The National Cancer Institute estimates that 232,000 new cases of prostate cancer will be diagnosed this year. Thirty thousand men will die of the disease and 15 billion dollars will be spent for screening, diagnosis, treatment, and research. Prostate cancer is lethal only when it spreads to other organs. Preventing the spread of prostate cancer would significantly reduce the morbidity and mortality associated with this disease. In order to disseminate to other organs, prostate cancer cells must acquire the ability to detach from the tumor and to attach to components of the tissue that surrounds them. Detachment from the main tumor and attachment to the surrounding tissue involves cell surface adhesion molecules that act to either hold tumor cells together or that facilitate interaction of cells with the extra-cellular matrix (ECM). A balance between these two opposing forces is required to maintain tumors in a non-invasive state. A switch in this balance away from cell-cell cohesion and towards cell-ECM adhesion would promote cancer cell invasion. Maintaining this balance of forces, or reversing it towards cell-cell adhesion could potentially be useful in maintaining tumor integrity and reducing invasive and metastatic potential of prostate cancer. The central theme of this grant is to better understand how these forces influence invasion and to determine whether it will be possible to genetically or pharmacologically alter them in favor of invasion suppression. Forces generated by cell-cell and cell-ECM adhesion, and the molecules which give rise to them, impart to tumors mechanical properties that can be accurately measured. We have previously shown that one such property, tumor cohesivity (TC), is not only strongly correlated with invasiveness of various cancers, but is also a fundamental driving force mediating interactions between tumor cells and the surrounding tissues into which they invade. We have developed methods to accurately measure TC and to discriminate between high and low affinity interactions between tumor and stromal cells. Tissue surface tensiometry (TST) exploits the liquid-like behavior of tumor tissue to measure a key regulator of invasion, namely, tumor cohesivity (TC). We discriminate between low and high affinity interactions using a model based on the observation that when mixed together, cells which do not recognize one another do not remain mixed, but rather, sort-out into two separate phases, whereas cells that have a high affinity for one another tend to remain intermixed. This behavior can be explained using the same physical principles underlying the mixing of liquids. Ethanol and water intermix because they have high affinity for one another, whereas oil and water separate because the affinity of water for itself or oil for itself is greater than that of oil for water. In liquids, affinity is a reflection of the balance between surface and interfacial tension. In cellular systems, these two parameters are a reflection of how strongly cells interact with their own kind, relative to how strongly they interact to other types of cells. This proposal has three objectives. First, we will determine whether TC measurements correlate with invasiveness. Second, we will explore how manipulating particular molecular components leads to associated alterations in TC and invasiveness. Third, we will investigate how TC regulates tumor-stromal interaction. Devising strategies aimed at altering tumor cohesion, maintaining or even restoring compartmentalization between tumor and stromal cells and reducing invasion, are critical to successful treatment of prostate cancer. This proposal aims to elucidate the role of cohesion, not only as a force holding tumor cells together, but also as a regulator of establishing specific spatial relationships between tumor and stromal cells. The information generated will establish a connection between tumor rheology and its molecular underpinnings. Successful completion of these aims will enhance our knowledge of how physical interactions between cancer cells and their surrounding tissue influence invasion.

Public Health Relevance

Prostate cancer is rarely deadly unless it spreads. In man, prostate cancer most often spreads to bone. Bone metastasis can severely influence the quality of life of patients with advanced disease. Preventing spread of the disease can markedly improve outcome. In order to spread, cancer cells must detach from the tumor and must acquire the ability to interact with other cells in order to gain access to the general or lymphatic circulation. They do so as a consequence of complex changes in the expression and function of molecules that regulate forces that not only serve to hold tumor cells together but also allow tumor cells to interact with the environment into which they spread. These forces impart to tumors mechanical properties that can be measured and correlated with invasiveness. This proposal explores how these forces and the molecules giving rise to them contribute to invasiveness.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA118755-05
Application #
8303013
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2008-09-01
Project End
2013-06-30
Budget Start
2012-08-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$275,459
Indirect Cost
$98,883
Name
University of Medicine & Dentistry of NJ
Department
Surgery
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Lim, Jung-won; Gonzalez, Patricia; Wang-Letzkus, Ming F et al. (2013) Health behavior changes following breast cancer treatment: a qualitative comparison among Chinese American, Korean American, and Mexican American survivors. J Health Care Poor Underserved 24:599-618
Foty, Ramsey A (2013) Tumor cohesion and glioblastoma cell dispersal. Future Oncol 9:1121-32
Jia, Dongxuan; Entersz, Ildiko; Butler, Christine et al. (2012) Fibronectin matrix-mediated cohesion suppresses invasion of prostate cancer cells. BMC Cancer 12:94
Wilken, Jason A; Baron, Andre T; Foty, Ramsey A et al. (2011) Identification of immunoreactive regions of homology between soluble epidermal growth factor receptor and ýý5-integrin. Biochemistry 50:4309-21
Butler, Christine M; Foty, Ramsey A (2011) Measurement of aggregate cohesion by tissue surface tensiometry. J Vis Exp :
Hu, Song; Maslov, Konstantin; Wang, Lihong V (2011) Three-dimensional optical-resolution photoacoustic microscopy. J Vis Exp :
Foty, Ramsey (2011) A simple hanging drop cell culture protocol for generation of 3D spheroids. J Vis Exp :
Sabari, Joshua; Lax, Daniel; Connors, Daniel et al. (2011) Fibronectin matrix assembly suppresses dispersal of glioblastoma cells. PLoS One 6:e24810
Schwarz, Margaret A; Zheng, Haihua; Legan, Susan et al. (2011) Lung self-assembly is modulated by tissue surface tensions. Am J Respir Cell Mol Biol 44:682-91
Caicedo-Carvajal, Carlos E; Shinbrot, Troy; Foty, Ramsey A (2010) Alpha5beta1 integrin-fibronectin interactions specify liquid to solid phase transition of 3D cellular aggregates. PLoS One 5:e11830

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