The Gene Expression Program of Prostate Fibroblast Senescence Modulates Neoplastic Epithelial Cell Proliferation through Paracrine Mechanisms

Abstract

The greatest risk factor for developing carcinoma of the prostate is advanced age. Potential molecular and physiologic contributors to the frequency of cancer occurrence in older individuals include the accumulation of somatic mutations through defects in genome maintenance, epigenetic gene silencing, oxidative stress, loss of immune surveillance, telomere dysfunction, chronic inflammation, and alterations in tissue microenvironment. In this context, the process of prostate carcinogenesis can be influenced through interactions between intrinsic cellular alterations and the extrinsic microenvironment and macroenvironment, both of which change substantially as a consequence of aging. In this study, we sought to characterize the molecular alterations that occur during the process of prostate fibroblast senescence to identify factors in the aged tissue microenvironment capable of promoting the proliferation and potentially the neoplastic progression of prostate epithelium. We evaluated three mechanisms leading to cell senescence: oxidative stress, DNA damage, and replicative exhaustion. We identified a consistent program of gene expression that includes a subset of paracrine factors capable of influencing adjacent prostate epithelial growth. Both direct coculture and conditioned medium from senescent prostate fibroblasts stimulated epithelial cell proliferation, 3-fold and 2-fold, respectively. The paracrine-acting proteins fibroblast growth factor 7, hepatocyte growth factor, and amphiregulin (AREG) were elevated in the extracellular environment of senescent prostate fibroblasts. Exogenous AREG alone stimulated prostate epithelial cell growth, and neutralizing antibodies and small interfering RNA targeting AREG attenuated, but did not completely abrogate the growthpromoting effects of senescent fibroblast conditioned medium. These results support the concept that aging-related changes in the prostate microenvironment may contribute to the progression of prostate neoplasia. (Cancer Res 2006; 66(2): 794-802)

Drug-induced senescence bystander proliferation in prostate cancer cells in vitro and in vivo

“…SAb-gal activity in cells has been putatively identified in ageing tissues, including skin and benign prostatic hyperplasia specimens (Dimri et al, 1995;Choi et al, 2000). Consistent with the hypothesis that ageing induces a procarcinogenic environment, fibroblasts passaged to replicative senescence induce the proliferation of local bystander cells both in vitro and in xenografts (Krtolica et al, 2001;Bavik et al, 2006). To determine whether senescent cancer cells generate a bystander effect or not, we chemically induced senescence in prostate cancer cells using doxorubicin and examined their effect on a bystander cancer cells in vitro and in vivo.…”

“…Senescent cells express a variety of growth factors and secreted proteins that may stimulate as well as inhibit cell proliferation (Chang et al, 2002;Schwarze et al, 2002Schwarze et al, , 2005Untergasser et al, 2002;Bavik et al, 2006). In contrast to apoptosis, a programme of cellular destruction, senescent cells persist and remain viable.…”

Extracellular influences on tumour angiogenesis in the aged host

“…Once a cell has entered senescence, its transcriptome is altered such that genes associated with angiogenesis are activated. Inflammatory cytokines (IL-8), growth factors (TGF-b, EGF), matrix metalloproteinases (MMPs), and extracellular matrix proteins (laminins, collagens, fibronectin) are among the genes upregulated by senescent cells (Zhang et al, 2003;Campisi, 2005;Bavik et al, 2006). This alteration in expressed genes affects not only the senescent cell itself, but the cells surrounding it as well.…”

“…This alteration in expressed genes affects not only the senescent cell itself, but the cells surrounding it as well. Senescent fibroblasts that were co-cultured with breast or prostate epithelial cells increased the proliferation and tumorigenicity of those epithelial cells, both in vitro and in vivo (Campisi, 2005;Bavik et al, 2006). Senescence, then, inhibits cancer formation early on but over time the build up of senescent cells alters the microenvironment to one that can promote the initiation of epithelial cancers.…”

“…Accordingly, laminins have been postulated to influence the cancer phenotype of breast and prostate epithelium. Recent studies have shown that senescent prostate epithelial cells found in regions of benign prostatic hyperplasia as well as senescent prostate fibroblasts have increased expression of the laminin a4 and b1 chains (Luo et al, 2002;Bavik et al, 2006). Fujita et al (2005) also demonstrated a switch from LM421 to LM411 expression in breast tumour vasculature, implying that increased expression of the LM411 chains may be associated with progression of some epithelial cancers (Fujita et al, 2005).…”