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Dr. Daniel W. Rosenberg and his project Co-Investigators are conducting a research study called "Mechanisms of Early Onset Colorectal Cancer" to examine the composition of cells that line the colon wall. Specifically, they will focus on fibroblasts, which are responsible for producing the structural framework (stroma) of connective tissue and coordinating the activities of epithelial, endothelial and immune cells in the tissue. Background & Hypothesis: Fibroblasts can exist in a number of distinct states with dramatically different activities. Resident fibroblasts in healthy tissue are non-dividing cells that help establish tissue architecture and crypt cell dynamics. However, when they are present adjacent to cancerous cells, fibroblasts can become persistently activated as cancer-associated fibroblasts (CAFs), promoting tumor growth and new blood vessel growth, while suppressing immune responses. CAFs can also become senescent and acquire an irreversible senescence-associated secretory phenotype (SASP) that establishes a "permanent" cancer-promoting microenvironment. We propose that the underlying stroma advances rapidly in EOCRC to drive early disease development. Specifically, we speculate that environmental and/or life-style factors cause abnormal fibroblast activation that negatively impacts the normal function of immunoregulatory cells within the stroma, while promoting epithelial cell division. The exploratory experiments proposed here will assess fibroblast proliferation (rapid division of cells), activation and senescence at different stages of cancer development in young patients. Understanding fibroblast dysregulation in individuals at risk of EOCRC could provide important information for understanding the factors responsible for the increasing incidence of EOCRC and ultimately point to therapeutic approaches that reduce this risk. Study Design: This study will screen 100 men or women between the ages of 30-45 years who are scheduled to undergo a routine screening or surveillance colonoscopy. Only patients found to have significant polyps, or healthy control patients, will be included in the final study population. A total target enrollment of 20 subjects (10 subjects found to have significant polyps; 10 healthy (no polyps) sex-matched controls) will fulfill this study's requirements. Main Outcome Measures/Analyses: 1) Study fibroblast populations resected near colonic lesions, 2) Classify fibroblast cell-types from colonic biopsies; Identify activated and senescent fibroblasts, 3) Define the distinguishing set of molecular alterations that characterize EOCRC cases, 4) Determine how a hyper-responsive stromal microenvironment established by activated and/or senescent fibroblasts relates to other stromal events that contribute to the rapid advancement of EOCRC.
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