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.

The drug-induced phenotypic landscape of colorectal cancer organoids

“…2 Tumor plasticity, as well as the stemness of neoplastic cells have been proposed as major factors in treatment resistance and tumor progression under antineoplastic therapies. 3,4 However, mechanisms behind these tumor cell states and drugs modulating or targeting them are not well understood.…”

Cancer Stem Cells and Their Vesicles, Together with Other Stem and Non-Stem Cells, Govern Critical Cancer Processes: Perspectives for Medical Development

“…Therefore, more in-depth knowledge and technology are still required to develop novel therapies. Moreover, novel strategies are needed to effectively eradicate both tumor growth and metastasis, while taking into account the TME, which plays a key role in tumor-cell plasticity [ 95 ]. At present, studies involving the engineering of stem cell therapies may ultimately induce the development of new agents employed for clinical practice.…”

“…For this, they intend to establish sources of cancer cell types and analyze their diseases. It will be important to identify animal models that are appropriate for the initial experiments and that are essential for future studies based on toxicities and pharmacological investigations [ 95 ]. The manufacturing of molecules will then be started, also keeping in mind the number of potential patients considered.…”

Tribbles Pseudokinases in Colorectal Cancer

“…The generation of in vivo knock-out models using CRISPR technology would certainly contribute to decipher the role of each Tribble isoform in CRC development. On the other hand, colon cancer stem cells (CCSC) have been associated with patient relapse and chemoresistance, with diverse molecular mechanisms involved [ 105 ]. Importantly, high Tribbles levels have been linked with quiescent stem cell population, at least in hematopoietic diseases [ 106 ].…”