Epithelial-Mesenchymal Transition Induced by Senescent Fibroblasts

Abstract

Depending on the cell type and tissue environment, epithelial and mesenchymal cell phenotypes are not static and can be highly dynamic. Epithelial-mesenchymal transitions (EMTs) and reverse EMTs provide flexibility during embryogenesis. While EMTs are a critical normal process during development and wound healing, properties of the EMT have been implicated in human pathology, particularly cancer metastasis. A normal undamaged epithelium does not typically exhibit features of an EMT. However, particularly under the influence of the surrounding microenvironment, cancer cells may reactivate developmental phenotypes out of context in the adult. This reactivation, such as the EMT, can facilitate tumor cell invasion and metastasis, and therefore is a major mechanism of tumor progression. Conversely, cellular senescence, which is associated with aging, is a process by which cells enter a state of permanent cell cycle arrest, thereby constituting a potent tumor suppressive mechanism. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescenceassociated secretory phenotype (SASP) that turns senescent fibroblasts into pro-inflammatory cells having the ability to promote tumor progression, in part by inducing an EMT in nearby epithelial cells. Here, we summarize the potential impacts of SASP factors, particularly interleukins, on tissue microenvironments and their ability to stimulate tumor progression through induction of an EMT.

Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells

“…SASPcontaining CM from senescent fibroblasts stimulated 3.5-fold more invasion than CM from non-senescent fibroblasts, and apigenin reduced this stimulation to non-senescent levels. Consistent with this finding, apigenin suppressed the ability of the SASP to induce an epithelial-mesenchymal transition (EMT) and confer on epithelial cells their invasive and metastatic properties, which is an important step during cancer progression (Laberge et al 2012b). By immunofluorescence (Fig.…”

SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells

“…We show here, for the first time, that pemetrexed treatment of mesothelioma cell lines and primary MPM cells readily induces a senescent phenotype with features of SASP (Coppe et al, 2010) (Figure 1). SASP consists of premature senescence and secretion of a complex mix of cytokines, chemokines and growth factors (Laberge et al, 2011). We show that treatment of naive MPM cells with CM derived from pemetrexed-treated MPM cells promotes the emergence of mesenchymal-like, chemoresistant cell subpopulations endowed with high levels of ALDH activity (ALDH bright cells).…”

“…In addition, genotoxic stress and oncogene expression promote a complex senescence leading to the secretion of cytokines and pro-mitogenic factors, named SASP (senescenceassociated secretory phenotype; Rodier et al, 2005;Young and Narita, 2009;Coppe et al, 2010;Laberge et al, 2011). SASP-induced chemokines are known to induce EMT (epithelial-to-mesenchymal)-like changes in neighboring cell populations, and this may be considered as a mechanism of tumor progression (Laberge et al, 2011). However, it is not entirely clear whether SASP signaling can impinge on the progression of the neoplastic disease by modulating chemoresistance and tumor-initiating-activity.…”

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

“…Mechanistically, we speculate that DNA damage signaling from therapy-induced recurrent and/or persistent DNA lesions (e.g. from senescent cells 65 ) may promote the observed phenotypic switch via the ATM-induced cytokine network 66 including TGFb family members that can shape the phenotype of treated cancer cells toward EMT and stem cell enrichment in a paracrine manner. Finally, we suggest that such treatment resistance (see Supplementary Figure 7) could be overcome, and that the dependency on signaling cascades we report here reveal vulnerabilities potentially exploitable in cancer treatment.…”