PROJECT SUMMARY The rate of early onset colorectal cancer (EOCRC; <50 years of age at diagnosis)
continues to increase, even as CRC rates for individuals over 50 have been declining, largely as a result of
prevention by enhanced colonoscopic screening. Cancers diagnosed in younger patients tend to be more
distal/rectal, mucinous, poorly differentiated and diagnosed at an advanced stage, suggesting a rapid disease
progression. Although sporadic EOCRCs are less likely to show aneuploidy, BRAF mutations or CIMP, they are
otherwise similar at a molecular level to cancers in individuals greater than 50 years of age. Given the early
formation and rapid progression of EOCRC, it is likely that strong promotional factors are at play. Fibroblasts are
a key cell type in establishing a microenvironment conducive to cancer progression as they coordinate the
activities of epithelial, endothelial and immune cells in the tissue. Fibroblasts can exist in a number of distinct
states with dramatically different activities. Resident fibroblast in healthy tissue are non-dividing cells that help
establish tissue architecture and crypt cell dynamics. However, when adjacent to cancerous cells, fibroblasts
can become persistently activated as cancer-associated fibroblasts (CAFs) that promote tumor growth and
angiogenesis, 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 hypothesize that the underlying stroma advances rapidly in EOCRC to drive
early disease pathogenesis. Specifically, we propose that environmental and/or life-style factors cause aberrant
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, 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 approaches
that reduce this risk. We will study fibroblast populations in colonic lesions from patients under 45 and over 60
years old. Using a combination of laser-capture microdissection combined with targeted RNA expression
analysis and Imaging Mass CytometryTM, we will define the distinguishing set of molecular alterations characterize
define EOCRC cases. Our study population will include normal mucosa, preneoplastic tissue with activated
fibroblasts, advanced adenomas and CRCs. Overall, these studies will determine how a hyper-responsive “hot”
stromal microenvironment established by activated and/or senescent fibroblasts relates to other stromal events
that contribute to the rapid advancement of EOCRC. Once details of the activated fibroblast populations present
in these tissues is determined, long term studies would aim to determine how personal factors relate to their
appearance and how their activity might be mitigated to suppress CRC risk.