Developing a murine model for arsenic-induced skin neoplasm

Summary

Principal Investigator: Mohammad Athar
Abstract: It is known that about 15 million Americans are chronically exposed to environmental arsenic whereas the global picture of arsenic exposure is much grimmer as more than 100 million humans throughout the world consume arsenic contaminated drinking water. Inorganic arsenic is a known human carcinogen and therefore is a well-defined threat to human health. Epidemiological data indicate that chronic human exposure to arsenical compounds is associated with an increased incidence of cancers of the lung, skin (both basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs)), bladder, liver, prostate as well as in other organs. However, the mechanism(s) underlying the carcinogenicity of arsenicals remains elusive particularly due to unavailability of suitable murine model. Originally described in patients with the nevoid basal cell carcinoma syndrome (NBCCS), mutations in sonic hedgehog (shh) signaling genes including patched (ptch), and smoothened (smo) are also known to underlie sporadic BCCs. It is reported that BCCs in arsenic-exposed individuals may also carry ptch mutations. Shh activation including that due to mutations in ptch/smo drives overexpression of transcription factors, gli, which ultimately lead to proliferation of neoplastic lesions. The Shh signaling pathway is one of the most fundamental signal transduction pathways during embryonic development. In this proposal, we will investigate whether aberrant activation of shh pathway is involved in the molecular pathogenesis of arsenic-induced skin cancers (BCCs and SCCs) and possibly in other arsenic- induced cancers. We will also test whether blocking shh activation may reduce the risk of arsenic-induced cancer. In addition, we will investigate the role of arsenic-induced reactive oxygen species (ROS) and associated cell signaling related to stress and cell survival pathways as well as the possible additive or synergistic effects of ROS on shh in augmenting cell proliferation during arsenic-induced skin carcinogenesis. We will utilize our recently developed murine model, ptc1/SKH-1 hairless mice, which are highly susceptible to the induction of both BCCs and SCCs. These studies will provide insights into the mechanisms involved in arsenic-induced human skin carcinogenesis utilizing a highly relevant murine model and could lead to important advances in mechanism-based chemoprevention of these skin neoplasms in arsenic-exposed humans. PUBLIC HEALTH RELEVANCE: Arsenic is a known human carcinogen and a well defined threat to human health. About 15 million Americans and more than 100 million humans throughout the world are chronically exposed to this carcinogen and this exposure is responsible for the enhanced risk of lung, skin, bladder, liver, prostate and other cancers. However, the mechanism of arsenic-induced carcinogenesis is largely elusive, particularly due to lack of suitable animal models. This grant application focuses on the development of a murine model that can recapitulate cutaneous lesions induced by arsenic in humans. These studies are likely to provide the molecular targets which may be involved in arsenic mediated skin carcinogenesis and may eventually lead to the development of cancer chemopreventive and therapeutic protocols for arsenic-induced neoplasm.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption
    Ritesh K Srivastava
    Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL, USA
    Toxicol Appl Pharmacol 272:879-87. 2013
  2. ncbi Arsenic-induced cutaneous hyperplastic lesions are associated with the dysregulation of Yap, a Hippo signaling-related protein
    Changzhao Li
    Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL 35205, USA
    Biochem Biophys Res Commun 438:607-12. 2013
  3. pmc Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model
    Deepali Kurundkar
    Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294 0019, USA
    Toxicol Appl Pharmacol 266:233-44. 2013
  4. pmc IL-17 mediated inflammation promotes tumor growth and progression in the skin
    Donggou He
    Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
    PLoS ONE 7:e32126. 2012
  5. pmc Unfolded protein response signaling and MAP kinase pathways underlie pathogenesis of arsenic-induced cutaneous inflammation
    Changzhao Li
    Department of Dermatology and Skin Diseases Research Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
    Cancer Prev Res (Phila) 4:2101-9. 2011
  6. pmc Rapamycin and mTORC1 inhibition in the mouse: skin cancer prevention
    Mohammad Athar
    Department of Dermatology, Skin Diseases Research Center and UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA
    Cancer Prev Res (Phila) 4:957-61. 2011
  7. pmc Liver kinase B1 (LKB1) in the pathogenesis of epithelial cancers
    Jennifer L Herrmann
    Department of Dermatology, University of Alabama at Birmingham, USA
    Cancer Lett 306:1-9. 2011
  8. pmc Pharmacological activation of p53 in cancer cells
    Mohammad Athar
    Department of Dermatology, The University of Alabama at Birmingham, Volker Hall, Room 509, 1530 3rd Avenue South, Birmingham, Alabama 35294 0019, USA
    Curr Pharm Des 17:631-9. 2011
  9. pmc Procarcinogenic effects of cyclosporine A are mediated through the activation of TAK1/TAB1 signaling pathway
    Jianmin Xu
    Department of Dermatology, University of Alabama at Birmingham, AL 35294, USA
    Biochem Biophys Res Commun 408:363-8. 2011
  10. pmc Cyclosporine a mediates pathogenesis of aggressive cutaneous squamous cell carcinoma by augmenting epithelial-mesenchymal transition: role of TGFβ signaling pathway
    Stephanie B Walsh
    Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, USA
    Mol Carcinog 50:516-27. 2011

