Discovering the origins of cancer is a major goal for many scientists as knowing the origins can bring humanity closer to finding ways to prevent cancer. Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in the US. While it is known that most CRC starts as a polyp, there is still much left to be explored as far as what causes some polyps to develop into CRC. Many of the risk factors for CRC can be modified, such as physical inactivity, tobacco use, and consumption of red meat. One major risk factor that is impossible to modify is advanced age, but understanding aging-specific factors that affect CRC development may allow their manipulation for better outcomes.
The Grady lab (Clinical Research Division) published a study in the journal Aging Cell looking at how accumulation of senescent fibroblasts in the normal in the normal colon tissue increases CRC risk and promotes the development of CRC. Senescent cells are those that are still viable but no longer divide in response to a plethora of stresses including telomere shortening, oxidative stress, genotoxic stress or expression of oncogenes. Senescent cells can promote cancer through secreted proteins such as cytokines, chemokines, and growth factors, in what is known as senescent-associated secretory phenotype (SASP).
To determine whether there is a correlation between senescent fibroblasts in the colon and risk for CRC, the authors assessed normal human colon tissue samples from different risk groups. They found an increased number of senescent fibroblasts in individuals with advanced adenomas and CRC compared to those free of polyps.
The authors then used an ex vivo model to better study the potential tumorigenic effects of senescent fibroblasts in colon tissue. They set up a realistic ex vivo co-culture system composed of the primary fibroblasts and normal colon 3-D organoids, both directly from human patients, or colon adenoma and CRC cell lines. The authors observed senescent fibroblasts promoted oncogenic behaviors in normal colon organoids as well as in adenoma and CRC cell lines. Next, the authors analyzed the gene expression profiles of the colon fibroblasts to identify colon-specific SASPs. They found over one hundred up-regulated genes in the colon senescent fibroblasts, including a secreted protein known as growth differentiation factor 15 (GDF15). Previous studies revealed that GDF15 may be involved in promoting aggressive cancer behaviors. The researchers observed increased levels of GDF15 in the media of senescent fibroblast cultures as well as in the mucous membranes of human colons with CRC, further correlating its secretion from senescent fibroblasts and the transformation of colon cells into CRC. When they suppressed the expression of GDF15 with shRNA in senescent fibroblasts co-cultured with organoids, the oncogenic behaviors in the colon epithelial cells were significantly reduced in the co-culture system. The researchers further determined that the secreted GDF15 mediates these pro-oncogenic effects through the activation of ERK, p38 and PI3K signaling pathways in colon epithelial cells.
“This paper provides strong evidence that the accumulated senescent fibroblasts and their secretion of GDF15 creates a tumor-promoting tissue microenvironment,” said Jessica Ayers, a research technician in the Grady lab and one of the lead authors on the paper. “This work helps add to the field’s growing knowledge of the cellular mechanisms that mediate CRC risk with the goal of being able to develop novel strategies for colon cancer prevention.”
“One of the most compelling questions is the causes (or the stresses) in the at-risk colon that lead to the accumulation of senescent fibroblasts,” said Dr. Ming Yu, one of the senior authors on the paper and a Principal Staff Scientist in the Grady lab. “A variety of plausible mechanisms have been proposed, including advanced age, the increased oxidative stress from a diet rich in red meat, the genotoxic stress from gut microbiome, or the decline of the immune function in clearing the senescent cells in the colon. Exploring these intriguing mechanisms takes us to several paths of new and exciting research. Meanwhile, we are actively elucidating the function of candidate SASP factors other than GDF15 that were identified from this study, in the hope that they will give us novel insight into how the senescent-associated microenvironment in the colon contribute to colon cancer formation.”
This work was supported by the National Institutes of Health.
Fred Hutch/UW Cancer Consortium members Drs. Polly Newcomb, Christopher Li, and William Grady contributed to this research.
Guo Y, Ayers JL, Carter KT, Wang T, Maden SK, Edmonds D, Newcomb P P, Li C, Ulrich C, Yu M, Grady WM. Senescence-associated tissue microenvironment promotes colon cancer formation through the secretory factor GDF15. Aging Cell. 2019 Aug 6;:e13013. doi: 10.1111/acel.13013. [Epub ahead of print] PubMed PMID: 31389184.