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Review
. 2019 Dec;23(12):1041-1051.
doi: 10.1080/14728222.2019.1565658. Epub 2019 Jan 15.

Pro- and anti-tumorigenic functions of the senescence-associated secretory phenotype

Lena Lau  1 , Gregory David  1   2   3
Affiliations
Review

Pro- and anti-tumorigenic functions of the senescence-associated secretory phenotype

Lena Lau et al. Expert Opin Ther Targets. 2019 Dec.

Abstract

Introduction: Cellular senescence is a stable form of cell cycle exit. Though they no longer divide, senescent cells remain metabolically active and secrete a plethora of proteins collectively termed the senescence-associated secretory phenotype (SASP). Although senescence-associated cell cycle exit likely evolved as an anti-tumor mechanism, the SASP contains both anti- and pro-tumorigenic potential.Areas covered: In this review, we briefly discuss the discovery of senescent cells and its relationship to cancer and aging. We also describe the initiation and regulation of the SASP upon senescence stimulus onset. We focus on both the pro- and anti-tumorigenic properties of the SASP. Finally, we speculate on the potential benefits of therapy-induced senescence combined with selective SASP inhibition for the treatment of cancer.Expert opinion: Further identification and characterization of the SASP factors that are pro-tumorigenic and those that are anti-tumorigenic in specific contexts will be crucial in order to develop personalized therapeutics for the successful treatment of cancer.

Keywords: Cancer; SASP; cellular senescence; inflammation; senescence-associated secretory phenotype; tumorigenesis.

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Conflict of interest statement

Declaration of Interests

G David has received support from The Samuel Waxman Cancer Research Foundation and a Feinberg NYU individual grant. L. Lau was supported by a predoctoral NIH/NCI NRSA (F31 CA206387). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Figures

Figure 1.
Figure 1.
The pro- and anti-tumorigenic properties of the senescence-associated secretory phenotype (SASP). The SASP can act to reinforce cell cycle exit in a cell-autonomous manner, induce neighboring cells to exit the cell cycle (termed paracrine senescence), and recruit immune cells that will clear away senescent and potentially cancerous cells. Conversely, the SASP can also promote the proliferation of neoplastic cells, induce epithelial-to-mesenchymal transition in malignant cells, promote the emergence of cancer stem cells, and create an immunosuppressive or inflammatory environment that further drives tumorigenesis.
Figure 2.
Figure 2.
Senescence-associated secretory phenotype (SASP)-mediated immune cell recruitment aiding in tumor clearance. Both the innate and adaptive immune systems have been described to aid in SASP-mediated tumor clearance. (A) Various SASP factors recruit natural killer (NK) cells, macrophages, and neutrophils to the site of tissue damage, resulting in the clearance of both senescent and cancerous cells. (B) Various SASP factors recruit macrophages and monocytes, as well as cytotoxic CD4+ T cells. Macrophages and monocytes can activate these T cells, which then kill senescent and cancer cells.
Figure 3.
Figure 3.
Senescence-associated secretory phenotype (SASP)-mediated immune cell recruitment that favors tumor progression. The SASP has been described in various contexts to create an immunosuppressive environment that drives tumor progression. (A) In the liver, the SASP factor CCL2 acts to recruit immature myeloid cells. However, combined with tumor-secreted factors, CCL2 drives myeloid cells to block the maturation of macrophages and inhibit natural killer (NK) cell activity, resulting in uninhibited tumor growth. (B) In skin, the SASP factor IL-6 recruits Gr-1+ myeloid cells, regulatory T cells, and granulocytic and monocytic myeloid-derived suppressor cells (MDSCs), which reduce CD8+ T cell responsiveness. This immunosuppressive environment allows tumor cell proliferation. (C) In the prostate, the SASP recruits Gr-1+ myeloid cells, which secrete IL-1 receptor antagonist (IL-1RA). IL-1RA binds IL-1R, blocking IL-1-mediated SASP production necessary for the induction of paracrine senescence, thus allowing tumor growth.
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