Paracrine roles of cellular senescence in promoting tumourigenesis

Abstract

Senescent cells activate genetic programmes that irreversibly inhibit cellular proliferation, but also endow these cells with distinctive metabolic and signalling phenotypes. Although senescence has historically been considered a protective mechanism against tumourigenesis, the activities of senescent cells are increasingly being associated with age-related diseases, including cancer. An important feature of senescent cells is the secretion of a vast array of pro-inflammatory cytokines, chemokines, and growth factors collectively known as the senescence-associated secretory phenotype (SASP). Recent research has shown that SASP paracrine signalling can mediate several pro-tumourigenic effects, such as enhancing malignant phenotypes and promoting tumour initiation. In this review, we summarise the paracrine activities of senescent cells and their role in tumourigenesis through direct effects on growth and proliferation of tumour cells, tumour angiogenesis, invasion and metastasis, cellular reprogramming and emergence of tumour-initiating cells, and tumour interactions with the local immune environment. The evidence described here suggests cellular senescence acts as a double-edged sword in cancer pathogenesis, which demands further attention in order to support the use of senolytic or SASP-modulating compounds for cancer treatment.

Fig. 1

Overview of senescence inducers, changes in cell physiology, and activation of the senescence-associated secretory phenotype (SASP). The senescence programme can be activated by different stress stimuli (shown in blue) such as: cytotoxic chemotherapeutic drugs, replicative stress (which occurs due to deficiencies in the DNA replication machinery or maintenance of cell cycle checkpoints), ionising radiation, oncogenic signalling, and oxidative stress. The main cellular and molecular effects are shown in red and include an expansion of the lysosomal compartment, metabolic and mitochondrial alterations, accumulation of DNA damage and rearrangement of the chromatin landscape, resistance to apoptosis, and an irreversible arrest of the cell cycle. Most senescent cells also activate a senescence-associated secretory phenotype (SASP), which is composed of growth factors, cytokines, chemokines, and metalloproteinases. Examples of common SASP factors are shown. These secreted factors can signal in an autocrine fashion to reinforce the senescence phenotype, or paracrinally with multiple effects on neighbouring cells. EGF epithelial growth factor, FGFs fibroblast growth factors, BMPs bone morphogenetic proteins, IL1 interleukin 1, IL6 interleukin 6, IL8 interleukin 8, CCL2 C–C motif chemokine ligand 2, MMP2 matrix metallopeptidase 2, MMP3 matrix metallopeptidase 3

Fig. 2

Summary of the paracrine effects of the SASP in promoting tumourigenesis