who receive ketorolac (Toradol) for postoperative pain relief compared with other analgesic agents. Ketorolac is a racemic drug. The S-enantiomer inhibits cyclooxygenases; R-ketorolac is a selective inhibitor of the small GTPases Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42), which are signaling molecules up-regulated during breast cancer progression and metastasis. The goal of this study was to determine whether R-ketorolac altered breast cancer development in the mouse mammary tumor virus-polyoma middle T-antigen model. Mice were administered ketorolac orally at 1 mg/kg twice daily to approximate the typical human dose. Mammary glands were analyzed for tumor number and immunohistochemical markers of proliferation and differentiation. R-ketorolac treatment significantly reduced mammary epithelial proliferation, based on Ki67 staining, and suppressed tumor development. Proliferative mammary epithelium from R-ketorolac-treated mice displayed greater differentiation, based on significantly higher total E-cadherin and decreased keratin 5 staining than epithelium of placebo-treated mice. No differences were detected in estrogen receptor, progesterone receptor, β-catenin, or vimentin expression between placebo and R-ketorolac treatment groups. These findings indicate that R-ketorolac treatment slows tumor progression in an aggressive model of breast cancer. R-ketorolac may thus represent a novel therapeutic approach for breast cancer prevention or treatment based on its pharmacologic activity as a Rac1 and Cdc42 inhibitor.
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http://dx.doi.org/10.1016/j.ajpath.2017.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785557PMC
February 2018

The p53 R72P polymorphism does not affect the physiological response to ionizing radiation in a mouse model.

Cell Cycle 2017 Jun 8;16(12):1153-1163. Epub 2017 Jun 8.

a Department of Epigenetics and Molecular Carcinogenesis , The University of Texas MD Anderson Cancer Center , Smithville , TX , USA.

Tissue culture and mouse model studies show that the presence of the arginine (R) or proline (P) coding single nucleotide polymorphism (SNP) of the tumor suppressor gene p53 at codon 72 (p53 R72P) differentially affects the responses to genotoxic insult. Compared to the P variant, the R variant shows increased apoptosis in most cell cultures and mouse model tissues in response to genotoxins, and epidemiological studies suggest that the R variant may enhance cancer survival and reduce the risks of adverse reactions to genotoxic cancer treatment. As ionizing radiation (IR) treatment is often used in cancer therapy, we sought to test the physiological effects of IR in mouse models of the p53 R72P polymorphism. By performing blood counts, immunohistochemical (IHC) staining and survival studies in mouse populations rigorously controlled for strain background, sex and age, we discovered that p53 R72P polymorphism did not differentially affect the physiological response to IR. Our findings suggest that genotyping for this polymorphism to personalize IR therapy may have little clinical utility.
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http://dx.doi.org/10.1080/15384101.2017.1312234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499914PMC
June 2017

Analysis of DNA polymerase ν function in meiotic recombination, immunoglobulin class-switching, and DNA damage tolerance.

PLoS Genet 2017 Jun 1;13(6):e1006818. Epub 2017 Jun 1.

Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, United States of America.

DNA polymerase ν (pol ν), encoded by the POLN gene, is an A-family DNA polymerase in vertebrates and some other animal lineages. Here we report an in-depth analysis of pol ν-defective mice and human cells. POLN is very weakly expressed in most tissues, with the highest relative expression in testis. We constructed multiple mouse models for Poln disruption and detected no anatomic abnormalities, alterations in lifespan, or changed causes of mortality. Mice with inactive Poln are fertile and have normal testis morphology. However, pol ν-disrupted mice have a modestly reduced crossover frequency at a meiotic recombination hot spot harboring insertion/deletion polymorphisms. These polymorphisms are suggested to generate a looped-out primer and a hairpin structure during recombination, substrates on which pol ν can operate. Pol ν-defective mice had no alteration in DNA end-joining during immunoglobulin class-switching, in contrast to animals defective in the related DNA polymerase θ (pol θ). We examined the response to DNA crosslinking agents, as purified pol ν has some ability to bypass major groove peptide adducts and residues of DNA crosslink repair. Inactivation of Poln in mouse embryonic fibroblasts did not alter cellular sensitivity to mitomycin C, cisplatin, or aldehydes. Depletion of POLN from human cells with shRNA or siRNA did not change cellular sensitivity to mitomycin C or alter the frequency of mitomycin C-induced radial chromosomes. Our results suggest a function of pol ν in meiotic homologous recombination in processing specific substrates. The restricted and more recent evolutionary appearance of pol ν (in comparison to pol θ) supports such a specialized role.
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http://dx.doi.org/10.1371/journal.pgen.1006818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472330PMC
June 2017

Energy Balance Modulation Impacts Epigenetic Reprogramming, ERα and ERβ Expression, and Mammary Tumor Development in MMTV-neu Transgenic Mice.

