Senescent remodeling of the innate and adaptive immune system in the elderly men with prostate cancer

Abstract

Despite years of intensive investigation that has been made in understanding prostate cancer, it remains a major cause of death in men worldwide. Prostate cancer emerges from multiple alterations that induce changes in expression patterns of genes and proteins that function in networks controlling critical cellular events. Based on the exponential aging of the population and the increasing life expectancy in industrialized Western countries, prostate cancer in the elderly men is becoming a disease of increasing significance. Aging is a progressive degenerative process strictly integrated with inflammation. Several theories have been proposed that attempt to define the role of chronic inflammation in aging including redox stress, mitochondrial damage, immunosenescence, and epigenetic modifications. Here, we review the innate and adaptive immune systems and their senescent remodeling in elderly men with prostate cancer.

Figure 1

Multistate prostate carcinogenesis determined by the progression of different qualitative states identifiable in the development of cancer from normal tissue. The time parameter (t ₀, t ₁,…, t _n−1, t _n) depends on a large number of variables interconnected in many ways in a nonlinear manner. This makes it extremely difficult to predict the exact time interval between two successive states. Although carcinogenesis is a continuum, its differentiation into successive states is based on differences in histological and clinical data. Proliferative inflammatory atrophy (PIA) is a frequently observed lesion in prostate biopsies and some investigators have postulated its involvement in prostate carcinogenesis. PIA shares genetic alterations with high-grade prostatic intraepithelial neoplasia (HGPIN) and prostate cancer. HGPIN is currently regarded as the precursor lesion on the basis of pathological, epidemiological, and cytogenetic evidence. HGPIN lesions can be subdivided into at least four different architectural patterns.

Figure 2

Histopathological examination reveals that prostate cancer is associated with diverse immune cell infiltrates and that, in the cancer context, epithelial cells coexist with extracellular matrix components and nonneoplastic cell types, including fibroblasts and endothelial cells, which collectively form the tumour stroma. Evidence supports the concept that tumour stromal cells are not merely a scaffold, but rather they influence growth, survival, and invasiveness of cancer cells, dynamically contributing to the tumour microenvironment. The interactions between epithelium and the surrounding stroma are required to maintain organ function and provide proliferative and migratory restraints that define anatomical and positional information, mediated by several growth factors, cytokines, chemokines, and extracellular matrix components. When cancer develops, transformed cells lose these constraints while stroma adapts and coevolves to support the “function” of the tumour.