Prostate cancer is the second most common malignancy in men worldwide. Advanced age is the greatest risk factor for prostate cancer in humans. Many studies have examined the influence of age on prostate cells. It has been noted that ageing alters both stromal and epithelial aged prostate cells' secretory profile, which is characterized by increased expression of inflammatory mediators, such as CXC chemokines. This has been attributed to a "senescent secretary phenotype" and is thought to contribute to both benign and malignant prostate diseases onset. However, much less is known as to how age affects the prostate matrix and its subsequent interactions with resident cells. Prostate matrix is primarily comprised of collagen I. Young and aged collagen differ in several physical parameters including decreased density, greater fragmentation, and increased disorganization in aged relative to young collagen I. The aim of this proposal is to investigate the underlying mechanisms that alter the local prostate environment in relation to the collagen matrix regulation of cancer cell behavior: both function and secretion. However, collagen matrices derived from prostate glands are not yet feasible and studies of the effect of aged mouse tissues on the behavior of human cancer cells are limited by the lack of compatible murine hosts, as immunodeficient mice do not live past middle age. Consequently, we will use young and aged collagen I obtained from young and aged mouse tail tendons and polymerized into a 3 dimensional (3D) matrix - a known simulation of aged collagen in vitro. We propose that aged 3D collagen I, relative to that of young collagen I, influences prostate cancer cells to decrease the expression of integrins that mediate cellular invasion. At the same time, we propose that aged collagen I increases the ability of prostate cancer cells to secrete chemokines that promote angiogenesis in the tumor microenvironment. We will utilize 3 human prostate cancer cell lines (LNCaP, LNCaPC4-2, and VCaP) that will be examined for the relative function of differentially expressed adhesion molecules during invasion through young and aged 3D collagen I. We will also examine the secretory profile of chemokines known to induce an invasive prostate cancer phenotype. This aged collagen I matrix will specifically elucidate cell-matrix interactions that can uncover potential therapeutic targets in prostate cancer.


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