Cancer Res 2017 05 3;77(9):2500-2511. Epub 2017 Apr 3.

Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

The association between obesity and breast cancer risk and prognosis is well established in estrogen receptor (ER)-positive disease but less clear in HER2-positive disease. Here, we report preclinical evidence suggesting weight maintenance through calorie restriction (CR) may limit risk of HER2-positive breast cancer. In female MMTV-HER2/neu transgenic mice, we found that ERα and ERβ expression, mammary tumorigenesis, and survival are energy balance dependent in association with epigenetic reprogramming. Mice were randomized to receive a CR, overweight-inducing, or diet-induced obesity regimen ( = 27/group). Subsets of mice ( = 4/group/time point) were euthanized after 1, 3, and 5 months to characterize diet-dependent metabolic, transcriptional, and epigenetic perturbations. Remaining mice were followed up to 22 months. Relative to the overweight and diet-induced obesity regimens, CR decreased body weight, adiposity, and serum metabolic hormones as expected and also elicited an increase in mammary ERα and ERβ expression. Increased DNA methylation accompanied this pattern, particularly at CpG dinucleotides located within binding or flanking regions for the transcriptional regulator CCCTC-binding factor of and consistent with sustained transcriptional activation of ERα and ERβ. Mammary expression of the DNA methylation enzyme was stable in CR mice but increased over time in overweight and diet-induced obesity mice, suggesting CR obviates epigenetic alterations concurrent with chronic excess energy intake. In the survival study, CR elicited a significant suppression in spontaneous mammary tumorigenesis. Overall, our findings suggest a mechanistic rationale to prevent or reverse excess body weight as a strategy to reduce HER2-positive breast cancer risk. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964334PMC
May 2017

Longitudinal Assessment of Lung Cancer Progression in Mice Using the Sodium Iodide Symporter Reporter Gene and SPECT/CT Imaging.

PLoS One 2016 30;11(12):e0169107. Epub 2016 Dec 30.

Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.

Lung cancer has the highest mortality rate of any tissue-specific cancer in both men and women. Research continues to investigate novel drugs and therapies to mitigate poor treatment efficacy, but the lack of a good descriptive lung cancer animal model for preclinical drug evaluation remains an obstacle. Here we describe the development of an orthotopic lung cancer animal model which utilizes the human sodium iodide symporter gene (hNIS; SLC5A5) as an imaging reporter gene for the purpose of non-invasive, longitudinal tumor quantification. hNIS is a glycoprotein that naturally transports iodide (I-) into thyroid cells and has the ability to symport the radiotracer 99mTc-pertechnetate (99mTcO4-). A549 lung adenocarcinoma cells were genetically modified with plasmid or lentiviral vectors to express hNIS. Modified cells were implanted into athymic nude mice to develop two tumor models: a subcutaneous and an orthotopic xenograft tumor model. Tumor progression was longitudinally imaged using SPECT/CT and quantified by SPECT voxel analysis. hNIS expression in lung tumors was analyzed by quantitative real-time PCR. Additionally, hematoxylin and eosin staining and visual inspection of pulmonary tumors was performed. We observed that lentiviral transduction provided enhanced and stable hNIS expression in A549 cells. Furthermore, 99mTcO4- uptake and accumulation was observed within lung tumors allowing for imaging and quantification of tumor mass at two-time points. This study illustrates the development of an orthotopic lung cancer model that can be longitudinally imaged throughout the experimental timeline thus avoiding inter-animal variability and leading to a reduction in total animal numbers. Furthermore, our orthotopic lung cancer animal model is clinically relevant and the genetic modification of cells for SPECT/CT imaging can be translated to other tissue-specific tumor animal models.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169107PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5201271PMC
July 2017

The p53 inhibitor Mdm4 cooperates with multiple genetic lesions in tumourigenesis.

J Pathol 2017 03 6;241(4):501-510. Epub 2017 Jan 6.

Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The p53 inhibitor Mdm4 is present at high levels in multiple human cancers. Overexpression of Mdm4 in mice drives the spontaneous development of mostly lymphomas and sarcomas. In this study, we explored the ability of Mdm4 to cooperate with lesions in tumour development. The Mdm4 transgene contributed to mammary tumour development in a BALB/cJ background. High levels of Mdm4 enhanced tumour development in a mutant p53R172H heterozygous background, and reduced the need to lose the wild-type p53 allele, as compared with mice heterozygous only for the p53R172H mutation. Additionally, high levels of Mdm4 cooperated with an oncogenic K-ras mutation to drive lung tumourigenesis in vivo. Finally, we examined p53-independent functions of Mdm4 by studying the contribution of Mdm4 to tumour development in the absence of p53. Whereas the overall survival times of p53-null mice with and without the Mdm4 transgene were similar, male mice with both alterations showed significantly shorter survival than p53-null male mice, and showed differences in tumour spectrum, demonstrating a p53-independent function of Mdm4 in tumourigenesis. Furthermore, p53-null mice with the highest level of Mdm4 tended to have multiple tumours. Thus, a detailed analysis of Mdm4 transgenic mice in various genetic backgrounds shows synergy in tumour development in vivo. Mdm4 may thus serve as a therapeutic target in cancers. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315583PMC
March 2017

Slug Modulates UV Radiation-Induced Cutaneous Inflammation by Regulating Epidermal Production of Proinflammatory Cytokines.

