More than 570,000 new cases of esophageal cancer are estimated to be diagnosed annually worldwide. Risk factors include gender, age, tobacco use and dietary habits leading to tissue injury and ultimately cancer. While prognoses for other cancers have improved, the 5-year survival for patients with esophageal cancer is only 20%. During the repair process, cell proliferation is increased and is associated with inflammation. Slow-cycling lifetime residential stem cells, called quiescent cells, facilitate repair but are thought to accumulate mutations during DNA replication eventually giving rise to cancer. We hypothesize that esophageal stem cells become activated upon injury and are regulated by Transforming Growth Factor beta 1 (TGFβ1), a known regulator of cell proliferation and differentiation. We established an in vitro model of quiescence using normal esophageal epithelial (STR) and oral (OKF6) cells treated with recombinant human TGFβ1. Flow cytometry showed increases in cells arrested in G1/G0 phase of the cell cycle in TGFβ1 treated cells for both cell lines (STR p < 0.01, OKF6 p < 0.05). EdU (5-ethynyl-2'-deoxyuridine) positive recovery cells indicated quiescence in both cell lines (p < 0.01). Analysis of TGFβ1 regulation of putative stem cell markers via western blot and qRT-PCR showed increases in ITGB1, PDPN and K15 as well as XPC, and MeCP2 in treated cells. To apply our in vitro findings, we performed immunohistochemistry staining on tissue microarrays. Proliferation marker Ki67 increased in disease progression from normal to inflammation to hyperplasia (p < 0.001) while TGFβ1 target markers decrease. Our data indicate that the onset of cancer-associated inflammation correlates with the loss of TGF?1 mediated stemness markers and increased basal proliferation suggesting cancer is a stem cell disease.
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Master of Science (M.S.)
College of Medicine
Length of Campus-only Access
Masters Thesis (Campus-only Access)
Troia, Alexandra, "Investigating Changes in Quiescence in Oral and Esophageal Epithelium in Response to Injury" (2019). Electronic Theses and Dissertations. 6808.