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Review
. 2020 Feb;20(2):89-106.
doi: 10.1038/s41568-019-0222-9. Epub 2019 Dec 13.

How the ageing microenvironment influences tumour progression

Mitchell Fane  1   2 , Ashani T Weeraratna  3   4   5
Affiliations
Review

How the ageing microenvironment influences tumour progression

Mitchell Fane et al. Nat Rev Cancer. 2020 Feb.

Abstract

Most cancers arise in individuals over the age of 60. As the world population is living longer and reaching older ages, cancer is becoming a substantial public health problem. It is estimated that, by 2050, more than 20% of the world's population will be over the age of 60 - the economic, healthcare and financial burdens this may place on society are far from trivial. In this Review, we address the role of the ageing microenvironment in the promotion of tumour progression. Specifically, we discuss the cellular and molecular changes in non-cancerous cells during ageing, and how these may contribute towards a tumour permissive microenvironment; these changes encompass biophysical alterations in the extracellular matrix, changes in secreted factors and changes in the immune system. We also discuss the contribution of these changes to responses to cancer therapy as ageing predicts outcomes of therapy, including survival. Yet, in preclinical studies, the contribution of the aged microenvironment to therapy response is largely ignored, with most studies designed in 8-week-old mice rather than older mice that reflect an age appropriate to the disease being modelled. This may explain, in part, the failure of many successful preclinical therapies upon their translation to the clinic. Overall, the intention of this Review is to provide an overview of the interplay that occurs between ageing cell types in the microenvironment and cancer cells and how this is likely to impact tumour metastasis and therapy response.