J Invest Dermatol 2017 02 23;137(2):532-534. Epub 2016 Sep 23.

Department of Pathology, School of Medicine, University of New Mexico, Albuquerque, New Mexico, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2016.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831371PMC
February 2017

Oral Tolerance to Environmental Mycobacteria Interferes with Intradermal, but Not Pulmonary, Immunization against Tuberculosis.

PLoS Pathog 2016 05 6;12(5):e1005614. Epub 2016 May 6.

Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, United States of America.

Bacille Calmette-Guérin (BCG) is currently the only approved vaccine against tuberculosis (TB) and is administered in over 150 countries worldwide. Despite its widespread use, the vaccine has a variable protective efficacy of 0-80%, with the lowest efficacy rates in tropical regions where TB is most prevalent. This variability is partially due to ubiquitous environmental mycobacteria (EM) found in soil and water sources, with high EM prevalence coinciding with areas of poor vaccine efficacy. In an effort to elucidate the mechanisms underlying EM interference with BCG vaccine efficacy, we exposed mice chronically to Mycobacterium avium (M. avium), a specific EM, by two different routes, the oral and intradermal route, to mimic human exposure. After intradermal BCG immunization in mice exposed to oral M. avium, we saw a significant decrease in the pro-inflammatory cytokine IFN-γ, and an increase in T regulatory cells and the immunosuppressive cytokine IL-10 compared to naïve BCG-vaccinated animals. To circumvent the immunosuppressive effect of oral M. avium exposure, we vaccinated mice by the pulmonary route with BCG. Inhaled BCG immunization rescued IFN-γ levels and increased CD4 and CD8 T cell recruitment into airways in M. avium-presensitized mice. In contrast, intradermal BCG vaccination was ineffective at T cell recruitment into the airway. Pulmonary BCG vaccination proved protective against Mtb infection regardless of previous oral M. avium exposure, compared to intradermal BCG immunization. In conclusion, our data indicate that vaccination against TB by the pulmonary route increases BCG vaccine efficacy by avoiding the immunosuppressive interference generated by chronic oral exposure to EM. This has implications in TB-burdened countries where drug resistance is on the rise and health care options are limited due to economic considerations. A successful vaccine against TB is necessary in these areas as it is both effective and economical.
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http://dx.doi.org/10.1371/journal.ppat.1005614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859477PMC
May 2016

Role of the Slug Transcription Factor in Chemically-Induced Skin Cancer.

J Clin Med 2016 Feb 3;5(2). Epub 2016 Feb 3.

Department of Epigenetics and Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, P.O. Box 389, Smithville, TX 78957, USA.

The Slug transcription factor plays an important role in ultraviolet radiation (UVR)-induced skin carcinogenesis, particularly in the epithelial-mesenchymal transition (EMT) occurring during tumor progression. In the present studies, we investigated the role of Slug in two-stage chemical skin carcinogenesis. Slug and the related transcription factor Snail were expressed at high levels in skin tumors induced by 7,12-dimethylbenz[α]anthracene application followed by 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment. TPA-induced transient elevation of Slug and Snail proteins in normal mouse epidermis and studies in Slug transgenic mice indicated that Slug modulates TPA-induced epidermal hyperplasia and cutaneous inflammation. Although Snail family factors have been linked to inflammation via interactions with the cyclooxygenase-2 (COX-2) pathway, a pathway that also plays an important role in skin carcinogenesis, transient TPA induction of Slug and Snail appeared unrelated to COX-2 expression. In cultured human keratinocytes, TPA induced Snail mRNA expression while suppressing Slug expression, and this differential regulation was due specifically to activation of the TPA receptor. These studies show that Slug and Snail exhibit similar patterns of expression during both UVR and chemical skin carcinogenesis, that Slug and Snail can be differentially regulated under some conditions and that in vitro findings may not recapitulate in vivo results.
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http://dx.doi.org/10.3390/jcm5020021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773777PMC
February 2016

Increased Susceptibility to Skin Carcinogenesis Associated with a Spontaneous Mouse Mutation in the Palmitoyl Transferase Zdhhc13 Gene.

J Invest Dermatol 2015 Dec 19;135(12):3133-3143. Epub 2015 Aug 19.

Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA. Electronic address:

Here we describe a spontaneous mutation in the Zdhhc13 (zinc finger, DHHC domain containing 13) gene (also called Hip14l), one of 24 genes encoding palmitoyl acyltransferase (PAT) enzymes in the mouse. This mutation (Zdhhc13luc) was identified as a nonsense base substitution, which results in a premature stop codon that generates a truncated form of the ZDHHC13 protein, representing a potential loss-of-function allele. Homozygous Zdhhc13luc/Zdhhc13luc mice developed generalized hypotrichosis, associated with abnormal hair cycle, epidermal and sebaceous gland hyperplasia, hyperkeratosis, and increased epidermal thickness. Increased keratinocyte proliferation and accelerated transit from basal to more differentiated layers were observed in mutant compared with wild-type (WT) epidermis in untreated skin and after short-term 12-O-tetradecanoyl-phorbol-13-acetate treatment and acute UVB exposure. Interestingly, this epidermal phenotype was associated with constitutive activation of NF-κB (RelA) and increased neutrophil recruitment and elastase activity. Furthermore, tumor multiplicity and malignant progression of papillomas after chemical skin carcinogenesis were significantly higher in mutant mice than WT littermates. To our knowledge, this is the first report of a protective role for PAT in skin carcinogenesis.
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http://dx.doi.org/10.1038/jid.2015.314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898190PMC
December 2015

Role of the epidermal growth factor receptor in ultraviolet radiation induction of Snail family transcription factors.

J Dermatol Sci 2014 Nov 16;76(2):149-51. Epub 2014 Sep 16.

Department of Molecular Carcinogenesis, Science Park, MD Anderson Cancer Center, University of Texas, Smithville, TX 78957, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jdermsci.2014.09.001DOI Listing
November 2014

Melanocyte and melanoma cell activation by calprotectin.

J Skin Cancer 2014 12;2014:846249. Epub 2014 Aug 12.

Department of Molecular Carcinogenesis, Science Park, University of Texas MD Anderson Cancer Center, 1808 Park Road 1C, Smithville, TX 78957, USA.

Calprotectin, a heterodimer of S100A8 and S100A9, is a proinflammatory cytokine released from ultraviolet radiation-exposed keratinocytes. Calprotectin binds to Toll-like receptor 4, the receptor for advanced glycation end-products, and extracellular matrix metalloproteinase inducer on target cells to stimulate migration. Melanocytes and melanoma cells produce little if any calprotectin, but they do express receptors for the cytokine. Thus, keratinocyte-derived calprotectin has the potential to activate melanocytes and melanoma cells within the epidermis in a paracrine manner. We examined the ability of calprotectin to stimulate proliferation and migration in normal human melanocytes and melanoma cells in vitro. We first showed, by immunofluorescence and quantitative RT-PCR, that the melanocytic cells employed expressed a calprotectin receptor, the receptor for advanced end-products. We then demonstrated that calprotectin significantly enhanced proliferation, migration, and Matrigel invasion in both normal human melanocytes and melanoma cells. Thus, calprotectin is one of the numerous paracrine factors released by ultraviolet radiation-exposed keratinocytes that may promote melanomagenesis and is a potential target for melanoma prevention or therapy.
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http://dx.doi.org/10.1155/2014/846249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146350PMC
September 2014

MIF antagonist (CPSI-1306) protects against UVB-induced squamous cell carcinoma.

Mol Cancer Res 2014 Sep 21;12(9):1292-302. Epub 2014 May 21.

Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio.

Unlabelled: Macrophage migration inhibitory factor (MIF) is a homotrimeric proinflammatory cytokine implicated in chronic inflammatory diseases and malignancies, including cutaneous squamous cell carcinomas (SCC). To determine whether MIF inhibition could reduce UVB light-induced inflammation and squamous carcinogenesis, a small-molecule MIF inhibitor (CPSI-1306) was utilized that disrupts homotrimerization. To examine the effect of CPSI-1306 on acute UVB-induced skin changes, Skh-1 hairless mice were systemically treated with CPSI-1306 for 5 days before UVB exposure. In addition to decreasing skin thickness and myeloperoxidase (MPO) activity, CPSI-1306 pretreatment increased keratinocyte apoptosis and p53 expression, decreased proliferation and phosphohistone variant H2AX (γ-H2AX), and enhanced repair of cyclobutane pyrimidine dimers. To examine the effect of CPSI-1306 on squamous carcinogenesis, mice were exposed to UVB for 10 weeks, followed by CPSI-1306 treatment for 8 weeks. CPSI-1306 dramatically decreased the density of UVB-associated p53 foci in non-tumor-bearing skin while simultaneously decreasing the epidermal Ki67 proliferation index. In addition to slowing the rate of tumor development, CPSI-1306 decreased the average tumor burden per mouse. Although CPSI-1306-treated mice developed only papillomas, nearly a third of papillomas in vehicle-treated mice progressed to microinvasive SCC. Thus, MIF inhibition is a promising strategy for prevention of the deleterious cutaneous effects of acute and chronic UVB exposure.

