Novel Therapeutic Approaches Targeting Colorectal Cancer Stem Cells

Abstract

As a complex and multifaceted disease, cancer is a disease of the genomic abnormality which consequently represented as an aberrant cellular adaptation to uncontrollable and dynamic intracellular and intercellular stimuli. In this vein, cancer stem cells (CSC) play a pivotal role throughout all stages of tumourigenesis, which allows outrageous cell population to overcome multiple environmental hurdles and acquire refractoriness to successfully survive and manifest themselves in distant organs. This process necessitates ongoing reprogramming of gene expression in order for tumours to adapt to varied settings, which is a unique feature of CSCs. CSCs are a minor subpopulation of tumour cells that are capable for self-renewal and multi-lineage differentiation. The most clinically relevant trait of CSCs is their ability to metastasise and escape from standard chemotherapy. Understanding the molecular mechanisms that participate to the CSC phenotype is critical to designing improved cancer therapeutics. Herein, two different therapeutic strategies targeting CSC were investigated. In part 1, I propounded a therapeutic approach of interrupting CSC-enhanced survival signalling by disrupting lipid raft, a critical signalling platform of cells to survive. Empirically, miltefosine, alklyphospholipid drug, treatment was deemed to efficiently inhibits CSC survival and alleviate therapy resistance in colorectal cancer (CRC) via mechanistically altering LR/CHEK1 axis, releasing cell cycle checkpoints and driving the inappropriate mitotic entry in the presence of unresolved DNA damage accumulation, thus inducing catastrophic cell death, preferentially in CSCs. In part 2, I intended to target a CSC-specific marker, DCLK1. As the exact molecular mechanism by which DCLK1 drives the aggressive phenotype of cancer cells is incompletely determined, I performed comprehensive genomics and proteomics analyses to identify binding proteins of DCLK1 to elucidate mechanistic view of DCLK1 downstream signalling. Experimentally, I was able to propose DCLK1/XRCC5/COX2 axis which consequently induces PGE2 production to eventually mediates the pro-inflammatory function of CSCs. Collectively, these two distinctive approaches of targeting CSCs provides a mechanistic insight of remained ambiguous aspects of novel subpopulation which is known to be in charge of metastasis and therapy resistance as well as a new preclinical rationale to broaden the clinical evaluation of CSC-specific targeting strategies for CRC treatment.