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

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.

Cancer Associated Fibroblasts and Senescent Thyroid Cells in the Invasive Front of Thyroid Carcinoma

“…To the best of our knowledge, no studies about senescent TC cells and CAFs are currently available. Some studies have assessed the interactions between senescent cells and other cell types as platelets [20] and immune cells [21]. In addition, our laboratory has recently described an interplay between senescent thyrocytes and macrophages [22].…”

Platelet Activation Is Triggered by Factors Secreted by Senescent Endothelial HMEC-1 Cells In Vitro

“…First described in human primary cells subjected to long-term culture [14], a similar phenotype can be triggered prematurely in response to various forms of stress, including genotoxic, oxidative, oncogenic and therapeutic stress [15]. Indeed, several anticancer drugs are capable of inducing cellular senescence in cancer cells, including conventional chemotherapeutic drugs (i.e., Doxorubicin) [16] and more recently developed CDK4/6 inhibitors [17,18]. Importantly, cellular senescence has also been described in developmental contexts, in the absence of stressful stimuli [19][20][21], and senescent cells accumulate in aging tissues and sites of tissue damage [19,20].…”

Clinical Significance of Systemic Inflammation Response Index and Platelet–lymphocyte Ratio in Patients with Adenocarcinoma of The Esophagogastric Junction and Upper Gastric Cancer

“…Nie et al [46] showed that expression of a large number of monocytes can inhibit the immune response of T cells near the tumor and promote immune escape of cancer cells by increasing cyclo-oxygenase-2 expression. Senescence-associated secretory phenotype interaction between platelets also plays an important role in metastasis and invasion of cancer cells [47]. Tumor occurrence, development and metastasis lead to changes in immune cells and in ammation in the tumor microenvironment, which would affect the circulating immune cells with disease progression.…”