The Role of Cancer Stem Cells in Colorectal Cancer: From the Basics to Novel Clinical Trials

Abstract

The treatment options available for colorectal cancer (CRC) have increased over the years and have significantly improved the overall survival of CRC patients. However, the response rate for CRC patients with metastatic disease remains low and decreases with subsequent lines of therapy. The clinical management of patients with metastatic CRC (mCRC) presents a unique challenge in balancing the benefits and harms while considering disease progression, treatment-related toxicities, drug resistance and the patient's overall quality of life. Despite the initial success of therapy, the development of drug resistance can lead to therapy failure and relapse in cancer patients, which can be attributed to the cancer stem cells (CSCs). Thus, colorectal CSCs (CCSCs) contribute to therapy resistance but also to tumor initiation and metastasis development, making them attractive potential targets for the treatment of CRC. This review presents the available CCSC isolation methods, the clinical relevance of these CCSCs, the mechanisms of drug resistance associated with CCSCs and the ongoing clinical trials targeting these CCSCs. Novel therapeutic strategies are needed to effectively eradicate both tumor growth and metastasis, while taking into account the tumor microenvironment (TME) which plays a key role in tumor cell plasticity.

Keywords: cancer stem cells; clinical trials; colorectal cancer; drug resistance.

Figure 1

Phenotypic sorting of CSCs through the expression of CSC markers recognized by antibodies coupled to either magnetic beads, MACS (1), or fluorochromes, FACS (2). Once the antibodies are added, the cell suspension is passed through either a MACS column in a magnetic field that retains the antibody-labeled cells (1) or through a flow cytometer that distinguishes and isolates labeled cells from unlabeled cells (2). CSC: cancer stem cell; MACS: magnetic-activated cell sorting; FACS: fluorescence-activated cell sorting.

Figure 2

Functional sorting of CSCs due to their specific properties such as enhanced detoxification (1), ALDH (1a) and SP (1b), in vitro self-renewal and differentiation capacity, colony- (2) and sphere-forming (3) assays, and the ability to form tumors in vivo, tumorigenicity assay (4). CSC: cancer stem cell; ALDH: aldehyde dehydrogenase; SP: side population.

Figure 3

Biophysical sorting of CSCs according to their size, density, shape and rigidity using the SdFFF technique, which does not require cell labelling or fixation. The SdFFF is composed of a pump (1) to transport the mobile phase (PBS) and the cells, an injector (2) to introduce the cell suspension, a motor (3) to rotate the separation channel (4) and a detector (5) coupled to a computer to obtain the elution profile of the cell suspension (6). Psi is a common unit of pressure. CSC: cancer stem cell; SdFFF: sedimentation field-flow fractionation; PBS: phosphate-buffered saline; Abs: absorbance.

Figure 4

Major mechanisms of anticancer drug resistance attributed to CSCs such as changes in drug transport (1); impaired drug metabolism (2); alterations in drug targets (3); enhanced DNA damage repair (4); impaired balance between apoptosis and survival pathways (5); and the role of the tumor microenvironment comprising cellular and non-cellular components (6). CSC: cancer stem cell; DNA: deoxyribonucleic acid.