According to the latest statistics from the National Cancer Institute, more than 60% of cancer patients are 65 or older and the median age at diagnosis is 66. In fact, age is the largest risk factor for developing most common cancers. During our daily lives we are exposed to carcinogens, such as UV radiation from sun exposure, tobacco smoke and car pollution, hot drinks, alcohol, overeating, and viruses. While our bodies have a tremendous capacity to heal and repair damage, these processes are not perfect. Over time, cells can acquire mutations that change their ability to grow and divide, leading to the development of cancer.
In addition to age-related mutations and epigenetic changes, our bodies also accumulate senescent cells. Cellular senescence is a state of irreversible cell cycle arrest, characterized by cellular enlargement and flattening, and increased cellular vacuoles, organelles important for storing and processing cellular waste molecules. Like programmed cell death (apoptosis), senescence is a built-in tumor suppressor mechanism that can be activated when a cell suffers an oncogenic insult, preventing the mutated cell from replicating and potentially forming a tumor. There is another aspect of senescence that is important in cancer formation. While senescent cells no longer divide, they are still metabolically active and can modulate cells in their surrounding tissue microenvironment by secreting signaling molecules, such as cytokines, in a process known as the senescence-associated secretory phenotype (SASP). Many of these SASP factors activate the immune system and it is thought that senescent cells in the tissue microenvironment may contribute to cancer by inducing chronic inflammation.
So even though senescent cells are not themselves directly forming tumors, Fred Hutch investigators Drs. Namita Hattangady, Ming Yu, and William Grady are seeking to better understand how SASP factors may cause cancer and how to prevent them from doing so. Dr. Grady and his team are particularly interested in understanding the association between aging, senescence, and colorectal cancer (CRC). CRC is the third most common cancer in United States with ~150,000 new cases each year and patients have a median age at diagnosis of 68. The Grady lab previously showed that patients with CRC have an increased number of senescent fibroblast cells in normal healthy tissue adjacent to their tumors. “We believed a better understanding of the colon fibroblast SASP and their effects on the cell polarization and function in the surrounding tissue microenvironment will lead to novel and effective CRC prevention and treatment strategies,” says Dr. Namita Ganesh Hattangady, first author on a follow-up story from the Grady Lab, recently published in Aging.
While the connection between SASP and cancer development has been known for some time, “SASP is heterogenous, cell-specific and inducer-specific, and the precise senescence profile of colon fibroblasts has not been well-defined,” says Dr. Hattangady, first author on the study. “To fill this gap in knowledge, we induced senescence in primary human colon fibroblasts in vitro using various stressors and analyzed the resulting transcriptome. We uncovered a core senescent profile consisting of SASP factors that are commonly upregulated in all senescence induction methods and that might play a significant role in shaping the colon microenvironment.”
Their study identified and validated several potentially oncogenic SASP factors in human colon fibroblasts. However, the role of individual SASP genes on the surrounding tissue and tumor microenvironment remains unknown. “We wish to elucidate how SASP communicates with colorectal epithelial cells as well as immune cells to influence their polarization, recruitment, and function. We are conducting functional studies in both ex vivo and in vivo models to determine the role of senescent fibroblasts during CRC initiation and progression and whether senescence cell removal by senolytic drug treatment can prevent CRC,” says Dr. Hattangady. “We have observed an enrichment of SASP factors in colon cancer precancerous tissues using spatial transcriptomics. We are currently expanding these studies to identify the role of our newly identified colon fibroblast ‘Core SASP’ in cancer and pre-cancer settings. Our goal is to identify key features or targets that may be used towards generating biomarkers or therapies to prevent cancer formation and progression.”
The spotlighted research was supported by the National Institutes of Health/National Cancer Institute, the Listwin Family Foundation, the Cottrell Family Fund, R.A.C.E. Charities, and the Interdisciplinary Training Grant in Cancer Research.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium member Dr. William Grady contributed to this work.
Hattangady NG, Carter K, Maroni-Rana B, Wang T, Ayers JL, Yu M, Grady WM. (2024) Mapping the core senescence phenotype of primary human colon fibroblasts. Aging 6(4):3068-3087.