Implications: Macrophage migration inhibitory factor is a viable target for the prevention of UVB-induced cutaneous SSCs.
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http://dx.doi.org/10.1158/1541-7786.MCR-14-0255-TDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284200PMC
September 2014

Tumor-suppressive functions of 15-Lipoxygenase-2 and RB1CC1 in prostate cancer.

Cell Cycle 2014 14;13(11):1798-810. Epub 2014 Apr 14.

Department of Molecular Carcinogenesis; The University of Texas MD Anderson Cancer Center; Smithville, TX USA; Cancer Stem Cell Institute; Research Center for Translational Medicine; Shanghai East Hospital; Tongji University School of Medicine; Shanghai, China.

15-Lipoxygenase-2 (15-LOX2) is a human-specific lipid-peroxidizing enzyme most prominently expressed in epithelial cells of normal human prostate but downregulated or completely lost in>70% of prostate cancer (PCa) cases. Transgenic expression of 15-LOX2 in the mouse prostate surprisingly causes hyperplasia. Here we first provide evidence that 15-LOX2-induced prostatic hyperplasia does not progress to PCa even in p53(+/-) or p53(-/-) background. More important, by generating 15-LOX2; Hi-Myc double transgenic (dTg) mice, we show that 15-LOX2 expression inhibits Myc-induced PCa development, such that in the 3-month- and 6-month-old dTg mice, there is a significant reduction in prostate intraneoplasia (PIN) and PCa prevalent in age-matched Hi-Myc prostates. The dTg prostates show increased cell senescence and expression of several senescence-associated molecules, including p27, phosphorylated Rb, and Rb1cc1. We further show that in HPCa, 15-LOX2 and c-Myc manifest reciprocal protein expression patterns. Moreover, RB1CC1 accumulates in senescing normal human prostate (NHP) cells, and in both NHP and RWPE-1 cells, the 15-LOX2 metabolic products 15(S)-HPETE and 15(S)-HETE induce RB1CC1. We finally show that unlike 15-LOX2, RB1CC1 is not lost but rather frequently overexpressed in PCa samples. RB1CC1 knockdown in PC3 cells enhances clonal growth in vitro and tumor growth in vivo. Together, our present studies provide evidence for tumor-suppressive functions for both 15-LOX2 and RB1CC1.
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http://dx.doi.org/10.4161/cc.28757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4111726PMC
January 2015

Extended UVB Exposures Alter Tumorigenesis and Treatment Efficacy in a Murine Model of Cutaneous Squamous Cell Carcinoma.

J Skin Cancer 2013 27;2013:246848. Epub 2013 Oct 27.

Department of Pathology, The Ohio State University, 1645 Neil Avenue, 129 Hamilton Hall, Columbus, OH 43210, USA.

Epidemiological studies support a link between cumulative sun exposure and cutaneous squamous cell carcinoma (SCC) development. However, the presumed effects of extended ultraviolet light B (UVB) exposure on tumorigenesis in the sexes have not been formally investigated. We examined differences in ultimate tumorigenesis at 25 weeks in mice exposed to UVB for either 10 or 25 weeks. Additionally, we investigated the effect of continued UVB exposure on the efficacy of topical treatment with anti-inflammatory (diclofenac) or antioxidant (C E Ferulic or vitamin E) compounds on modulating tumorigenesis. Vehicle-treated mice in the 25-week UVB exposure model exhibited an increased tumor burden and a higher percentage of malignant tumors compared to mice in the 10-week exposure model, which correlated with increases in total and mutant p53-positive epidermal cells. Only topical diclofenac decreased tumor number and burden in both sexes regardless of UVB exposure length. These data support the commonly assumed but not previously demonstrated fact that increased cumulative UVB exposure increases the risk of UVB-induced SCC development and can also affect therapeutic efficacies. Our study suggests that cessation of UVB exposure by at-risk patients may decrease tumor development and that topical NSAIDs such as diclofenac may be chemopreventive.
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http://dx.doi.org/10.1155/2013/246848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826430PMC
November 2013

Glyoxal leads to defective keratinocyte migration and down-regulation of Snai2.

J Dermatol Sci 2014 Feb 18;73(2):166-9. Epub 2013 Oct 18.

Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jdermsci.2013.10.001DOI Listing
February 2014

Slug expression in mouse skin and skin tumors is not regulated by p53.

J Invest Dermatol 2014 Feb 5;134(2):566-568. Epub 2013 Sep 5.

Department of Molecular Carcinogenesis, Science Park, University of Texas M.D. Anderson Cancer Center, Smithville, Texas, USA. Electronic address:

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http://dx.doi.org/10.1038/jid.2013.363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947144PMC
February 2014

In vivo functional studies of tumor-specific retrogene NanogP8 in transgenic animals.

Cell Cycle 2013 Aug 26;12(15):2395-408. Epub 2013 Jun 26.

