Tumor-stroma interaction in esophageal cancer

Medientyp: E-Book

Titel: Tumor-stroma interaction in esophageal cancer

Beteiligte: Lux, Martin [Verfasser]; Laßmann, Silke [Akademischer Betreuer]; Laßmann, Silke [Sonstige]; Reinheckel, Thomas [Sonstige]

Körperschaft: Institut für Klinische Pathologie ; Albert-Ludwigs-Universität Freiburg, Fakultät für Biologie

Erschienen: Freiburg: Universität, 2022

Umfang: Online-Ressource

Sprache: Englisch

DOI: 10.6094/UNIFR/225402

Identifikator:

Schlagwörter: Krebs ; Speiseröhrenkrebs ; Carcinogenese ; Esophageal cancer ; Tumor microenvironment ; Cancer-associated fibroblast ; Organotypic culture ; (local)doctoralThesis

Entstehung:

Hochschulschrift: Dissertation, Universität Freiburg, 2021

Anmerkungen:

Beschreibung: Abstract: The tumor microenvironment (TME) plays a decisive role in the pathogenesis of esophageal cancer – highly aggressive tumors of the esophageal tube, and the 6th most common cause of cancer-associated deaths worldwide. Fibroblasts are a major component of the TME and have been reported to contribute to the development and progression of many cancers at all stages. However, in esophageal cancer, the role of fibroblasts within the TME remains to be elucidated. The aim of this study was to investigate how fibroblasts affect esophageal tumor cell progression and to identify involved secreted factors. For this, primary case-matched normal esophageal fibroblasts (NOFs) and cancer-associated fibroblasts (CAFs) were co-cultured with esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cell lines. In 2D migration experiments (ibidi), there was indication for NOFs to inhibit esophageal tumor cell migration, whereas CAFs significantly increased the migration of KYSE-410, OE21 and OE33 cells. Cytokine profiling and whole secretome analyses of fibroblast-conditioned medium revealed in total six secreted factors as potential migration targets; two NOF-associated/tumor suppressive (BECN1, ESM1) and four CAF-associated/tumor supportive (CYTL1, IL6, IL8 and TIMP1). In combinatory siRNA knockdown/ibidi migration experiments, the mRNA expression of individual targets was manipulated (in fibroblasts) to investigate the influence on co-cultured KYSE-410 tumor cells. By this, IL6 and TIMP1 were identified as positive regulators of ESCC tumor cell migration. Furthermore, the interaction of fibroblasts and tumor cells was investigated in 3D organotypic culture models (OTC). Thereby, all cell lines morphologically resembled their tumor of origin (ESCC and EAC) and exhibited matrix invasion. Moreover, the invasiveness of tumor cells appeared to be more aggressive, when cultured on top of CAF-embedded matrices. Additionally, NOFs and CAFs were characterized at protein and mRNA level for a number of fibroblast activation markers (e.g. αSMA, FAP, TGFβ). Similar expression patterns recorded in both types of fibroblasts indicate that NOFs used in this study represent an activated fibroblast subtype, different in function (tumor-suppressive). In summary, this study demonstrates the influence of fibroblasts on esophageal cancer cells in 2D and 3D co-culture experiments. Conditioned media analyses by novel cytokine and quantitative secretome profiling revealed IL6 and TIMP1 as CAF-secreted factors, driving ESCC cell migration. Furthermore, NOFs were considered to represent an activated and so far unreported tumor-suppressive fibroblast subtype in esophageal cancer

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