Proteomic Identification of Mediators Implicated in the Metastatic Progression of Ovarian Cancer
Year: 2015
Type: dissertation
Abstract: Ovarian cancer (OvCa) is the leading cause of death among gynecological malignancies, and is characterized by peritoneal metastasis and increased resistance to chemotherapy. Acquired drug resistance is often attributed to the formation of multicellular aggregates (MCAs) in the peritoneal cavity, which seed abdominal surfaces, particularly, the mesothelial lining of the peritoneum. Given that the presence of metastatic implants is a predictor of poor survival, a better understanding of the underlying biology surrounding OvCa metastasis may lead to the identification of key molecules that are integral to the progression of the disease, which therefore, may serve as practicable therapeutic targets. To that end, in vitro cell line models of cancer-peritoneal interaction and aggregate formation were used to identify proteins that are differentially expressed during cancer progression, using mass spectrometry-based approaches. First, we performed a proteomics analysis of a co-culture model of ovarian cancer and mesothelial cells, in which we identified numerous proteins that were differentially regulated during cancer-peritoneal interaction. We further validated one protein, MUC5AC, and confirmed its expression at the cancer-peritoneal interface. Next, we conducted a quantitative proteomics analysis of a cell line grown as a monolayer and as MCAs. After identifying a subset of overexpressed proteins, we determined that CLCA1 plays a role in MCA formation. Additional studies using a CLCA1 blocker, as well as siRNA knockdown of CLCA1 in OvCa cells, resulted in a decreased ability of cancer cells to aggregate, a reduced ability to adhere to extracellular matrix components, and decreased cell viability. Moreover, we demonstrated that CLCA1 is able to regulate MUC5AC expression, as CLCA1-knockdown cells exhibited reduced expression of MUC5AC. In summary, the research presented in this thesis adds to our current understanding about ovarian cancer progression, and identifies two proteins that play a role in OvCa progression, which may serve as novel therapeutic targets.
Source: TSpace (University of Toronto)
Author: Natasha Musrap
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2566187824