*1.6. The Role of Senescence and the Senescence Associated Secretory Phenotype (SASP) in the Pathogenesis of ACP*

In the normal physiological state, cellular senescence develops in response to both extracellular and intracellular stressors and pushes the cell into cell cycle arrest. This prevents propagation of the damaged cell and, when this occurs in the context of cancer, can ultimately result in tumor suppression [53]. Paradoxically, senescent cells can go on to develop secretory functions that result in changes to the cellular microenvironment and may ultimately promote tumor growth [53]. Senescent cells can persist in a metabolically active state, ultimately developing what is termed the Senescence Associated Secretory Phenotype (SASP) [53]. In such a state, cells can secrete a variety of interleukins, inflammatory cytokines, growth factors, and proteases, which can affect the surrounding cells and tumor microenvironment. SASP factors include pro-inflammatory mediators such as IL-6, IL-1, certain Matrix Metalloproteinases, and various chemokines [53,54]. Of these, Rodier et al. [54] found that IL-6 was the most important in allowing senescent cells to promote cell invasion. Gonzalez-Meljem et al. [55] demonstrated that the SASP plays a prominent role in both genetically engineered mouse models of ACP and human ACP. They used gene set enrichment analysis (GSEA) to demonstrate that beta-catenin accumulating cluster cells in the mouse models of ACP had gene expression profiles that were significantly enriched for SASP genes. Similarly, they utilized ELISA cytokine arrays to demonstrate that multiple SASP associated proteins such as IL-6, IL-1a, MMP2, MMP3, CXCL1, and CXCL11 were all upregulated in the murine cluster cells [55]. In addition, other studies, such as those by Gump et al. [11], and Apps et al. [10], used various techniques to demonstrate the overexpression of several of these proteins in human ACP. Meljem et al. [55] then used laser-capture microdissection and RNA sequencing to analyze the molecular signature of the beta-catenin accumulating cell clusters in human ACP. They performed hierarchical clustering analysis that demonstrated similar molecular profiles between the cluster cells from the mouse models and those from human ACP. Subsequent GSEA of human clusters also demonstrated a strong SASP signature. They thus concluded that the human and mouse clusters represent equivalent structures and share a common senescent molecular signature. Given the critical role that these cell clusters are thought to play in ACP tumorigenesis, they posited that the SASP may play a critical role in the pathogenesis of ACP [55]. This paper aimed to demonstrate the critical role played by inflammation in the pathogenesis of ACP. Given that human ACPs seem to harbor a very strong SASP signature and the SASP induces a strong pro-inflammatory state, it is very possible that the SASP plays a critical role in producing the pro-inflammatory milieu and invasive nature of ACP. Trials examining the use of senolytic drugs are currently in their incipient stages and it is possible that such therapies may provide an attractive treatment strategy for ACP in the future [56].
