SASP-Dependent Interactions between Senescent Cells and Platelets Modulate Migration and Invasion of Cancer Cells.

Claudio A Valenzuela,Angel Cayo,Nelson E Brown,Rodrigo Moore-Carrasco,Alexandra Olate-Briones,Whitney Venturini,Ricardo Quintanilla,Daniel Mancilla

doi:10.3390/ijms20215292

Claudio A Valenzuela, Angel Cayo + Show 6 more

Open Access

https://doi.org/10.3390/ijms20215292

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Abstract

Alterations in platelet aggregation are common in aging individuals and in the context of age-related pathologies such as cancer. So far, however, the effects of senescent cells on platelets have not been explored. In addition to serving as a barrier to tumor progression, cellular senescence can contribute to remodeling tissue microenvironments through the capacity of senescent cells to synthesize and secrete a plethora of bioactive factors, a feature referred to as the senescence-associated secretory phenotype (SASP). As senescent cells accumulate in aging tissues, sites of tissue injury, or in response to drugs, SASP factors may contribute to increase platelet activity and, through this mechanism, generate a microenvironment that facilitates cancer progression. Using in vitro models of drug-induced senescence, in which cellular senescence was induced following exposure of mammary epithelial cells (MCF-10A and MCF-7) and gastric cancer cells (AGS) to the CDK4/6 inhibitor Palbociclib, we show that senescent mammary and gastric cells display unique expression profiles of selected SASP factors, most of them being downregulated at the RNA level in senescent AGS cells. In addition, we observed cell-type specific differences in the levels of secreted factors, including IL-1β, in media conditioned by senescent cells. Interestingly, only media conditioned by senescent MCF-10A and MCF-7 cells were able to enhance platelet aggregation, although all three types of senescent cells were able to attract platelets in vitro. Nevertheless, the effects of factors secreted by senescent cells and platelets on the migration and invasion of non-senescent cells are complex. Overall, platelets have prominent effects on migration, while factors secreted by senescent cells tend to promote invasion. These differential responses likely reflect differences in the specific arrays of secreted senescence-associated factors, specific factors released by platelets upon activation, and the susceptibility of target cells to respond to these agents.

Highlights

Cellular senescence is a unique form of irreversible cell cycle arrest characterized by specific changes in gene expression, morphology, and function [1,2]
In order to examine the effects of senescence-associated secretory phenotype (SASP) factors on platelet aggregation, we first optimized the experimental conditions for drug-induced senescence in three cellular systems, namely, human gastric cancer cells (AGS), immortalized mammary epithelial cells (MCF-10A), and breast cancer cells (MCF-7)
In order to assess the expression of SASP factors in Palbociclib-induced senescent cells, we selected 16 factors on the basis of their previously documented capacity to directly or indirectly affect platelet aggregation or the fibrinolytic system

Summary

Introduction

Cellular senescence is a unique form of irreversible cell cycle arrest characterized by specific changes in gene expression, morphology, and function [1,2]. Proliferative arrest in senescent cells is associated with activation of the p53–p21KIP1/CIP1 and/or p16INK4A–pRB tumor suppressor pathways [8,9] As these pathways are commonly disrupted in cancer cells, cellular senescence has traditionally been considered a potent failsafe program that prevents the development of cancer by limiting aberrant proliferation of preneoplastic cells [10]. Besides these in vitro features of senescent cells, several lines of evidence point to the existence of functionally distinct types of senescence in vivo. The elimination of senescent cells in aging mice increases the health span and reduces the consequences of age-related pathologies or chemotherapy [20,21]

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