Esophageal Extracellular Matrix Hydrogel to Restore Dysregulated Microenvironment-Cell Signaling for Treatment of Pre-Malignant and Neoplastic Esophageal DiseaseSaldin, Lindsey/T (2019) Esophageal Extracellular Matrix Hydrogel to Restore Dysregulated Microenvironment-Cell Signaling for Treatment of Pre-Malignant and Neoplastic Esophageal Disease. Doctoral Dissertation, University of Pittsburgh. (Unpublished)
AbstractEsophageal adenocarcinoma (EAC) has a 20% five-year survival rate, and the standard of care esophagectomy has a 20% mortality and 50% morbidity. EAC pathogenesis involves dysplastic and metaplastic changes within the mucosa in response to dysregulated microenvironmental cues, i.e., gastric reflux and chronic inflammation. Extracellular matrix (ECM) is a primary component of the microenvironment that influences cell phenotype through dynamic reciprocity. ECM bioscaffolds have been used to treat 14 EAC patients after mucosal resection resulting in preservation of esophageal function, restoration of a near normal mucosa, and no recurrence of cancer for 1-8 years. The implanted ECM bioscaffolds completely degraded within 2 weeks, suggesting that the ECM degradation products normalized cell phenotype in the post-cancer resection niche. ECM bioscaffolds can be digested by pepsin in vitro to simulate ECM degradation products, and furthermore these degradation products can be formulated as a hydrogel for clinical therapy. The objectives of the present dissertation were to determine the effects of solubilized non-malignant, metaplastic, and neoplastic esophageal ECM upon macrophage activation and epithelial cell function, to further understand the role of ECM-cell crosstalk in EAC progression. Solubilized, non-malignant ECM hydrogel was evaluated for its potential to mitigate diseased esophageal epithelial cells in vitro and in vivo. Metaplastic and neoplastic ECM contained distinctive matrix-bound nanovesicle (MBV) miRNA cargo and ECM protein signatures that activated macrophages toward a pro-inflammatory, TNFalpha+ state, and increased epithelial cell migration. Non-malignant esophageal ECM (eECM) hydrogel downregulated cancer cell proliferation and signaling pathways (e.g., PI3K-Akt, cell cycle/DNA replication), with a minimal effect on normal esophageal epithelial cells. eECM hydrogel treatment mitigated macroscopic esophagitis, regressed Barrett’s epithelium toward normal squamous epithelium, and downregulated the pro-inflammatory TNFalpha+ cell infiltrate in a pre-clinical, large animal model of Barrett’s esophagus. Similar results were seen with eECM hydrogel treatment in an in vivo rodent model of EAC. Finally, practical aspects of the clinical translation of eECM hydrogels were determined. eECM hydrogel mechanical properties can be tailored to facilitate oral, endoscopic, or submucosal injection delivery. Taken together, we conclude that eECM hydrogel is a suitable therapy for esophageal disease based upon the accepted concepts of cell-matrix interactions. Share
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