Cancer cell attachment to distant tissues is fundamental to metastasis. We propose that signals within tumor cells interact with the cytoskeleton to modify the adhesiveness of cell surface receptors required for adhesion and metastasis. Based on preliminary data using established cell lines, a murine model, and primary cells from human colon cancers, we hypothesize that inside-out regulation of integrin receptors governs cancer cell adhesion. In particular, we have shown that increased extracellular pressure, such as may occur during passage through the venous or lymphatic system, during surgical procedures, or postoperatively due to increased intra-abdominal pressure, stimulates FAK-Src interaction and activates PI3-K together with the PI3-K substrate Akt. Preliminary studies suggest that these signa/s influence cancer cell adhesion in a manner that requires an intact actin cytoske/eton. We will now use pressure activation to further define the mechanisms of inside-out regulation of cancer cell adhesion. We will delineate the signals involved, explore the role of the cytoskeleton, and determine whether adhesiveness is regulated by changes in integrin affinity or avidity by measuring both integrin clustering and the bond strength of individual integrin-matrix bonds in cancer cells subjected to pressure. We will test our hypothesis in human primary cancer cells and in a mouse model, to establish its relevance to intact organisms. This work will elucidate a scientifically important paradigm for inside-out signaling that may explain why some circulating cancer cells may adhere while others do not. The signals we define will represent important targets for perioperative intervention to reduce iatrogenic tumor spread during surgery and perhaps new targets for cancer therapy to inhibit metastasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK060771-06S2
Application #
7348166
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Hamilton, Frank A
Project Start
2001-05-01
Project End
2010-08-31
Budget Start
2007-01-01
Budget End
2007-08-31
Support Year
6
Fiscal Year
2007
Total Cost
$46,154
Indirect Cost
Name
Wayne State University
Department
Surgery
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Basson, M D; Zeng, B; Wang, S (2015) Akt1 binds focal adhesion kinase via the Akt1 kinase domain independently of the pleckstrin homology domain. J Physiol Pharmacol 66:701-9
Basson, Marc D; Zeng, Bixi; Downey, Christina et al. (2015) Increased extracellular pressure stimulates tumor proliferation by a mechanosensitive calcium channel and PKC-?. Mol Oncol 9:513-26
Patterson, Kevin C; Yang, Ruiguo; Zeng, Bixi et al. (2013) Measurement of cationic and intracellular modulation of integrin binding affinity by AFM-based nanorobot. Biophys J 105:40-7
Chaturvedi, Lakshmi S; Zhang, Ping; Basson, Marc D (2012) Effects of extracellular pressure and alcohol on the microglial response to inflammatory stimulation. Am J Surg 204:602-6
Downey, Christina; Craig, David H; Basson, Marc D (2011) Isoform-specific modulation of pressure-stimulated cancer cell proliferation and adhesion by ?-actinin. Am J Surg 202:520-3
Wang, Shouye; Basson, Marc D (2011) Protein kinase B/AKT and focal adhesion kinase: two close signaling partners in cancer. Anticancer Agents Med Chem 11:993-1002
Yu, Guangxiang; Dymond, Michael; Yuan, Lisi et al. (2011) Propofol's effects on phagocytosis, proliferation, nitrate production, and cytokine secretion in pressure-stimulated microglial cells. Surgery 150:887-96
Wang, Shouye; Basson, Marc D (2011) Akt directly regulates focal adhesion kinase through association and serine phosphorylation: implication for pressure-induced colon cancer metastasis. Am J Physiol Cell Physiol 300:C657-70
Perry, Brandon C; Wang, Shouye; Basson, Marc D (2010) Extracellular pressure stimulates adhesion of sarcoma cells via activation of focal adhesion kinase and Akt. Am J Surg 200:610-4
Opreanu, Razvan C; Kuhn, Donald; Basson, Marc D (2010) Influence of alcohol on mortality in traumatic brain injury. J Am Coll Surg 210:997-1007

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