Department of Molecular Carcinogenesis; University of Texas MD Anderson Cancer Center; Smithville, TX USA; Program in Molecular Carcinogenesis; University of Texas Graduate School of Biomedical Sciences (GSBS); Houston, TX USA.

The current study was undertaken to investigate potential oncogenic functions of NanogP8, a tumor-specific retrogene homolog of Nanog (expressed in pluripotent cells), in transgenic animal models. To this end, human primary prostate tumor-derived NanogP8 was targeted to the cytokeratin 14 (K14) cellular compartment, and two lines of K14-NanogP8 mice were derived. The line 1 animals, expressing high levels of NanogP8, experienced perinatal lethality and developmental abnormalities in multiple organs, including the skin, tongue, eye, and thymus in surviving animals. On postnatal day 5 transgenic skin, for example, there was increased c-Myc expression and Ki-67(+) cells accompanied by profound abnormalities in skin development such as thickened interfollicular epidermis and dermis and lack of hypodermis and sebaceous glands. The line 3 mice, expressing low levels of NanogP8, were grossly normal except cataract development by 4-6 mo of age. Surprisingly, both lines of mice do not develop spontaneous tumors related to transgene expression. Even more unexpectedly, high levels of NanogP8 expression in L1 mice actually inhibited tumor development in a two-stage chemical carcinogenesis model. Mechanistic studies revealed that constitutive NanogP8 overexpression in adult L1 mice reduced CD34(+)α6(+) and Lrig-1(+) bulge stem cells, impaired keratinocyte migration, and repressed the expression of many stem cell-associated genes, including Bmp5, Fgfr2, Jmjd1a, and Jun. Our study, for the first time, indicates that transgenically expressed human NanogP8 is biologically functional, but suggests that high levels of NanogP8 may disrupt normal developmental programs and inhibit tumor development by depleting stem cells.
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http://dx.doi.org/10.4161/cc.25402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841319PMC
August 2013

Differential effects of topical vitamin E and C E Ferulic® treatments on ultraviolet light B-induced cutaneous tumor development in Skh-1 mice.

PLoS One 2013 14;8(5):e63809. Epub 2013 May 14.

Department of Pathology, The Ohio State University, Columbus, Ohio, USA.

Because of the ever-increasing incidence of ultraviolet light B (UVB)-induced skin cancer, considerable attention is being paid to prevention through the use of both sunscreens and after sun treatments, many of which contain antioxidants. Vitamin E is included as an antioxidant in many sunscreens and lotions currently on the market. Studies examining the efficacy of vitamin E as a topical preventative agent for UVB-induced skin cancer have yielded conflicting results. A likely contributor to differences in study outcome is the stability of vitamin E in the particular formulation being tested. In the current study we examined the effects of topical vitamin E alone as well as vitamin E combined with vitamin C and ferulic acid in a more stable topical formula (C E Ferulic®). Mice were exposed to UVB for 10 weeks in order to induce skin damage. Then, before the appearance of any cutaneous lesions, mice were treated for 15 weeks with a topical antioxidant, without any further UVB exposure. We found that topical C E Ferulic decreased tumor number and tumor burden and prevented the development of malignant skin tumors in female mice with chronically UVB-damaged skin. In contrast, female mice chronically exposed to UVB and treated topically with vitamin E alone showed a trend towards increased tumor growth rate and exhibited increased levels of overall DNA damage, cutaneous proliferation, and angiogenesis compared to vehicle-treated mice. Thus, we have demonstrated that topical 5% alpha tocopherol may actually promote carcinogenesis when applied on chronically UVB-damaged skin while treating with a more stable antioxidant compound may offer therapeutic benefits.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063809PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653797PMC
December 2013

Modeling gene-environment interactions in oral cavity and esophageal cancers demonstrates a role for the p53 R72P polymorphism in modulating susceptibility.

Mol Carcinog 2014 Aug 8;53(8):648-58. Epub 2013 Mar 8.

Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.

A large number of epidemiological studies have linked a common single-nucleotide polymorphism (SNP) in the human p53 gene to risk for developing a variety of cancers. This SNP encodes either an arginine or proline at position 72 (R72P) of the p53 protein, which can alter the apoptotic activity of p53 via transcriptional and non-transcriptional mechanisms. This SNP has also been reported to modulate the development of human papilloma virus (HPV)-driven cancers through differential targeting of the p53 variant proteins by the E6 viral oncoprotein. Mouse models for the p53 R72P polymorphism have recently been developed but a role for this SNP in modifying cancer risk in response to viral and chemical carcinogens has yet to be established experimentally. Here, we demonstrate that the p53 R72P polymorphism modulates the hyperprolferative, apoptotic and inflammatory phenotypes caused by expression of the HPV16 E6 and E7 oncoproteins. Moreover, the R72P SNP also modifies the carcinogenic response to the chemical carcinogen 4NQO, in the presence and absence of the HPV16 transgene. Our findings confirm several human epidemiological studies associating the codon 72 proline variant with increased risk for certain cancers but also suggest that there are tissue-specific differences in how the R72P polymorphism influences the response to environmental carcinogens.
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http://dx.doi.org/10.1002/mc.22019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926899PMC
August 2014

Dual role for mammalian DNA polymerase ζ in maintaining genome stability and proliferative responses.

