Two hundred million people worldwide are affected by thyroid proliferative diseases (TPD), which include goiter, cancer and adenoma. Women are three times more susceptible than men and overall the incidence of thyroid dysfunction occurring in one in eight women is a sizable health issue. The thyroid is a vascularized tissue and one of the cellular mediators of neo-vasculature are bone marrow derived endothelial progenitor cells (CD31+, CD34+, VCAM+). BM-EPCs normally reside in the marrow but migrate to tissues in response to inflammation, injury or cancer and estradiol (E2) enhances this migration. We observed that estradiol (E2) enhances peripheral circulation and migration of BM-EPCs to tumor tissues, induces neo-vasculature and up regulates cell survival pathways, Akt and ERK, in an E2 dependent manner. These EPCs that migrate to tissues under the influence of E2 to induce vasculogenesis are novel targets of anti-estrogen therapy in TPD. We propose to test the activity of the anti-estrogen DIM in animal and cell culture models and in human patients using E2 regulated vasculogenesis and cell survival pathways, Akt and ERK, as targets of DIM action.
The aims are to: I. Examine estradiol induced neovasculature using a xenograft animal model with orthotopic implantation of N-Thy-ori3-1(differentiated), B-CPAP (undifferentiated), KAT50TS goiter cell lines in ovariectomized (OVX) Balb/c/nu/nu mice ? E2 supplementation ? DIM incorporated in the diet. II. Examine the regulation of the activation of Akt and ERK pathway in BM-EPC and TPD cells by E2-ER multiprotein complexes and the possible molecular intervention targets of DIM. III. Determine if oral administration of an absorption-enhanced formulation of DIM (Bioresponse DIM) achieves adequate thyroid tissue bioavailability and examine DIM levels in blood and urine of patients. IV. Examine the status of activated Akt/ERK ? DIM in thyroid tissue and define the profile of E2 responsive DIM mediated molecular changes in TPD by gene array analysis followed by validation at the expression level. This basic translational research is directed to reduce possible unnecessary surgery in TPD using bioactive food component, DIM, and determining the cellular and molecular basis of the gender bias of TPD.

Public Health Relevance

This translational research with a novel basic component is directed to reduce possible unnecessary surgery in thyroid proliferative diseases using bioactive food component, Diindolylmethane, DIM. Surgical tissues obtained will be used to analyze estrogen mediated functions that can shed light on the observed 3:1 gender bias in the incidence of this disease in women.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA131946-04
Application #
8287683
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Agelli, Maria
Project Start
2009-06-02
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$318,481
Indirect Cost
$99,752
Name
New York Medical College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
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Hanly, Elyse K; Rajoria, Shilpi; Darzynkiewicz, Zbigniew et al. (2014) Disruption of mutated BRAF signaling modulates thyroid cancer phenotype. BMC Res Notes 7:187
Rajoria, Shilpi; Suriano, Robert; George, Andrea L et al. (2012) Estrogen activity as a preventive and therapeutic target in thyroid cancer. Biomed Pharmacother 66:151-8
Kummer, Nicolas T; Nowicki, Theodore S; Azzi, Jean P et al. (2012) Arachidonate 5 lipoxygenase expression in papillary thyroid carcinoma promotes invasion via MMP-9 induction. J Cell Biochem 113:1998-2008
Shanmugam, Arulkumaran; Rajoria, Shilpi; George, Andrea L et al. (2012) Synthetic Toll like receptor-4 (TLR-4) agonist peptides as a novel class of adjuvants. PLoS One 7:e30839
Nowicki, Theodore S; Zhao, Hong; Darzynkiewicz, Zbigniew et al. (2011) Downregulation of uPAR inhibits migration, invasion, proliferation, FAK/PI3K/Akt signaling and induces senescence in papillary thyroid carcinoma cells. Cell Cycle 10:100-7
Kamat, Ameet; Rajoria, Shilpi; George, Andrea et al. (2011) Estrogen-mediated angiogenesis in thyroid tumor microenvironment is mediated through VEGF signaling pathways. Arch Otolaryngol Head Neck Surg 137:1146-53
George, Andrea L; Bangalore-Prakash, Pradeep; Rajoria, Shilpi et al. (2011) Endothelial progenitor cell biology in disease and tissue regeneration. J Hematol Oncol 4:24
Darr, E Ashlie; Patel, Anand D; Yu, Guopei et al. (2011) Reduced Cx43 gap junction plaque expression differentiates thyroid carcinomas from benign disease. Arch Otolaryngol Head Neck Surg 137:1161-5
Nowicki, Theodore S; Moscatello, Augustine L; Shin, Edward et al. (2011) The urokinase plasminogen activator system in metastatic papillary thyroid carcinoma: a potential therapeutic target. J Clin Endocrinol Metab 96:3062-4

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