Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Gunaratnam, Lakshman

Abstract

Renal Cell Carcinoma (RCC) is the most common and fatal type of kidney cancer. Over 30% of patients that are diagnosed with RCC exhibit metastases. Almost 88% of patients with distant metastases succumb to the disease within 5 years of diagnosis. Kidney Injury Molecule-1 (KIM-1) is a cell surface glycoprotein that is not expressed in a healthy kidney but becomes highly expressed on proximal tubular epithelial cells (PTECs) following injury. Data from the Cancer Genome Atlas (TCGA) reveals that >90% of RCC tumours express KIM-1 mRNA and that higher expression levels correlate with increased overall survival rates of patients. The pathophysiological role of KIM-1 in RCC is not well understood. Using human (786-O) and murine (RENCA) models, we recently uncovered that KIM-1 may inhibit the metastatic properties (invasion and extravasation) of RCC cells using in vivo and in vitro systems. The aim of this thesis work was to elucidate the mechanism by which KIM-1 regulates RCC tumour progression using syngeneic and pre-clinical orthotopic RENCA models.

Transcriptomic analysis of RENCA cells lacking or overexpressing KIM-1, and The Cancer Genome Atlas (TCGA), revealed significant upregulation of genes involved in extracellular matrix (ECM) interactions in association with KIM-1 expression. In vivo, subcutaneous implantation of RENCA tumours resulted in the development of thick, collagen dense, stromal capsules surrounding the tumours. This was observed in both immune-competent and immune-deficient mice. In a pre-clinical (orthotopic) model, KIM-1 expression inhibits primary RENCA tumour growth within the kidneys. Lastly, significant phenotypic differences in primary tumour growth, and histology were observed in between subcutaneous and orthotopic implantation of RENCA tumours.

Summary for Lay Audience

Kidney cancer comprises almost 4% of all adult malignancies and is the 8th most common type of cancer in humans. Renal Cell Carcinoma (RCC) is the most common and lethal type of kidney cancers. RCC is most lethal when it spreads to distant sites because it is resistant to many forms of anti-cancer therapy including chemo-, radio- and even modern immunotherapies. Over one third of patients have cancer that has spread at the time of diagnosis. Kidney Injury Molecule-1 (KIM-1) is a normal protein that is found in injured human kidneys and is aberrantly present in over 90% of RCC tumour samples obtained from cancer patients. Patients whose tumours have high amounts of KIM-1 seem to survive longer (due to cancer spread likely) but the reason for this is not known. The objective of my thesis was to determine how KIM-1 may protect patents with RCC from dying using genetic techniques and animal models of kidney cancer.

My work suggests that the role of KIM-1 in RCC greatly depends on the tumour model used. Overall, KIM-1 may protect patients with RCC by slowing the growth of tumours, and potentially, the spread of cancer cells to distant sites from the primary tumour. Our genetic studies suggest that KIM-1 may achieve this by altering the genes produced by the kidney tumours to produce a thick, collagen dense “capsule” around them. Further studies of these “protective” genes may help us to develop treatments for patients with RCC and potentially other cancers.

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