The goal of this project is to understand the mechanism by which infantile hemangioma (IH) grows. This will inform us about the fundamental process of vascular morphogenesis and, importantly, identify specific pathways for which targeted therapies can be developed to improve the lives of children affected by IH and other vascular diseases. IH is the most common tumor of childhood, affecting 2-5% of infants. It rapidly enlarges after birth and can cause significant morbidity: bleeding, ulceration, infection, destruction of important structures (e.g., nose, lips), blockage of vision or breathing, organ failure, and death. Currently the mechanism for IH is unknown and there is no cure for the lesion. Drugs may be given in an attempt to slow the growth of IH, but these medications are associated with significant morbidity and their mechanism of action is unknown. We propose the novel hypothesis that follicle-stimulating hormone (FSH) is responsible for the mechanism of IH. The secretion of the FSH exactly mirrors the growth cycle of IH, and its elevation in infancy correlates with an increased risk of having IH. Our preliminary data has shown that IH uniquely expresses the receptor for FSH (FSHR), in contrast to other normal and pathological vascular tissues. The goal of these studies is to test whether FSH (or its antagonists) affects the growth of IH.
Our first aim will test the effects of FSH on the angiogenic/vasculogenic properties of human-derived IH cells. Cell based assays will be used to determine whether FSH causes human IH endothelial cells (HemECs), pericytes (HemPCs), or stem cells (HemSCs) to exhibit a phenotype that promotes neovascularization.
Our second aim will test whether systemically administered FSH (or antagonists) affects the growth of IH in vivo. A validated murine model of IH will be created by implanting human-derived IH stem cells (HemSCs) placed subcutaneously into the backs of immunodeficient mice. The effects of FSH on the size, blood flow, and microvessel density on the IH implants will be tested. These experiments would be high impact when we succeed in identifying the mechanism responsible for IH. For the first time we would be able to pursue a targeted approach for treating this common and morbid tumor. For example, pathway specific topical, intralesional, and/or systemic FSH inhibitors could be developed to prevent IH formation or growth. Also, discoveries into the cause of IH will help us understand the mechanisms that underlie other pediatric vascular lesions, and will improve our ability to manipulate neovascularization in other systems (e.g., cancer, tissue repair, engineering).

Public Health Relevance

Infantile hemangioma is the most common tumor of infancy and can cause significant suffering in children, primarily because they grow rapidly after birth. Children cannot be cured, and drug therapy to limit the growth of the tumor is associated with significant morbidity. This study will determine the reasons for the growth of infantile hemangioma so that drugs may be developed to keep these lesions small, and prevent their complications.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HD081004-01
Application #
8751873
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Tamburro, Robert F
Project Start
2014-08-15
Project End
2016-07-31
Budget Start
2014-08-15
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$263,750
Indirect Cost
$113,750
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115