Aging‐related alterations in the extracellular matrix modulate the microenvironment and influence tumor progression

Abstract

Age is the greatest risk factor for the development of epithelial cancers. In this minireview, we will examine key extracellular matrix and matricellular components, their changes with aging, and discuss how these alterations might influence the subsequent progression of cancer in the aged host. Because of the tight correlation between advanced age and the prevalence of prostate cancer, we will use prostate cancer as the model throughout this minireview.Most tissues undergo significant modification with age. For the purposes of this review, the term aged refers to hosts that have reached greater than 75% of their species life expectancy and that generally have a larger percentage of cells (relative to young hosts) defined as senescent in many of their tissues.1-4 Senescent cells, which have ceased replicating but remain metabolically active, as well as normal aged cells influence the microenvironment of tissues. The relative contribution of senescent cells versus normal aged cells in remodeling the microenvironment is speculative, especially in regard to the effect of specific cell types (e.g., endothelial, epithelial, fibroblasts). In this review, we will explore the possible effects of senescent cells as just one of many factors that can alter the microenvironment in an aged host, thereby influencing tumor progression.Whereas cells have been the focus of most research in tissue aging, it is increasingly appreciated that pervasive changes also occur in the components of the extracellular space. [5][6][7][8] Modifications in the local environment, in turn, impact cellular functions. As an example, loss of tissue architecture is a defining characteristic of epithelial cancer initiation and progression. Thus an extracellular environment that provides the correct cues can serve as a powerful tumor suppressor-placing cells containing preneoplastic as well as oncogenic mutations into a normal tissue architecture reverts those cells back to a normal phenotype (e.g., polarization of epithelial cancer cells) despite the continued presence of oncogenic mutations. Conversely an environment that is rich in growth promoting mediators can spur on cells containing mutations to develop into cancer.6-8 These processes continually alter the composition of the microenvironment and subsequently influence tumor progression in the aged host.Within this extracellular environment, the influence of various growth factors has been at the core of cancer research. However, there is increasing interest in the roles of other components during tumor progression. The term Ó microenvironmentÓ now includes the extracellular matrix (e.g., collagens, laminins), matricellular components, soluble factors (hormones, cytokines, growth factors, enzymes) that are released by resident and circulating cells or transmitted by other organs, and a myriad of cell types (e.g., various immune cell populations, endothelial cells, fibroblasts, epithelial cells).6,9 Cells use membrane receptors, such as integrins and syndecans, to physically attach to components ...

Key participants of the tumor microenvironment of the prostate: An approach of the structural dynamic of cellular elements and extracellular matrix components during epithelial–stromal transition

“…During carcinogenesis elevated levels of proteases, including matrix metalloproteinases (MMPs), are produced by tumor and/or stromal cells which are currently thought to endow cells with invasive properties (Fülöp and Larbi, 2002). These MMPs are able to degrade a variety of ECM molecules such as type IV collagen, elastin, laminina (Fülöp and Larbi, 2002) and type I collagen, in normal physiological processes and pathological stages (Roy et al, 2009;Hatfield et al, 2010;Sprenger et al, 2010). They are secreted as pro-enzymes and have to be activated by partial proteolytic cleavage to become biologically active, mainly by plasminogen activator.…”

Non homologous end joining-mediated DNA break repair is impaired in B lymphocytes of aging mice

“…Furthermore, there is a strong correlation between some types of cancer occurrence and age progression (Henry et al, 2011;Sprenger et al, 2010). Accumulation of DNA damage and mutations as a result of impaired DNA repair mechanisms can lead to neoplastic transformation (Helleday, 2011).…”

Nuclear morphometry, nucleomics and prostate cancer progression

“…[19][20][21][22][23] In conjunction with these critical drivers of carcinogenesis, other factors related to the etiopathogenesis of cancer involve energy metabolism [24][25][26] and evasion of the immune surveillance system. [27][28][29] When cancer spread and metastasis occur, the 'tumor microenvironment' in the bone of PCa patients may allow cells to remain dormant or senescent and eventually allow the establishment of a 'seed and soil' site where PCa proliferation and growth may occur over time. 29,30 These molecular alterations can be evaluated with a variety of protocols that detect the numerous changes in chromosome structure and organization in cancer and other diseases.…”

“…[27][28][29] When cancer spread and metastasis occur, the 'tumor microenvironment' in the bone of PCa patients may allow cells to remain dormant or senescent and eventually allow the establishment of a 'seed and soil' site where PCa proliferation and growth may occur over time. 29,30 These molecular alterations can be evaluated with a variety of protocols that detect the numerous changes in chromosome structure and organization in cancer and other diseases. These protocols include nucleic acid sequencing, real-time PCR, methylation-specific qRT-PCR, comparative genomic hybridization, chromosome staining, fluorescence in situ hybridization, genotyping and cloning.…”