Characterization of Tumour-initiating Cells in Human Colorectal Cancer

It has been hypothesized that tumours are caricatures of normal tissue organization, where a minority cell population, the ‘stem cell’ of cancer, holds the exclusive ability for tumour propagation. These cancer stem cells (CSCs), or tumour-initiating cells, possess extensive self-renewal ability, through which they ensure maintenance of the tumourigenic clone. Such cells have been identified in various cancers, including colorectal, and have been proposed to be the source of tumour re-initiation following therapy. An important and currently unanswered question in solid tumours is whether all CSCs are equal or whether there is a gradient of potency within the CSC compartment. Using primary human colon tumour cells and sensitive in vivo functional assays, we have determined that colon CSCs are not uniform; rather, they vary with respect to their proliferative capacity, which is also linked to their response to chemotherapy. These findings hold therapeutic implications for colorectal cancer treatment since all types of CSCs must be eradicated to remove the risk of tumour relapse. While the CSC model may provide attractive answers to some challenging questions, it remains controversial. Ascertaining the importance of CSCs will come from targeted CSC therapies. Here we demonstrate that human colorectal CSC function is dependent on the self-renewal regulator BMI-1. Down-regulation of BMI-1 inhibits the ability of colorectal tumour-initiating cells to self-renew resulting in the abrogation of their tumourigenic potential. Treatment of primary colorectal cancer xenografts with small molecule BMI-1 inhibitors resulted in colorectal tumour-initiating cell loss with long-term and irreversible impairment of tumour growth. Targeting the BMI-1 related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer. Collectively, we have advanced the CSC field in two areas of importance. We show for the first time that the CSC pool encompasses a gradient of proliferative potential linked to chemotherapeutic response. Second, we provide critical proof for the clinical relevance of CSCs by inhibiting tumour growth through targeting of the self-renewal machinery. This body of work significantly advances our understanding of colorectal tumour-initiating cells.Ph