Transforming growth factor beta (TGFbeta) signaling plays a complex role in cancer development. Loss of TGFbeta type II receptor (TGFbetaRII), and paradoxical overexpression of TGFbeta1 ligand occur frequently in human cancers. In this application, we will further dissect the mechanisms that mediate the complex functions of TGFbeta1 and its primary receptor, TGFbetaRII, in skin carcinogenesis. We are asking the following questions: 1) Does TGFbeta1- induced inflammation contribute to a tumor promotion effect that overrides its own tumor suppressive effect? 2) Does TGFbetaRII loss in tumor epithelia elicit multiple oncogenic events that promote malignant progression? 3) Do cancers harboring both increased TGFbeta1 and TGFbetapRII loss have a poorer prognosis as a result of the cooperation on malignant progression between these two events? To address these questions, we will use our inducible and keratinocyte-specific transgenic/knockout mice which mimic alterations of TGFbeta1 and TGFbetaRII in human cancer. Skin chemical carcinogenesis experiments, which mimic discrete stages of skin cancer development, will be applied to these mouse models. We propose three specific aims: 1. To assess the role of TGFbeta1-induced inflammation in skin carcinogenesis. 2. To assess the effect epithelial TGFbetaRII loss on malignant progression during skin carcinogenesis and analyze pathological and molecular alterations in TGFbetaRII-null tumor epithelia. 3. To assess the pathological and molecular mechanisms of the cooperation between TGFbeta1 overexpression and TGFbetaRII loss in malignant progression. Assessing the effects of TGFbeta1 overexpression and TGFbetaRII loss on carcinogenesis will provide important insights into cancer prognosis and therapeutic strategies in the future. Furthermore, controlled TGFbeta1 transgene induction or TGFbetaRII deletion will greatly enhance our ability to identify direct molecular targets of TGFbeta1 signaling in carcinogenesis, since changes in gene expression can be examined both shortly after TGFbeta1 induction or TGFbetaRII deletion as well as at later time points after sustained TGFbeta1 induction or TGFbetaRII deletion. Identification of these molecular targets will provide important insights into the molecular and cellular mechanisms of TGFbeta signaling in skin carcinogenesis as well as biomarkers for cancer prognosis and targeted therapies in the future.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA079998-09
Application #
7219388
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Poland, Alan P
Project Start
1999-01-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
9
Fiscal Year
2007
Total Cost
$248,100
Indirect Cost
Name
Oregon Health and Science University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Mitra, Doyel; Fernandez, Pamela; Bian, Li et al. (2013) Smad4 loss in mouse keratinocytes leads to increased susceptibility to UV carcinogenesis with reduced Ercc1-mediated DNA repair. J Invest Dermatol 133:2609-2616
Malkoski, Stephen P; Wang, Xiao-Jing (2012) Two sides of the story? Smad4 loss in pancreatic cancer versus head-and-neck cancer. FEBS Lett 586:1984-92
Swindell, William R; Johnston, Andrew; Carbajal, Steve et al. (2011) Genome-wide expression profiling of five mouse models identifies similarities and differences with human psoriasis. PLoS One 6:e18266
Han, Gangwen; Li, Fulun; Ten Dijke, Peter et al. (2011) Temporal smad7 transgene induction in mouse epidermis accelerates skin wound healing. Am J Pathol 179:1768-79
Han, Gangwen; Williams, Cortny A; Salter, Kelli et al. (2010) A role for TGFbeta signaling in the pathogenesis of psoriasis. J Invest Dermatol 130:371-7
Hoot, Kristina E; Oka, Masako; Han, Gangwen et al. (2010) HGF upregulation contributes to angiogenesis in mice with keratinocyte-specific Smad2 deletion. J Clin Invest 120:3606-16
Honeycutt, Kimberly A; Waikel, Rebekah L; Koster, Maranke I et al. (2010) The effect of c-myc on stem cell fate influences skin tumor phenotype. Mol Carcinog 49:315-9
White, R A; Malkoski, S P; Wang, X-J (2010) TGFýý signaling in head and neck squamous cell carcinoma. Oncogene 29:5437-46
Cohen, Jonah; Chen, Zhong; Lu, Shi-Long et al. (2009) Attenuated transforming growth factor beta signaling promotes nuclear factor-kappaB activation in head and neck cancer. Cancer Res 69:3415-24
Huang, Xiao R; Chung, Arthur C K; Wang, Xiao J et al. (2008) Mice overexpressing latent TGF-beta1 are protected against renal fibrosis in obstructive kidney disease. Am J Physiol Renal Physiol 295:F118-27

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