Year: 2014
Type: dissertation
Abstract: Cancer-associated fibroblasts (CAFs) comprise a proponent compartment of the tumor microenvironment and are implicated in tumor progression. Local invasion and tumor-budding formation, i.e. detachment of individual cancer cells from the tumor invasion front, are regulated by CAFs and the desmoplastic stroma. Given accumulative evidence that such cells have undergone dedifferentiation and have acquired stem-like properties, it was hypothesized that they may be subjected to epithelial-to-mesenchymal transition (EMT) in a context-dependent manner. This thesis attempts to identify and characterize the contextual signals originating from the adjacent CAF population, responsible for mediating these malignant phenomena.Colorectal cancer was opted as model system to address these questions. Co-cultures mimicking the colorectal cancer desmoplastic tumor-host cell interface were generated. Mass spectrometry-based proteomic methods and bioinformatics pipelines were deployed to draw comprehensive signatures of growth factors/mediators secreted in these cocultures, with potential of regulating EMT in neoplastic invasive margins. Given previously-established, tumor-suppressive roles of the BMP pathway, a group of bone morphogenetic protein (BMP) antagonists, namely GREM1, FST and HTRA3, demonstrated attractive candidacy as potential EMT mediators. Using in vitro assays, this thesis further provided experimental insights that antagonist-dependent disruption of the BMP pathway induces enhanced motility and triggers mesenchymal phenotype switching in colon cancer cells. Finally, this thesis provided translational impact of these results in colon cancer patients. BMP antagonists, especially HTRA3 and GREM1, were overexpressed in desmoplastic stromata with tumor budding presence, and their expression significantly correlated with increased tumor-budding score. Additionally, GREM1 was more prominently expressed in invasion fronts with nuclear versus membranous beta-catenin expression.Overall, the data provided here support a working model, whereby contextual BMP antagonism may drive EMT, local invasion and de novo formation of tumor buds from the desmoplastic invasion front. Unraveling this axis thoroughly might be critical for clarifying pharmaceutical opportunities and proposing targeted strategies to manipulate metastasis.
Source: TSpace (University of Toronto)
Author: Georgios Karagiannis
Language: English
Topic: Cancer Cells and Metastasis
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2734749976