Imaging RhoC-induced Breast Cancer Invasion and Angiogenesis
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: Metastasis is the major cause of poor prognosis in breast cancer patients. Current evidence indicates that tumor cell metastasis requires the activation of cell migration and angiogenic programs, increased vascular permeability, proteolysis of the extracellular matrix (ECM), and decreased cell apoptosis. These key factors allow cancer cells to invade into the surrounding ECM, gain access to the vascular system, and survive and proliferate in distant tissues. We are interested in how the small GTPase, RhoC, affects the cellular processes that contribute to breast cancer metastasis. Rho-family GTPases are molecular switches that couple changes in the extracellular environment to intracellular signal transduction pathways. Recently, RhoC was shown to be upregulated and associated with poor patient outcome in inflammatory breast cancer (IBC). IBC is a highly aggressive and angiogenic form of the disease that affects about 5% of women diagnosed with breast cancer each year. Work with cultured cells demonstrates that overexpression of RhoC increases invasion and proangiogenic factors. Based on these initial findings, we will test the hypothesis that RhoC contributes to IBC by increasing the tumor cells’ ability to migrate in complex tissues and to actively change the structure of tumor-induced blood vessels. 
 
 
 
 
 
 
 
 However, understanding how tumor cell invasion and angiogenesis occur in developing tumors has been difficult because existing cancer models do not allow direct visualization in high resolution of these processes within living organisms. Therefore, we have developed a model of cancer that utilizes human tumor cells growing in optically clear Zebrafish. This model will allow tumor growth, angiogenesis, and invasion in response to RhoC expression to be directly visualized and imaged. Using in vivo confocal microscopy, we have monitored in time-lapse tumor formation and remodeling of the vasculature in vivo at the subcellular level. Our initial findings reveal that transplanted human breast tumor cells expressing red fluorescent protein rapidly home to existing blood vessels where they attach and form solid tumors. In these developing tumors, we observed that cancer cells induce remodeling of the existing vessels in a dynamic process that involves permeation of the vessel wall and the formation of loop-like structures that subdivide into channels, forming new blood vessel structures. These distinct structures formed only in close proximity to tumor cells and were dynamic, undergoing continual remodeling during tumor progression. Our findings represent the first high resolution observations of breast tumor formation and tumor-induced vascular remodeling in a living organism.
 
 
 
 
 
 
 
 In this CBCRP-funded fellowship, we will utilize our Zebrafish model to determine how the small GTPase, RhoC, induces breast cancer invasion and angiogenesis. Results from these studies will provide critical information on how amplification of RhoC contributes to breast cancer progression in vivo, which will provide a better understanding of how to design pharmacological and genetic agents to eradicate this disease.