Interstitial flow, varying from nearly zero in the center of tumor tissue to 4 micrometers/second in the periphery, modulates tumor cell growth and metastasis. Tumor cells located in the center of tumor are also subjected to a hypoxic microenvironment, which alters apoptotic, cell cycle and glycosylation pathways. Glycosylation is intimately involved in all steps of metastatic progression by modulating cadherin homophilic interactions (primary tumor) and selectin-ligand (vasculature) as well as integrin-ligand (intravasation, vasculature and extravasation) binding. The overarching goal of Project 3 is to investigate the effects of mechanical forces in prescribed oxygen tension microenvironments on tumor cell signaling and adhesion/migration using a synergistic combination of experimental and computational methods.
In Aim 1, we will investigate the effects of interstitial fluid flow and hypoxia on the regulation of intracellular signaling. We will also elucidate the combined effects of hypoxia and low fluid flow on the physics of key receptor-ligand interactions during the multi-step metastatic process (Aim 2). We will next study the effects of steric forces during the intravasation and extravasation process on tumor cell migration (Aim 3) and on intracellular signaling (Aim 4).
In Aim 5, we will investigate tumor cell targeting in vivo using (a) radiolabeled antibodies against CD44 variant isoforms (CD44v) and podocalyxin-like protein (PCLP) and (b) quantum dots conjugated with antibodies specific for CD44v and PCLP that are expressed by metastatic tumor cells but not normal blood cells. Linkage to PS-OC:
The specific aims of Project 3 fit the overarching theme of the Center of the role forces in the metastatic cascade;
Aims 1 -5 are synergistically connected to Aims 1 and 2 in Project 1 and Aims 1-4 in Project 2 for further research integration of the Center;all Students and Fellows in the Project will be enrolled in the Center Training Program;this project will make use of the resources provided by the Imaging Core and Microfabrication Core, as well as the Administrative Unit of the Center;cell lines and micromechanical methods will be the same as those used in all projects;computational efforts will be shared among all projects.
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|Wang, Pu; Guan, Pei-Pei; Wang, Tao et al. (2014) Interleukin-1? and cyclic AMP mediate the invasion of sheared chondrosarcoma cells via a matrix metalloproteinase-1-dependent mechanism. Biochim Biophys Acta 1843:923-33|
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|Wang, Ting; Gilkes, Daniele M; Takano, Naoharu et al. (2014) Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proc Natl Acad Sci U S A 111:E3234-42|
|Park, Kyung Min; Gerecht, Sharon (2014) Hypoxia-inducible hydrogels. Nat Commun 5:4075|
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