A recently emerging class of anti-cancer therapies has focused on blocking the growth of new blood vessels or angiogenesis, which is necessary to support tumor growth. This proposal is based on a clinical clue provided by a unique population, individuals with Down syndrome, and seeks to define the molecular mechanisms underlying the cancer protection observed in the Down syndrome population. Epidemiological data suggests that a gene(s) present in 3 copies on chromosome 21 exerts a broad anti-cancer effect by controlling some common aspect of tumorigenesis. This proposal focuses on one promising candidate for this activity - the Down syndrome candidate region-1 (Dscr1) gene. The Dscr1 gene encodes a protein that blocks angiogenesis and specifically endothelial cell activation by negatively regulating VEGF-calcineurin signaling. We hypothesize that trisomic expression of Dscr1 in Down Syndrome suppresses tumor growth by attenuating VEGF-calcineurin-NFAT signaling and restricting tumor angiogenesis.
In Specific Aim 1, we will determine whether over-expression of DSCR1 is responsible for suppression of tumor growth in Down syndrome by using genetically engineered mouse models recently generated in my lab.
In Specific Aim 2 we will examine the role of thrombospondin-1 (TSP-1), a recently identified target in my lab of VEGF-calcineurin-NFAT signaling in endothelial cells, in modulating tumor angiogenesis. We will confirm the mechanism of Tsp-1 regulation by VEGF-calcineurin signaling and determine its role in modulating the pro-angiogenic effects of VEGF. We will also determine the consequences of Tsp-1 loss on VEGF signaling in endothelial cells.
In Specific Aim 3, we will determine the differential mechanisms by which DSCR1 and the pharmacologic calcineurin inhibitor cyclosporin A, block calcineurin function using a combination of biochemical and mutational approaches and transplantable tumor models in mice. The experiments proposed will use this clinical insight to derive mechanistic insight into how tumor angiogenesis and ultimately tumor growth can be inhibited or reversed by modulating calcineurin activity and function. Finally these studies will also establish whether Dscr1 is a valid target for anti-cancer intervention.

Public Health Relevance

The Down syndrome candidate region-1 (Dscr1) gene encodes a protein that blocks tumor angiogenesis and specifically endothelial cell activation. DSCR1 negatively regulates the VEGF-calcineurin pathway, an important signaling pathway in endothelial cells to promote angiogenesis. These studies will establish whether Dscr1 is a valid target for anti-cancer intervention which may lead to novel therapeutic strategies for suppressing tumor angiogenesis in all cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA118374-03
Application #
7778284
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2009-07-01
Project End
2014-04-30
Budget Start
2010-06-01
Budget End
2011-04-30
Support Year
3
Fiscal Year
2010
Total Cost
$298,800
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Till, Jacob E; Yoon, Changhwan; Kim, Bang-Jin et al. (2017) Oncogenic KRAS and p53 Loss Drive Gastric Tumorigenesis in Mice That Can Be Attenuated by E-Cadherin Expression. Cancer Res 77:5349-5359
Schadler, Keri L; Thomas, Nicholas J; Galie, Peter A et al. (2016) Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy. Oncotarget 7:65429-65440
Yoon, Changhwan; Cho, Soo-Jeong; Aksoy, B├╝lent Arman et al. (2016) Chemotherapy Resistance in Diffuse-Type Gastric Adenocarcinoma Is Mediated by RhoA Activation in Cancer Stem-Like Cells. Clin Cancer Res 22:971-83
Lehman, Stacey L; Cerniglia, George J; Johannes, Gregg J et al. (2015) Translational Upregulation of an Individual p21Cip1 Transcript Variant by GCN2 Regulates Cell Proliferation and Survival under Nutrient Stress. PLoS Genet 11:e1005212
Casey, Stephanie C; Vaccari, Monica; Al-Mulla, Fahd et al. (2015) The effect of environmental chemicals on the tumor microenvironment. Carcinogenesis 36 Suppl 1:S160-83
Lehman, Stacey L; Ryeom, Sandra; Koumenis, Constantinos (2015) Signaling through alternative Integrated Stress Response pathways compensates for GCN2 loss in a mouse model of soft tissue sarcoma. Sci Rep 5:11781
Goodson 3rd, William H; Lowe, Leroy; Carpenter, David O et al. (2015) Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis 36 Suppl 1:S254-96
Lee, Joo-Hyeon; Bhang, Dong Ha; Beede, Alexander et al. (2014) Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis. Cell 156:440-55
Schadler, Keri L; Crosby, Erika J; Zhou, Alice Yao et al. (2014) Immunosurveillance by antiangiogenesis: tumor growth arrest by T cell-derived thrombospondin-1. Cancer Res 74:2171-81
Zhou, Alice Yao; Ryeom, Sandra (2014) Cyclosporin A promotes tumor angiogenesis in a calcineurin-independent manner by increasing mitochondrial reactive oxygen species. Mol Cancer Res 12:1663-76

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