Metastatic dormancy is defined as the ability of rests of metastatic cancer tissue to survive, but not invade and progress at distant sites. In thyroid cancer, patients with small lung metastases often survive for decades without radiographic or clinical progression, suggesting that restraint of progression at metastatic sites is intrinsic to many thyroid cancers. Because most thyroid cancer- related deaths are due to late-stage progressive metastatic disease, it is crucial to define mechanisms that by which these cancers escape from metastatic dormancy. Metastasis suppressors are negative regulators of cancer metastasis and growth that may serve a "gate-keeping" role in metastatic progression. By interrogating the KiSS-1/GPR54 metastasis inhibitory signaling cascade in cancer cells, we identified a motility-suppressor role for regulator of calcineurin 1-4 (RCAN1-4) in vitro;and demonstrated loss of this protein in metastatic thyroid cancer tissue samples. RCAN1-4 has also been shown to play a central role in VEGF-induced endothelial cell growth and motility. Interestingly, the RCAN1 (DSCR1) gene that encodes all RCAN1 isoforms is located on chromosome 21, and is one of many genes overexpressed in Down's syndrome (trisomy 21). It was recently demonstrated that Rcan1 plays a critical functional role in the reduced solid tumor incidence and progression associated with Down's syndrome. In mouse two Rcan1 isoforms are expressed that are homologous to the two dominant primary human isoforms, RCAN1-1 and RCAN1-4. Recent in vivo studies confirmed that short form of Rcan1 in mouse, which is homologous to human RCAN1-4, is the primary induced isoform in the neovasculature of tumor grafts, suggesting that it may be specifically important in tumor angiogenesis induced by VEGF However the functional role of this isoform on cancer progression has not been directly tested in vivo. The overall hypothesis of this proposal is that RCAN1-4 is a key gate-keeper that restrains thyroid cancer progression by inhibiting cancer cell invasion and by inhibiting endothelial cell response to VEGF and other angiogenic signals. We will use a variety of in vivo models to test this hypothesis.

Public Health Relevance

Project Narrative Metastatic dormancy, or the ability of cancer cells in metastatic sites to survive without progressing, is common in thyroid cancer, thus, this malignancy serves as an excellent model to study this important process. Moreover, defining mechanisms by which metastatic dormancy is maintained and/or lost has potential to identify new biomarkers and therapeutic targets for patients with progressive metastatic thyroid cancer for which there are no effective therapies. Based on preliminary laboratory and clinical data, we hypothesize in the current proposal that RCAN1-4 is a critical and highly regulated protein that maintains metastatic dormancy of thyroid cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA152066-02
Application #
8235810
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Snyderwine, Elizabeth G
Project Start
2011-03-03
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$335,919
Indirect Cost
$115,644
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Ringel, Matthew D; Nabhan, Fadi (2013) Approach to follow-up of the patient with differentiated thyroid cancer and positive anti-thyroglobulin antibodies. J Clin Endocrinol Metab 98:3104-10
Phay, John E; Ringel, Matthew D (2013) Metastatic mechanisms in follicular cell-derived thyroid cancer. Endocr Relat Cancer 20:R307-19
Ringel, Matthew D (2011) Metastatic dormancy and progression in thyroid cancer: targeting cells in the metastatic frontier. Thyroid 21:487-92