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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Fig. 1 |
Fig. 1 |. Stromal deregulation in the aged microenvironment drives tumorigenesis and progression.
Fibroblasts are the most common stromal component within tissues. They are responsible for regulating tissue structure via extracellular matrix (ECM) deposition and for supporting cellular and microenvironmental homeostasis via the tightly regulated secretion of soluble factors such as cytokines, chemokines, growth factors and other key signalling proteins. Within younger, healthier tissues, the fibroblast secretome provides a very growth-restrictive microenvironment for premalignant cells and helps in the prevention of other pathological conditions. Furthermore, studies highlight that, under healthy conditions, fibroblasts can undergo a short-lived senescence-associated secretory phenotype (SASP) that, through secretion of approximately 75 defined soluble factors (such as granulocyte–macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), IL-8 and IL-10), can increase immune infiltrates and provide other factors important in the clearance of apoptotic, senescent and malignant cells while also aiding in the wound healing response,,,. Following injury and damage, these senescent fibroblasts are quickly cleared by the body. As the body ages, the healthy fibroblast renewal rate decreases dramatically, and immunosenescence results in a decrease in effector immune cell function. As a result, aged tissue microenvironments have an accumulation of SASP-associated fibroblasts,, and a switch towards more immunosuppressive immune infiltrates, such as myeloid-derived suppressor cells (MDSCs)– and regulatory T (Treg) cells–, when compared with a younger tissue microenvironment. It can be hypothesized that this establishes a tumour- permissive, chronic inflammatory microenvironment that enables cancer cells to eventually expand in number and progress unabated by the immune system. Systemic increases in immunosuppressive M2 macrophages and N2 neutrophils in the elderly may also further contribute to increased immunosuppression, whereas immunosenescence of effector T cells, natural killer cells, macrophages and dendritic cells, all dramatically decrease their cytotoxic activities and infiltration within an aged tumour- promoting microenvironment–. Extensive accumulation of senescent cells has been shown to be responsible for many age-related pathologies and is a major driver of cancer progression. Many of the soluble factors within the SASP have been shown to promote tumour invasion (matrix metalloproteinases (MMPs), plasminogen activator inhibitors (PAIs) and tissue-type plasminogen activator (tPA)),–, growth (insulin-like growth factor binding protein (IGFBP)– and colony-stimulating factor (CSF)) and angiogenesis (vascular endothelial growth factor (VEGF)) as well as to sustain a protumour milieu by supporting tumour evasion of immune surveillance (CXC-chemokine ligand 1 (CXCL1) and CXCL2 (REFS,), IL-6 (REF.), IL-10 (REF.) and GM-CSF). Many of these factors also appear to have powerful paracrine effects that can induce SASP in surrounding stromal cells–. SASP fibroblasts also promote extensive ECM remodelling to increase key signalling components involved in tumorigenesis and to promote invasion of tumour cells and immune cell trafficking,. Recent evidence now also suggests that ageing reprogrammes the secretome of healthy human fibroblasts within the skin, whereby aged skin fibroblasts secrete factors such as secreted frizzled-related protein 2 (SFRP2), which significantly increases tumour cell invasion and dissemination, tumour angiogenesis, and resistance to targeted therapy.
Fig. 2 |
Fig. 2 |. Age-induced contextual changes in extracellular matrix structure and function in the tumour microenvironment.
The extracellular matrix (ECM) provides a scaffold responsible for protein and cell-specific trafficking across the body, while also providing structural integrity for tissue microenvironments. Components of the ECM serve as ligands for cell surface receptors known as integrins and these, along with the biophysical properties of the ECM including stiffness, crosslinking and fibre alignment, provide extrinsic cues that dramatically alter cellular phenotype. The loss of tissue ECM integrity encompasses one of the hallmarks of cancer, and ECM dysregulation is heavily associated with tumour progression and metastasis–. There is dramatic diversity in both the biochemical and biophysical nature of the ECM environment across different tissues. For example, the ‘basket-weave’ pattern seen in the ECM of skin has not been observed in breast tissues (not shown in this figure for simplicity). In healthy, younger individuals, softer tissues, such as the brain, lung and breast, require a more elastic, ‘looser’ connective tissue environment (bottom, left), whereas harder tissues, such as the skin and bone, require stiffer structures to provide a protective barrier (top, left). It has been clearly established that ECM integrity decreases substantially across the body as we age, which includes a decrease in collagen density– and ECM fibre area and thickness– as well as changes in the mechanical properties of the ECM such as stiffness. Furthermore, natural age-related turnover of collagen crosslinking proteins, such as fibulin, fibrillin and elastin,, decreases crosslinking within the ECM, which further impairs integrity (top and bottom, right). Studies reveal that age-related decreases in ECM integrity in the skin, which is known to be a stiff tissue microenvironment, can promote cancer progression. Specifically, these studies show that age-related decreases in the secretion of the ECM remodelling protein hyaluronan and proteoglycan link protein 1 (HAPLN1) from fibroblasts (and consequent breakdown of hyaluronic acid (HA)) result in significantly decreased collagen crosslinking and density while also increasing fibre alignment, resulting in increased melanoma cell invasion and progression (top, right). By contrast, the different context of softer tissue microenvironments means that they often require increased crosslinking and stiffening to promote efficient tumour progression,. Age-induced accumulation of senescence-associated secretory phenotype (SASP) stromal cells appears to be a key mechanism in inducing ECM stiffness in site-specific niches within these environments, such as the lung, which may ultimately allow increased tumorigenesis and dissemination; however, further studies are required to directly link these processes (bottom, right).
Fig. 3 |
Fig. 3 |. Immune cell switching, inflammaging and immunosenescence as drivers of age-induced tumour progression.
Many of the hallmarks of cancer require immune modulation as an important step in enabling efficient progression,. One of the critical factors involved in age-related pathologies is immunosenescence, a process defined as a dramatic decline in overall immune function,. Subpopulations of effector immune cells, including T cells, natural killer cells, macrophages and dendritic cells, exhibit a dramatic decrease in cytotoxic activity during the ageing process–. In younger and healthier tissues, these effector cells are responsible for acute responses to malignant tissue growth and clearance of senescent cells; thus, age-related immunosenescence plays a key role in promoting tumour formation and accumulation of senescence-associated secretory phenotype (SASP)-secreting cells. These age-related decreases in effector immune cell function also appear to induce tissue-specific switching towards more immunosuppressive cell populations. Many studies show that immunosuppressive myeloid-derived suppressor cells (MDSCs)– and regulatory T (Treg) cells– are significantly increased in aged tissues and blood, and depending on the context, contribute towards the progression of tumours in aged mouse models,. These immune components are also critical for the establishment of premetastatic niches across many cancer types,; however, a direct relationship between these immune cell populations and metastatic niche formation with ageing has yet to be investigated. Furthermore, in the elderly, effector cells, such as neutrophils and macrophages, appear to switch phenotypically towards immunosuppressive N2 (REF138) and M2 (REF133) states, respectively, both of which have been shown to promote tumorigenesis of various cancer types,; yet, more direct studies showing their involvement in age-related tumorigenesis 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 towards malignant tissue, induce infiltration of immunosuppressive MDSCs and Treg cells, and promote secretion of anti-inflammatory components such as cytokines, chemokines and ‘inflamma-miRs’–. As such, ‘inflammaging’ appears to play a key role in impairing antitumour immunity in aged individuals. ARG1, arginase 1; CRP, C-reactive protein; ECM, extracellular matrix; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFNγ, interferon-γ; IL, interleukin; ROS, reactive oxygen species; TGFβ, transforming growth factor-β; TNF, tumour necrosis factor.
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