Senescence-Induced Alterations in the Laminin Component of Prostate Epithelial Extracellular Matrix Regulate Progression of Prostate Cancer

Abstract

Approved for public release; distribution unlimitedThe purpose of this work was to determine how changes in laminin chains associated with senescence affected prostate cancer progression. In order to determine the effects of alterations to the laminin component of the tumor microenvironment, I overexpressed the laminin alpha 4, beta 2, or alpha 4 and beta 2 chains in a human prostate cancer cell line. I demonstrated that these lines secreted the specific laminin chains and incorporated them into the extracellular matrix. Stable expression of the laminin alpha 4 chain resulted in increased in vitro migration and increased in vivo angiogenesis and tumorigenicity of those cells compared to empty vector control cells. High expression of both the laminin alpha 4 and beta 2 chains decreased in vitro proliferation and migration and decreased in vivo tumorigenicity compared to control cells. Stable expression of the laminin beta 2 chain alone had a tumor promoting function as opposed to the tumor suppressive role seen with high protein levels of the laminin alpha 4 and beta 2 chains together. These data support the concept that since senescent cells secrete both tumor promoting and tumor inhibiting factors, it is the interaction of these factors that infl ences cell lar beha ior This dichotom also points to the importance of nderstanding prostate cancer, senescence, microenvironment, extracellular matrix, laminins U U U UU 28 Appendices…………………………………………………………………………….…...6 USAMRMCSprenger CC -1 INTRODUCTION:Age-associated epithelial cancers, such as breast and prostate, contribute significantly to the mortality of the elderly. One mechanism by which the body defends itself against epithelial cancers is to halt replication of damaged cells by senescence, in which cells are replicatively arrested but metabolically active. We have shown that senescent prostate cancer cells specifically alter the laminin component of their extracellular matrix (ECM) (Appendix C). Laminins are ECM proteins important to both the structure and function of the microenvironment. Our cell line model of a senescent prostate cancer cell, the M12mac25 cells, displayed increased expression of the laminin α4 and β2 chains. The purpose of this study was to determine how changes in laminin chains associated with senescence affected prostate cancer progression. BODY:In order to determine the effects of alterations to the laminin component of the tumor 1. Creation of prostate cancer cell lines overexpressing various laminin chains (α4, β2 or both α4β2).2. Demonstrated secretion and deposition of these chains into the extracellular matrix; this had not been accomplished for any laminin chains in prostate cell lines before.3. The novel finding that high expression of the laminin α4 and β2 chains together in prostate cancer cells led to a 3D deposition pattern for laminins as well as other matrix proteins, such as fibronectin. Previously, 3D deposition of laminins was reported only in co-cultures of epithelial cells and fibroblasts.4. Stable expression of the ...