Scientific Experts

  • Mohammad Athar
  • C A Elmets
  • Hui Xu
  • Changzhao Li
  • Jianmin Xu
  • Ritesh K Srivastava
  • Sandeep C Chaudhary
  • Levy Kopelovich
  • Stephanie B Walsh
  • Jennifer L Herrmann
  • Deepali Kurundkar
  • Farrukh Afaq
  • Mary E Ballestas
  • Donggou He
  • Yevgeniya A Byekova
  • Sadis Matalon
  • David R Bickers
  • Jessy S Deshane
  • David J Robbins
  • Hui Li
  • Nabiha Yusuf
  • Santosh K Katiyar
  • Fugui Li
  • Zoe M Verney
  • Jianming Wen
  • Conway C Huang
  • Zhiping Weng
  • Ashish R Kurundkar
  • William E Grizzle
  • Habibul Ahsan
  • Yevgeniya Byekova
  • Laura Timares
  • Akhil Maheshwari

Detail Information

Publications13

  1. ncbi Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption
    Ritesh K Srivastava
    Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL, USA
    Toxicol Appl Pharmacol 272:879-87. 2013
    ..These data also provide a novel strategy to block the ATO-dependent impairment in innate immune responses. ..
  2. ncbi Arsenic-induced cutaneous hyperplastic lesions are associated with the dysregulation of Yap, a Hippo signaling-related protein
    Changzhao Li
    Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL 35205, USA
    Biochem Biophys Res Commun 438:607-12. 2013
    ..These effects together may contribute to the carcinogenic effects of arsenic in the skin. ..
  3. pmc Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model
    Deepali Kurundkar
    Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294 0019, USA
    Toxicol Appl Pharmacol 266:233-44. 2013
    ..Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult...
  4. pmc IL-17 mediated inflammation promotes tumor growth and progression in the skin
    Donggou He
    Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
    PLoS ONE 7:e32126. 2012
    ..These results demonstrate that IL-17 mediated inflammation is an important mechanism for inflammation mediated promotion of tumor development. The study has major implications for targeting IL-17 in prevention and treatment of tumors...
  5. pmc Unfolded protein response signaling and MAP kinase pathways underlie pathogenesis of arsenic-induced cutaneous inflammation
    Changzhao Li
    Department of Dermatology and Skin Diseases Research Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
    Cancer Prev Res (Phila) 4:2101-9. 2011
    ..Our results identify novel pathways involved in the pathogenesis of arsenic-mediated cutaneous inflammation which may also be related to enhanced cancer risk in arsenic exposed cohorts...
  6. pmc Rapamycin and mTORC1 inhibition in the mouse: skin cancer prevention
    Mohammad Athar
    Department of Dermatology, Skin Diseases Research Center and UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA
    Cancer Prev Res (Phila) 4:957-61. 2011
    ....
  7. pmc Liver kinase B1 (LKB1) in the pathogenesis of epithelial cancers
    Jennifer L Herrmann
    Department of Dermatology, University of Alabama at Birmingham, USA
    Cancer Lett 306:1-9. 2011
    ..In short, LKB1 is a tissue and context-specific kinase. This review aims to summarize our current understanding of its role in the pathogenesis of epithelial cancers...
  8. pmc Pharmacological activation of p53 in cancer cells
    Mohammad Athar
    Department of Dermatology, The University of Alabama at Birmingham, Volker Hall, Room 509, 1530 3rd Avenue South, Birmingham, Alabama 35294 0019, USA
    Curr Pharm Des 17:631-9. 2011
    ..This review provides a description of various pharmacological approaches tested to activate p53 (both wild-type and mutant) and to assess the effects of activated p53 on neoplastic progression...
  9. pmc Procarcinogenic effects of cyclosporine A are mediated through the activation of TAK1/TAB1 signaling pathway
    Jianmin Xu
    Department of Dermatology, University of Alabama at Birmingham, AL 35294, USA
    Biochem Biophys Res Commun 408:363-8. 2011
    ..Activation of both NFκB and p38 MAP kinase provide mitogenic stimuli to augment the growth of SCCs...
  10. pmc Cyclosporine a mediates pathogenesis of aggressive cutaneous squamous cell carcinoma by augmenting epithelial-mesenchymal transition: role of TGFβ signaling pathway
    Stephanie B Walsh
    Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, USA
    Mol Carcinog 50:516-27. 2011
    ....
  11. pmc Liver kinase B1 (LKB1) in the pathogenesis of UVB-induced murine basal cell carcinoma
    Yevgeniya A Byekova
    Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL, USA
    Arch Biochem Biophys 508:204-11. 2011
    ..Thus, our data show that the LKB1/AMPK axis fails to regulate mTOR pathway, and a complex regulatory mechanism exists for the persistent mTOR activation in murine BCCs...
  12. pmc Pathogenesis of nonmelanoma skin cancers in organ transplant recipients
    Mohammad Athar
    Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL 35294 0019, USA
    Arch Biochem Biophys 508:159-63. 2011
    ..Finally, this review addresses possible strategies for the prevention of this cancer, particularly focusing on the aspects that may be incorporated to prevent negative effects of chemopreventive chemicals on graft survival...
  13. pmc Targeting ornithine decarboxylase for the prevention of nonmelanoma skin cancer in humans
    Craig A Elmets
    Department of Dermatology, UAB Skin Diseases Research Center and UAB Comprehensive Cancer Center, The University of Alabama at Birmingham, 35294 0019, USA
    Cancer Prev Res (Phila) 3:8-11. 2010
    ..discusses our knowledge of the contribution of polyamines to BCC pathogenesis, how this knowledge advanced the development of a new method to prevent BCCs, and prospects for future studies of DFMO in BCC prevention...