It is widely known that circulating tumor cells arrest in the microvasculature, but this arrest is not random. For example, breast cancer cells preferentially arrest in the small blood vessels of the lungs, liver, brain and bones. The underlying mechanisms responsible for this preferential arrest of breast cancer cells in distant organs are not well understood. The long-term goal of our research is to elucidate the relationships between microcirculation-induced mechanical factors, microvascular permeability (vascular integrity), cell adhesion molecules, nitric oxide and cytokines, and tumor metastasis in intact microvessels. The objective of this project is to investigate the relationships between localized shear rates and stresses in curved/stretched microvessels, VEGF (vascular endothelial growth factor)-induced microvascular hyperpermeability, and mammary tumor cell arrest and adhesion in intact microvessels. On the basis of our preliminary studies, we shall use a newly developed in vivo single vessel perfusion/bending method that can create non-uniformly distributed shear rates/stresses along the vessel wall to test two hypotheses: 1) Tumor cells prefer to arrest at the locations of higher shear rates/stresses and shear rate/stress gradients in the post-capillary venules of microvasculature. The higher shear rates/stresses and shear rate/stress gradients activate the endothelial cells and the tumor cells (specifically, activate cell adhesion molecules and endothelial nitric oxide synthase) to increase the binding of tumor cells to the vessel wall and to increase the accumulation of tumor cells;2) Tumor cells prefer to arrest in the microvessel with the increased permeability. The increased tumor cell adhesion to the microvessel wall with increased permeability is partially due to the radial pressure gradient that drives the cells towards the wall. These ideas will be explored using a combination of physiological, biochemical, mathematical and imaging approaches.
Specific aims are: 1) use quantitative fluorescence video and confocal microscopy to determine the adhesion rates of normal, non-malignant (MCF-10A), and malignant (AU-565) breast epithelial cells in straight and curved/stretched microvessels on rat mesentery under known bulk flow rates and a) under conditions of normal and increased permeability by VEGF, b) after pretreatment with the blocking antibodies to endothelial cell adhesion molecules, c) after pretreatment with the blocking antibodies to tumor cell adhesion molecules and d) after pretreatment with eNOS inhibitors to microvessel endothelial cells;2) use filter-based adhesion/transmigration assays to determine the adhesion/transmigration rates of above cells to/across cultured cell monolayers of microvascular endothelial cells isolated from the lung, brain, kidney and muscle under the same conditions as in Aim 1;3) use fluorescence video and confocal microscopy to quantify the nitric oxide production in straight and curved/stretched microvessels under various bulk flow rates and under the same conditions a and d in Aim 1, and in cultured cell monolayer of lung and brain, kidney glomerulus and skeleton muscle microvascular endothelial cells under the same conditions a and d in Aim 1;and 4) quantify the shear rate, shear stress, normal stress (pressure), velocity and vorticity profiles by numerical simulation in the straight and curved/stretched microvessels under known bulk flow rates and under the conditions of normal and increased permeability by VEGF.

Public Health Relevance

This project will lead to a quantitative understanding of the role of hydrodynamic factors, cell adhesion molecules and nitric oxide in tumor preferential metastasis, and hence help define a new class of targets for therapeutic drug design for cancer. We hope that inhibitory reagents that prevent cancer cell arrest and adhesion in the microcirculation and reagents that enhance the microvessel wall integrity may be used in combination with traditional therapies to combat this malignant disease more effectively.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Enhancement Award (SC1)
Project #
5SC1CA153325-04
Application #
8471667
Study Section
Special Emphasis Panel (ZGM1-MBRS-0 (NP))
Program Officer
Wali, Anil
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$143,312
Indirect Cost
$50,252
Name
City College of New York
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
603503991
City
New York
State
NY
Country
United States
Zip Code
10031
Xiao, L L; Liu, Y; Chen, S et al. (2016) Effects of flowing RBCs on adhesion of a circulating tumor cell in microvessels. Biomech Model Mechanobiol :
Zhang, Lin; Zeng, Min; Fu, Bingmei M (2016) Inhibition of endothelial nitric oxide synthase decreases breast cancer cell MDA-MB-231 adhesion to intact microvessels under physiological flows. Am J Physiol Heart Circ Physiol 310:H1735-47
Fan, Jie; Fu, Bingmei M (2016) Quantification of Malignant Breast Cancer Cell MDA-MB-231 Transmigration Across Brain and Lung Microvascular Endothelium. Ann Biomed Eng 44:2189-201
Zullo, Joseph A; Fan, Jie; Azar, Tala T et al. (2016) Exocytosis of Endothelial Lysosome-Related Organelles Hair-Triggers a Patchy Loss of Glycocalyx at the Onset of Sepsis. Am J Pathol 186:248-58
Xiao, L L; Liu, Y; Chen, S et al. (2016) Numerical simulation of a single cell passing through a narrow slit. Biomech Model Mechanobiol 15:1655-1667
Wei, Jie; Cai, Bin; Zhang, Lin et al. (2015) Automatic Classification and Quantification of Cell Adhesion Locations on the Endothelium. Ann Biomed Eng 43:1803-14
Fu, Bingmei M; Yang, Jinlin; Cai, Bin et al. (2015) Reinforcing endothelial junctions prevents microvessel permeability increase and tumor cell adhesion in microvessels in vivo. Sci Rep 5:15697
Yen, Wanyi; Cai, Bin; Yang, Jinlin et al. (2015) Endothelial surface glycocalyx can regulate flow-induced nitric oxide production in microvessels in vivo. PLoS One 10:e0117133
Guo, Peng; Cai, Bin; Lei, Ming et al. (2014) Differential arrest and adhesion of tumor cells and microbeads in the microvasculature. Biomech Model Mechanobiol 13:537-50
Shi, Lingyan; Palacio-Mancheno, Paolo; Badami, Joseph et al. (2014) Quantification of transient increase of the blood-brain barrier permeability to macromolecules by optimized focused ultrasound combined with microbubbles. Int J Nanomedicine 9:4437-48

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