The impact of the senescent microenvironment on tumorigenesis: Insights for cancer therapy

Abstract

The growing global burden of cancer, especially among people aged 60 years and over, has become a key public health issue. This trend suggests the need for a deeper understanding of the various cancer types in order to develop universally effective treatments. A prospective area of research involves elucidating the interplay between the senescent microenvironment and tumor genesis. Currently, most oncology research focuses on adulthood and tends to ignore the potential role of senescent individuals on tumor progression. Senescent cells produce a senescence-associated secretory phenotype (SASP) that has a dual role in the tumor microenvironment (TME). While SASP components can remodel the TME and thus hinder tumor cell proliferation, they can also promote tumorigenesis and progression via pro-inflammatory and pro-proliferative mechanisms. To address this gap, our review seeks to investigate the influence of senescent microenvironment changes on tumor development and their potential implications for cancer therapies.

Keywords: cancer; senescence‐associated secretory phenotype; senescent; tumor microenvironment.

FIGURE 1

Signs of human aging. The nine hallmarks of human aging include altered cellular communication, stem cell exhaustion, cellular senescence, mitochondrial dysregulation, disturbed energy metabolism, genetic instability, epigenetic changes, telomere shortening, and loss of protein homeostasis.

FIGURE 2

Factors affecting the aging of human cells and their consequences. The factors that promote cellular senescence (pink) are shown in the figure, along with the effects on the organism caused by the senescence‐associated secretory phenotype (SASP) (blue) produced by senescent cells.

FIGURE 3

Effects and consequences of therapy‐induced senescence on cellular senescence in the organism. The figure illustrates that therapy‐induced senescence (TIS) can lead to cellular senescence, with some senescent cells transforming into a transient senescent state (acute senescence). The organism then removes these senescent cells by immune surveillance. If these acute senescent cells are not removed, these senescent cells will enter a chronic senescent state, which in turn produces senescence‐associated secretory phenotype (SASP) accumulation, which may lead to the development of precancerous cells. This can further promote the formation, invasion, and metastasis of tumor cells.

FIGURE 4

Pathways and mechanisms involved in senescence‐associated secretory phenotype (SASP) production. SASP production in senescent cells. SASP production involves various metabolic pathways and mechanisms, with most pathways culminating in the production of inflammatory cytokines via transcription factors NF‐κB and C/EBPβ. ZCAN4 also induces inflammatory cytokines through NF‐κB. Furthermore, up‐regulation of Ras can regulate SASP production through the translation of mTOR‐regulated MAPKAPK2. The deletion of P53 also leads to SASP production via NF‐κB and C/EBPβ. Reactive oxygen species, by‐products of the mitochondrial electron transport chain in aerobic cells, accumulate during senescence and cause DNA damage, which promotes SASP production. Additionally, mitochondrial damage leads to changes in AMP/ATP and NAD+/NADH ratios, further inducing inflammatory cytokines through NF‐κB and C/EBPβ. DNA fragments from DNA damage and the deletion of lamin B1 promote inflammatory cytokine secretion via the cGAS‐STING pathway. Conversely, cellular autophagy can inhibit SASP production through the P62‐mediated inhibition of the GATA4 gene.

FIGURE 5

Effects of chemotherapy on tumor cell senescence and outcomes. Chemotherapy functions by damaging the DNA of malignant tumor cells. Cells that incur severe damage enter a death cycle, while the surviving tumor cells enter a senescence cycle and produce senescence‐associated secretory phenotype (SASP). This contributes to tumor suppression by activating the immune response and inhibiting apoptosis.

FIGURE 6

Prognosis of aging and tumor therapy. Elderly oncology patients who have undergone tumor removal surgery often experience physical debility. This debility can impact the body's ability to adapt to chemotherapy and increase the incidence of chemotherapy complications.