Role of Integrins in Lymphangiogenesis During Breast Cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Recent studies suggest that lymphangiogenesis, the growth of lymphatic vessels, plays a crucial role in the formation of local and distant tumor metastases, including those to the bone marrow. As breast cancer spreads predominantly via the lymphatic system, an understanding of the role of lymphangiogenesis in breast cancer could help develop new therapies to prevent the spread of breast cancer. Little is currently known about the roles of integrins in lymphangiogenesis. The altered expression and function of integrins contribute significantly to invasion and migration of cancer cells. Integrins are cell surface receptor molecules and consist of two associated proteins, termed α and β chains. They bind extracellular matrix proteins such as fibronectin, laminin and collagen. Their interior, cytoplasmic domains bind other proteins that connect them to the cytoskeleton or have signaling functions. Therefore, integrins are viewed as cell surface receptors that influence cell behavior including adhesion and migration, including metastatic spread of cancer cells.
 
 
 
 
 
 
 
 We propose to investigate the roles of key integrins in the regulation of lymphangiogenesis in breast cancer, especially for their role in promoting the migration and survival of lymphatic endothelial cells. The aims of the project include:
 
 1) The expression and function of integrins during lymphangiogenesis in whole animals will be examined using antagonists of integrins in animal models of lymphangiogenesis.
 
 2) Determine the expression and function of integrins on lymphatic endothelial cells in culture. The expression of vascular integrins α2β1, α4β1, αvβ3, α5β1 and αvβ5 on purified human and mouse lymphatic endothelial cells. We will explore the functional roles of lymphatic integrins.
 
 3) Examine the role of integrins in regulating metastasis via the lymphatic vessels using antagonists of integrins in mouse models of spontaneous and xenograft breast tumor growth and metastasis.
 
 
 
 
 
 
 
 The expression of integrins on lymphatic endothelial cells will determined by flow cytometry and immunohistochemistry (i.e., antibody staining) on purified human and mouse lymphatic endothelial cells and tissue sections from normal and tumor tissues. The roles of integrins in the promotion of lymphatic endothelial cell migration and tube formation will be examined by evaluating the effects of integrin antagonists or inhibitory, siRNA using purified lymphatic endothelial cells in culture. The roles of integrins in the promotion of lymphangiogenesis and breast tumor metastasis will be evaluated in animal models using integrin antagonists and siRNA approaches.
 
 
 
 
 
 
 
 Regional lymph node metastasis is common even in patients with small breast tumors and there is a strong correlation between the number of involved nodes and a poor prognosis. As tumor metastasis has been directly associated with a high level of lymphatic vessels in breast cancer, an understanding of the mechanisms that regulate lymphangiogenesis lead to new methods to inhibit breast tumor metastasis. If our hypothesis is correct, then integrin antagonists may be used to suppress breast tumor metastasis by suppressing lymph angiogenesis. Thus my studies may lead to new therapies to suppress the formation of metastases, as several anti-integrin drugs are currently in the clinic for other applications.