Proc Natl Acad Sci U S A 2013 Feb 5;110(8):E687-96. Epub 2013 Feb 5.

Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center Science Park, Smithville, TX 78957, USA.

DNA polymerase ζ (polζ) is critical for bypass of DNA damage and the associated mutagenesis, but also has unique functions in mammals. It is required for embryonic development and for viability of hematopoietic cells, but, paradoxically, skin epithelia appear to survive polζ deletion. We wished to determine whether polζ functions in a tissue-specific manner and how polζ status influences skin tumorigenesis. Mice were produced in which Rev3L (the catalytic subunit of polζ) was deleted in tissues expressing keratin 5. Efficient epidermal deletion of Rev3L was tolerated but led to skin and hair abnormalities, accompanied by evidence of DNA breaks. Unchallenged mice developed tumors in keratin 5-expressing tissues with age, consistent with the chromosomal instability accompanying a polζ defect. Unexpectedly, mice with the Rev3L deletion were much more sensitive to UVB radiation than mice defective in other DNA repair genes. Following irradiation, polζ-defective mice failed to mount skin-regenerative responses and responded to stress by mobilizing melanocytes to the epidermis. However, they did not develop skin tumors after chronic UVB irradiation. To determine the proliferative potential of polζ-deficient skin epithelia, keratinocytes were isolated and examined. These keratinocytes harbored chromosomal gaps and breaks and exhibited a striking proliferation defect. These results can be unified by a model in which slowly dividing cells accumulate replication-associated DNA breaks but otherwise survive Rev3L deletion, but functional polζ is essential for responses requiring rapid proliferation, both in cell culture and in vivo. The results reveal a biological role for mammalian polζ in tolerating DNA damage and enabling proliferative responses in vivo.
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http://dx.doi.org/10.1073/pnas.1217425110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581960PMC
February 2013

Proliferative and non-proliferative lesions of the rat and mouse integument.

J Toxicol Pathol 2013 ;26(3 Suppl):27S-57S

Charles River, Tranent, Edinburgh, UK.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) project is a joint initiative of the societies of toxicological pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP). Its aim is to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory rodents. A widely accepted international harmonization of nomenclature in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and will provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists. The purpose of this publication is to provide a standardized nomenclature for classifying microscopical lesions observed in the integument of laboratory rats and mice. Example colour images are provided for most lesions. The standardized nomenclature presented in this document and additional colour images are also available electronically at http://www.goreni.org. The nomenclature presented herein is based on histopathology databases from government, academia, and industrial laboratories throughout the world, and covers lesions that develop spontaneously as well as those induced by exposure to various test materials. (DOI: 10.1293/tox.26.27S; J Toxicol Pathol 2013; 26: 27S-57S).
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http://dx.doi.org/10.1293/tox.26.27SDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091526PMC
July 2014

Preventative topical diclofenac treatment differentially decreases tumor burden in male and female Skh-1 mice in a model of UVB-induced cutaneous squamous cell carcinoma.

Carcinogenesis 2013 Feb 3;34(2):370-7. Epub 2012 Nov 3.

Department of Pathology, The Ohio State University, Columbus, OH 43210, USA.

Ultraviolet B (UVB) light is the major environmental carcinogen contributing to non-melanoma skin cancer (NMSC) development. There are over 3.5 million NMSC diagnoses in two million patients annually, with men having a 3-fold greater incidence of squamous cell carcinoma (SCC) compared with women. Chronic inflammation has been linked to tumorigenesis, with a key role for the cyclooxygenase-2 (COX-2) enzyme. Diclofenac, a COX-2 inhibitor and non-steroidal anti-inflammatory drug, currently is prescribed to patients as a short-term therapeutic agent to induce SCC precursor lesion regression. However, its efficacy as a preventative agent in patients without evidence of precursor lesions but with significant UVB-induced cutaneous damage has not been explored. We previously demonstrated in a murine model of UVB-induced skin carcinogenesis that when exposed to equivalent UVB doses, male mice had lower levels of inflammation but developed increased tumor multiplicity, burden and grade compared with female mice. Because of the discrepancy in the degree of inflammation between male and female skin, we sought to determine if topical treatment of previously damaged skin with an anti-inflammatory COX-2 inhibitor would decrease tumor burden and if it would be equally effective in the sexes. Our results demonstrated that despite observed sex differences in the inflammatory response, prolonged topical diclofenac treatment of chronically UVB-damaged skin effectively reduced tumor multiplicity in both sexes. Unexpectedly, tumor burden was significantly decreased only in male mice. Our data suggest a new therapeutic use for currently available topical diclofenac as a preventative intervention for patients predisposed to cutaneous SCC development before lesions appear.
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http://dx.doi.org/10.1093/carcin/bgs349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564442PMC
February 2013

High incidence of scrotal hernias in a closed colony of FVB mice.

