The role of extracellular matrix in tumor progression and treatment response

Abstract

Due to inherent or acquired therapeutic resistance, Oral carcinoma and ovarian cancer (OC) are both considered to have a poor five-year survival rate with a high prevalence rate. Most patients are treated employing a platinum-based drug, carboplatin. However, 80% of patients will still develop recurrences due to chemotherapy resistance. Oral squamous cell carcinoma (OSCC)'s gold standard of treatment is primary surgical resection, with or without ionised radiation. This aggressive tumour has exhibited limited improvement in its prognosis in the last few decades. The tumour's microenvironment (TME) plays a role in the tumour’s survival and resistance to treatment. It comprises a specialized cellular component and a non-cellular component, the latter called the extra-cellular matrix (ECM). Cancer cells and their ECM constantly remodel while interacting dynamically, impacting drug transport, and signalling pathways and leading to tumour cell survival and resistance. The diverse makeup of the cancer cell in conjunction with ECM dynamics makes it difficult to combat therapy resistance. In this study, we established a more reliable way to investigate the effect of ECM on therapy resistance, in both cancer cells, by generating cost-effective in-vitro study models. This thesis focused on:

• Investigating the effect of ECM on therapy response, particularly in oral and OC cells.

• Establishment of a novel 3D model targeting the study of cancers in the head and neck region, specifically oral cancer, while distinguishing the model from other pre-existing research models through analytical data.

• Establishment of an in-vitro model for CAF generation and extracting their secreted ECM for further study of the TME.

• Analyzing OC cells’ key response to differently sourced ECMs that can potentially lead to advanced targeted therapeutics.

• Utilizing the data achieved to forecast the model’s probable implications for better patient prognosis.