Cellular senescence and the tumour microenvironment

Abstract

The senescence-associated secretory phenotype (SASP), where senescent cells produce a variety of secreted proteins including inflammatory cytokines, chemokines, matrix remodelling factors, growth factors and so on, plays pivotal but varying roles in the tumour microenvironment. The effects of SASP on the surrounding microenvironment depend on the cell type and process of cellular senescence induction, which is often associated with innate immunity. Via SASP-mediated paracrine effects, senescent cells can remodel the surrounding tissues by modulating the character of adjacent cells, such as stromal, immune cells, as well as cancer cells. The SASP is associated with both tumour-suppressive and tumour-promoting effects, as observed in senescence surveillance effects (tumour-suppressive) and suppression of anti-tumour immunity in most senescent cancer-associated fibroblasts and senescent T cells (tumour-promoting). In this review, we discuss the features and roles of senescent cells in tumour microenvironment with emphasis on their context-dependency that determines whether they promote or suppress cancer development. Potential usage of recently developed drugs that suppress the SASP (senomorphics) or selectively kill senescence cells (senolytics) in cancer therapy are also discussed.

Keywords: anti-tumour immunity; cellular senescence; senescence-associated secretory phenotype; senolysis; senomorphics; tumour microenvironment.

Fig. 1

Central regulators of cellular senescence. p16 and p21 are upregulated upon DNA damage and are the most important CDKIs that contribute to senescence‐associated cell cycle arrest. p53 is the major transcription factor that mediates DNA damage‐induced p21 activation. These CDKIs suppress de‐repression of E2F transcription factors that is mediated by CDK‐dependent phosphorylation of E2F repressor Rb. Cyclin D1 is known to be upregulated in senescent cells but it is reported to be dysfunctional [160]. [Colour figure can be viewed at wileyonlinelibrary.com]

Fig. 2

Markers of cellular senescence. Markers most commonly used to identify senescent cells include cell cycle arrest, p16, p21, Lamin B1 downregulation, γH2AX, SA‐β‐gal and the SASP. However, neither of these markers is truly specific to senescent cells. For example, quiescent cells also exhibit cell cycle arrest and, in some cases, increased SA‐β‐gal activity. It is important to combine several markers in a battery of tests in order to identify senescent cells. [Colour figure can be viewed at wileyonlinelibrary.com]

Fig. 3

Central regulators of the SASP. SASP is regulated at epigenetic, transcriptional and post‐transcriptional levels in senescent cells. Major pathways involved in SASP induction are depicted in the figure. Many of these pathways are activated by DNA damage. [Colour figure can be viewed at wileyonlinelibrary.com]

Fig. 4

SASP‐related innate immune responses. Cytoplasmic DNA‐induced cGAS‐STING innate immune pathway plays a pivotal role in SASP induction. Mechanisms underlying the senescence‐associated increase in cytoplasmic DNA include impaired nuclear membrane integrity, cytoplasmic chromatin fragment formation, de‐repression of LINE‐1, and reduced expression of DNase2 and TREX1. Extrinsic inducers of innate immune responses also contribute to the SASP. For example, gut microbiota‐derived LTA stimulates TLR2 expressed on senescent hepatic stellate cells and thereby upregulates COX2 expression, which then produces immunosuppressive PGE₂. [Colour figure can be viewed at wileyonlinelibrary.com]

Fig. 5

The context‐dependent roles of SASP in tumour microenvironment. (A) Tumour‐suppressive SASP. In normal or precancerous tissue, senescent cells have a tumour‐suppressive role by re‐enforcing senescence through the SASP, which has both autocrine and paracrine effects. SASP factors can recruit immune cells to clear themselves (senescence surveillance). (B) Tumour progressive SASP. In advanced cancer tissue, SASP factors produced by senescent cells can promote cancer progression by enhancing angiogenesis, cancer cell proliferation, EMT and the metastasis of cancer cells. SASP factors also suppress anti‐tumour immunity. [Colour figure can be viewed at wileyonlinelibrary.com]

Fig. 6

The effects of the SASP depends on tumour stage. (A) In precancerous tissues, the effects of the SASP are predominantly tumour‐suppressive, with the major tumour‐suppressive effects including autocrine and paracrine senescence and induction of immunosurveillance. (B) In advanced cancerous tissues, the SASP factors from stromal cells such as CAFs can promote tumour growth. [Colour figure can be viewed at wileyonlinelibrary.com]

Fig. 7

SASP in cancer therapy. (A) Schematic illustration of the effect of CDK4/6 inhibitor. (B) Schematic illustration of how the combination of chemotherapy and senolysis contribute to cancer therapy. [Colour figure can be viewed at wileyonlinelibrary.com]