Comp Med 2012 Oct;62(5):391-4

Department of Molecular Carcinogenesis, Science Park, University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.

Although inguinal hernias are rarely reported to occur in mice, a high incidence of scrotal hernias was observed in a closed breeding colony of FVB/N mice. Unilateral or bilateral hernias occurred in more than 20% of the male mice in the colony that were available for necropsy over 3 inbred and 1 outcross generations; no female mice were affected. Organs commonly present within the hernial sac included the cecum and seminal vesicles. Hernias did not adversely affect the fertility or lifespan of the affected male mice. Although the condition was heritable, no clear pattern of transmission was evident.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3472603PMC
October 2012

Ultraviolet radiation and the slug transcription factor induce proinflammatory and immunomodulatory mediator expression in melanocytes.

J Skin Cancer 2012 13;2012:410925. Epub 2012 Jun 13.

Department of Molecular Carcinogenesis, Science Park, The University of Texas MD Anderson Cancer Center, 1808 Park Road 1C, Smithville, TX 78957, USA.

Despite extensive investigation, the precise contribution of the ultraviolet radiation (UVR) component of sunlight to melanoma etiology remains unclear. UVR induces keratinocytes to secrete proinflammatory and immunomodulatory mediators that promote inflammation and skin tumor development; expression of the slug transcription factor in keratinocytes is required for maximal production of these mediators. In the present studies we examined the possibility that UVR-exposed melanocytes also produce proinflammatory mediators and that Slug is important in this process. Microarray studies revealed that both UVR exposure and Slug overexpression altered transcription of a variety of proinflammatory mediators by normal human melanocytes; some of these mediators are also known to stimulate melanocyte growth and migration. There was little overlap in the spectra of cytokines produced by the two stimuli. However IL-20 was similarly induced by both stimuli and the NFκB pathway appeared to be important in both circumstances. Further exploration of UVR-induced and Slug-dependent pathways of cytokine induction in melanocytes may reveal novel targets for melanoma therapy.
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http://dx.doi.org/10.1155/2012/410925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382223PMC
August 2012

High-anxious individuals show increased chronic stress burden, decreased protective immunity, and increased cancer progression in a mouse model of squamous cell carcinoma.

PLoS One 2012 25;7(4):e33069. Epub 2012 Apr 25.

Department of Psychiatry & Behavioral Sciences, Stanford University, Stanford, California, United States of America.

In spite of widespread anecdotal and scientific evidence much remains to be understood about the long-suspected connection between psychological factors and susceptibility to cancer. The skin is the most common site of cancer, accounting for nearly half of all cancers in the US, with approximately 2-3 million cases of non-melanoma cancers occurring each year worldwide. We hypothesized that a high-anxious, stress-prone behavioral phenotype would result in a higher chronic stress burden, lower protective-immunity, and increased progression of the immuno-responsive skin cancer, squamous cell carcinoma. SKH1 mice were phenotyped as high- or low-anxious at baseline, and subsequently exposed to ultraviolet-B light (1 minimal erythemal dose (MED), 3 times/week, 10-weeks). The significant strengths of this cancer model are that it uses a normal, immunocompetent, outbred strain, without surgery/injection of exogenous tumor cells/cell lines, and produces lesions that resemble human tumors. Tumors were counted weekly (primary outcome), and tissues collected during early and late phases of tumor development. Chemokine/cytokine gene-expression was quantified by PCR, tumor-infiltrating helper (Th), cytolytic (CTL), and regulatory (Treg) T cells by immunohistochemistry, lymph node T and B cells by flow cytometry, adrenal and plasma corticosterone and tissue vascular-endothelial-growth-factor (VEGF) by ELISA. High-anxious mice showed a higher tumor burden during all phases of tumor development. They also showed: higher corticosterone levels (indicating greater chronic stress burden), increased CCL22 expression and Treg infiltration (increased tumor-recruited immuno-suppression), lower CTACK/CCL27, IL-12, and IFN-γ gene-expression and lower numbers of tumor infiltrating Th and CTLs (suppressed protective immunity), and higher VEGF concentrations (increased tumor angiogenesis/invasion/metastasis). These results suggest that the deleterious effects of high trait anxiety could be: exacerbated by life-stressors, accentuated by the stress of cancer diagnosis/treatment, and mediate increased tumor progression and/or metastasis. Therefore, it may be beneficial to investigate the use of chemotherapy-compatible anxiolytic treatments immediately following cancer diagnosis, and during cancer treatment/survivorship.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033069PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338811PMC
September 2012