Angiogenesis is critical for solid tumor growth beyond minimal size. Among many angiogenic factors, Vascular Endothelial Growth Factor (VEGF-A) plays a central role in tumor angiogenesis and associated microvessel permeability to plasma proteins. Anti-VEGF neutralizing antibodies and VEGFR kinase/multiple kinase inhibitors have been successfully developed and widely used in the clinic. However, in addition to their toxic side effect, the VEGF-targeted therapy in cancer faces the problems of insufficient efficacy, resistance and intrinsic refractoriness. Therefore, it is desirable to identify additional angiogenesis targets. Recently, we found that Down Syndrome Candidate Region 1 isoform 1L (DSCR1-1L) is highly up-regulated in cultured endothelial cells and in mouse angiogenesis model induced by VEGF. Knockdown the expression of DSCR1-1L inhibits endothelial cell proliferation in vitro and Matrigel angiogenesis in mice induced by VEGF. Further, DSCR1-1L is exclusively expressed in tumor vasculature of human cancer tissues (ovarian and kidney), but not in normal tissues, suggesting that targeting DSCR1-1L has less side effect than targeting VEGF/VEGFR. It was reported that histamine and serotonin play a role in tumor growth. Recently, we found that histamine and serotonin induce angiogenesis. Our preliminary studies demonstrate that DSCR1-1L is also induced by histamine, serotonin and PAF, suggesting that targeting DSCR1-1L will inhibit several signaling pathways that lead to tumor angiogenesis.
In specific Aim, we will study whether DSCR1-1L regulates angiogenesis, tumor growth and metastasis. This research will demonstrate that DSCR1-1L is a novel therapeutic target for anti-angiogenesis. Hence, this application has translation potential.

Public Health Relevance

The proposed research is relevant to public health because discovery the function of DSCR1-1L in cancer growth and metastasis is expect to identify the novel target for cancer angiogenesis therapy. Thus, the proposed research is relevant to the part of NIH's mission that pertain to developing fundamental knowledge that will help to reduce the burdens of human disability.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA194795-01
Application #
8877789
Study Section
Special Emphasis Panel (ZCA1-SRB-C (J1))
Program Officer
Ault, Grace S
Project Start
2015-04-01
Project End
2017-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$87,000
Indirect Cost
$37,000
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Zeng, Yingling; Ye, Xiaoguang; Liao, Degui et al. (2017) Orphan Nuclear Receptor TR3/Nur77 is a Specific Therapeutic Target for Hepatic Cancers. J Clin Exp Oncol 6: