Research Paper Volume 16, Issue 4 pp 3068—3087
Mapping the core senescence phenotype of primary human colon fibroblasts
- 1 Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
- 2 Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
- 3 Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA 98195, USA
Received: May 16, 2023 Accepted: January 15, 2024 Published: February 21, 2024
https://doi.org/10.18632/aging.205577How to Cite
Copyright: © 2024 Hattangady et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Advanced age is the largest risk factor for many diseases and several types of cancer, including colorectal cancer (CRC). Senescent cells are known to accumulate with age in various tissues, where they can modulate the surrounding tissue microenvironment through their senescence associated secretory phenotype (SASP). Recently, we showed that there is an increased number of senescent cells in the colons of CRC patients and demonstrated that senescent fibroblasts and their SASP create microniches in the colon that are conducive to CRC onset and progression. However, the composition of the SASP is heterogenous and cell-specific, and the precise senescence profile of colon fibroblasts has not been well-defined. To generate a SASP atlas of human colon fibroblasts, we induced senescence in primary human colon fibroblasts using various in vitro methods and assessed the resulting transcriptome. Using RNASequencing and further validation by quantitative RT-PCR and Luminex assays, we define and validate a ‘core senescent profile’ that might play a significant role in shaping the colon microenvironment. We also performed KEGG analysis and GO analyses to identify key pathways and biological processes that are differentially regulated in colon fibroblast senescence. These studies provide insights into potential driver proteins involved in senescence-associated diseases, like CRC, which may lead to therapies to improve overall health in the elderly and to prevent CRC.
Abbreviations
SASP: Senescence associated secretory phenotype; CXCL-1,-2,-5,-8 and -14: C-X-C motif chemokine ligand 1, 2, 5, 8, and 14, respectively; MMP3 or MMP12: matrix metallopeptidase 3 and 12 respectively; CCL2, 5 and 20: C-C motif chemokine ligand 2, 5, and 20 respectively; CX3CL1: C-X3-C motif chemokine ligand 1; GDF15: growth differentiation factor 15; BMP2: bone morphogenetic protein 2; PLAT: plasminogen activator, tissue type; SERPINI1: serpin family I member 1; CST1: cystatin SN; CST 2: cystatin SA ; CST4: cystatin S; C3: complement C3; IGFBP2: insulin like growth factor binding protein 2; TNF: tumor necrosis factor; TNFSF13B/BAFF: TNF superfamily member 13b; TNFRSF10C: TNF receptor superfamily member 10c; NF-κB: nuclear factor kappa B; NOTCH3: notch receptor 3; NR4A2: nuclear receptor subfamily 4 group A member 2; FOSB: FosB proto-oncogene, AP-1 transcription factor subunit; RELB: RELB proto-oncogene, NF-kB subunit; STAT1: signal transducer and activator of transcription 1; STC1: stanniocalcin 1; cIAP1/2: Cellular Inhibitor of Apoptosis Protein 1/2; BIRC2: baculoviral IAP repeat containing 2; VCAM1: vascular cell adhesion molecule 1; CD40: CD40 molecule; RELB: RELB proto-oncogene, NF-kB subunit; KEGG: Kyoto Encyclopedia of Genes and Genomes.