Normal Aging and Its Role in Cancer Metastasis

Abstract

Metastasis is the most common cause of death, with treatments failing to provide a durable response. Aging is a key prognostic factor in many cancers. Emerging data suggest that normal age-related changes in the tumor microenvironment can contribute to metastatic progression. These changes encompass secreted factors, biophysical changes, and changes in both stromal and immune cell populations. These data also highlight the importance of conducting studies in preclinical models of appropriate age. Ultimately, therapies may also need to be tailored to reflect patient age, as markers of metastatic disease differ in young and aged populations. In this review, we will discuss some of the changes that occur during aging that increase the metastatic capacity of tumor cells.

Figure 1.

Secreted changes in the aged TME. Fibroblasts make up the largest proportion of the stromal microenvironment in tissues. They are responsible for regulating tissue structure via ECM deposition and supporting cellular and microenvironmental homeostasis via the tightly regulated secretion of soluble factors such as cytokines, chemokines growth factors, and other key signaling proteins. A decrease in fibroblast renewal rate in the elderly, coupled with decreased senescent cell clearance by the immune system results in aged tissue microenvironments having an accumulation of SASP fibroblast cells. The SASP is composed of about 75 defined soluble factors that promote metastatic progression via a diverse range of functions. A large number of proteases (MMPs, PAI, TPA) promote ECM remodeling to reinforce an invasive phenotype within the primary tumor and enable a growth permissive ECM in the metastatic tissue. They secrete angiogenic factors such as VEGF to promote angiogenesis to allow efficient dissemination and nutrient supply, and a large number of growth factors (IGFBP, CSF) to reinforce an aggressive cancer phenotype. Cytokines and chemokines including CXCL1-2, IL6, IL10, GMCSF, and others allow them to promote an immune microenvironment that favors metastatic progression. Many of these factors also appear to have powerful paracrine effects, which can induce a SASP phenotype in surrounding stromal cells. SASP fibroblasts also promote extensive ECM remodeling to increase key signaling components involved in metastatic outgrowth along with structurally altering deposition to promote invasion of tumor cells and efficient immune cell trafficking. Finally, dramatic metabolic changes in SASP cells results in the secretion of high energy metabolites, coupled with an increase in ROS and NO production, which not only further reprograms the microenvironment but also increases cancer aggressiveness. Recent evidence from our group shows that aging within the skin reprograms the fibroblast secretome of healthy patients. Aged skin fibroblasts secrete factors such as sFRP2, while decreasing secretion of molecules such as Klotho and HAPLN1, which significantly increases tumor cell invasion, dissemination, tumor angiogenesis, ECM remodeling, and resistance to targeted therapy. It remains to be seen if aging has an effect on healthy patient fibroblast secretomes in other tissues. Such a phenomenon may promote aggressive primary tumors or premetastatic niche formation which may help explain increased cancer metastasis in aged patients.

Figure 2.

ECM changes in the aged TME. The manner in which fibroblasts lay down matrix changes with age. Young dermal fibroblasts lay down matrices that are nonlinear, and in a “basketweave” pattern, and refract light at multiple different angles. This is visualized as multiple colors. Aged fibroblasts lay down matrices that are linear, and refract light in a singular direction, visualized as a single color. This change in cross-linking is in part directed by the loss of HAPLN1 during aging, which acts to stabilize the cross-links of collagen, elastin, and hyaluronic acid (HA). An aligned matrix predicts for more metastatic behavior. Further breakdown of the ECM around the vasculature can also affect the predicted route of metastasis for disseminated tumor cells.

Figure 3.

Changes in the aged tumor immune microenvironment. The immune system is crucial in recognizing and targeting cancer cells in both primary and metastatic sites. One of the critical factors involved in age-related pathologies is immunosenescence, a process defined by a decline in effector immune function. Subpopulations of effector immune cells including CD4/CD8 T cells, NK cells, macrophages, B-cells, and dendritic cells, all dramatically decrease in cytotoxic activity during the aging process. Studies are now finding that age-related immunosenescence seems to induce a systemic subtype switch toward more suppressive immune populations. In particular, MDSCs and Tregs are significantly increased in aged tissues and blood, and contextually contribute toward the progression of aged tumor models. These components are also critical for the establishment of premetastatic niche across many cancer subtypes; however, a direct relationship between aging and these populations in premetastatic niche formation has yet to be established. Furthermore, effector cells such as macrophages appear to switch phenotypically toward suppressive M2 states in the elderly, which has been shown to promote cancer cell aggressiveness and metastatic disease, but more direct studies of their involvement in age-related metastasis are warranted. The accumulation of SASP stromal components also results in “inflammaging,” a process defined by persistent low-grade inflammation. This process has been shown to disrupt acute inflammatory responses toward malignant tissue, induce infiltration of immunosuppressive MDSCs and promote the secretion of anti-inflammatory components. These overall changes in immune subtype and functionality appear to contribute toward immune evasion in primary and metastatic tumor sites, while also allowing an immunosuppressed premetastatic niche that promotes efficient outgrowth and increased trafficking of disseminated cancer cells toward these sites. More studies are warranted to directly relate age-related systemic increases in immunosuppressive populations and the effect it has on metastasis, specifically investigating how they may contribute to invasion and ECM remodeling.