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Abstract
Grant Number: 1R21AT001636-01A2 Project Title: Nutrient Regulated Breast Cancer Cell De-adhesion
PI Information: Name Title HARDY, ROBERT W. hardy@path.uab.edu ASSOCIATE PROFESSOR, SECTION HEAD OF CLI Abstract: DESCRIPTION (provided by applicant): Cellular interactions with the extracellular matrix (ECM) profoundly influence a variety of signaling events influencing phenotypic properties of tumor cells. Importantly cell adhesion is reversible during tissue remodeling, morphogenesis and wound healing, cellular metaplasia, cell proliferation and tumor metastasis. It has been proposed that the reversal of the adhesion process is also an important cellular process that has been termed "de-adhesion". Although cell adhesion has received much attention there is much less known about the process of cellular de-adhesion. De-adhesion can be conceptualized as a transition from a state of relatively strong adherence to a state of weaker adherence. This state of weaker adherence is characterized by a restructuring of focal adhesion plaques and stress fibers. Extracellular regulatory factors have been proposed for de-adhesion however the role of nutritional factors in modulating these events, to date, have not been explored. We have identified the long chain saturated fatty acid (LSCFA) stearate (C18:0) as a nutritional regulator of de-adhesion in tumor cells. Stearate is found in many foods including chocolate and meat, and specifically inhibits the capability of tumor cells to adhere to and invade human ECM in vitro by triggering de-adhesion. This occurs preferentially in tumor cells and specifically via tumor cell-laminin ECM interactions. This proposal is designed to test the hypothesis that changes in the bioavailability of stearate regulates the de-adhesive state of breast cancer cells. We postulate that tumor cell de-adhesion induced by stearate plays an important role in human breast cancer growth and metastasis. Using in vivo metastasis models and novel 'all human' in vitro models of cell-matrix adhesion, mimicking essential steps of the metastatic cascade, our goal is to determine the regulatory aspects of stearate on breast cancer cell de-adhesion. We shall first determine the effects of dietary stearate on lung metastasis using syngeneic BALB/c mouse and nude (immunodeficient) mouse models. Secondly we shall ascertain the key laminin receptor(s) responsible for stearate induced cancer cell de-adhesion. Finally we will examine alterations in breast tumor cell functions (adhesion, and growth) by stearate treatment utilizing a human in vitro cell-matrix and 'tumor-endothelial cell' co-culture system, we have developed. These studies will provide the in vivo and essential mechanistic data needed for an NIH-R01 proposal which will be necessary for future studies. Our hope is to eventually develop improved nutritional strategies for cancer prevention and control, and identify new therapeutic targets for breast cancer metastasis.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
breast neoplasm, cell adhesion, cell growth regulation, neoplastic cell, nutrition aspect of cancer, stearate
cancer prevention, cell cell interaction, cell proliferation, extracellular matrix, laminin, lung neoplasm, metastasis, neoplastic process
alternative medicine, flow cytometry, laboratory mouse, mixed tissue /cell culture, nutrition related tag, tissue /cell culture
Institution: UNIVERSITY OF ALABAMA AT BIRMINGHAM 1530 3rd Avenue South BIRMINGHAM, AL 35294 Fiscal Year: 2005 Department: PATHOLOGY Project Start: 01-FEB-2005 Project End: 31-JAN-2007 ICD: NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINE IRG: ZAT1