Title |
A Mouse Model of TGFB1 and Tumor Immunosurveillance in Squamous Cell Cancer
|
Institution |
PENNSYLVANIA STATE UNIVERSITY-UNIV PARK, UNIVERSITY PARK, PA
|
Principal Investigator |
GLICK, ADAM
|
NCI Program Director |
Neeraja Sathyamoorthy
|
Cancer Activity |
Tumor Biology
|
Division |
DCB
|
Funded Amount |
$214,552
|
Project Dates |
07/15/2006 - 05/31/2010
|
Fiscal Year |
2007
|
Project Type |
Grant
|
Research Topics w/ Percent Relevance |
Cancer Types w/ Percent Relevance |
Chemotherapy (50.0%)
|
N/A
|
Research Type |
Cancer Initiation: Oncogenes and Tumor Suppressor Genes
Cancer Progression and Metastasis
|
Abstract |
DESCRIPTION (provided by applicant): TGF?1 has both tumor suppressor and oncogenic roles in human cancer development, but the mechanisms underlying this change in function remain elusive. Identifying the mechanisms underlying these distinct functions of TGF?1 and how this change occurs will provide important new targets for cancer therapy. We have recently developed a TGF?1 conditional epidermal expression mouse model to identify tumor stage specific effects and targets of TGF?1 expression. Preliminary studies reveal that TGF?1 expression in the normal epidermis, benign and malignant skin tumors provokes profoundly distinct responses from the host immune system that are associated with tumor regression or progression. The central hypothesis of this research proposal is that the changing roles of TGF?1 during cancer progression are linked to distinct responses of the immune system to tumor cell derived TGF?1. Specific Aim 1 tests the hypothesis that the adaptive immune response to epidermally derived TGF?1 is stage specific using genetic and immunological means to deplete and restore specific immune cell subsets. The second specific aim is to test the hypothesis that overexpression of TGF?1 in the normal epidermis and the resulting inflammation is a tumor-promoting stimulus for epidermal keratinocytes harboring a chemically or genetically activated ras oncogene. Specific Aim 3 tests the hypothesis that NF-?B signaling is essential for the stage specific response of the immune system to TGF?1 in the normal epidermis and in squamous tumors using in vitro and in vivo biochemical and molecular analysis, and genetic methods to block NF-?B signaling. The increased incidence of non-melanoma skin cancer in the general population, and the increasing problem of aggressive SCC of the skin in immunocompromised organ transplant patients represent a significant public health problem. The goal of this research project are to use this conditional expression mouse model to understand how TGF?1 produced by developing tumor cells differentially regulates the anti-tumor immune response, so that ultimately therapeutic targets and strategies can be identified that will block the immunosuppressive effects and enhance the anti-tumor inflammatory effects of tumor derived TGF?1. |