Differential Effects of KIM-1 in Subcutaneous and Orthotopic Renca Models of Kidney Cancer
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.