Targeting Stem Cells in the Colorectal Cancer Microenvironment to Avert Drug Resistance in Pursuit of Novel Oncotherapies

Several studies have demonstrated the heightened prevalence of colorectal cancer (CRC) among young black men. Most of these men present with already metastasized CRC. Cancer stem cells (CSCs) play a pivotal role in CRC metastasis and drug resistance. The plasticity of CSCs promotes therapeutic resistance by continuously dividing into different phenotypes thwarting therapeutic targets. Phenotypic changes affect the expression of highly heterogeneous surface biomarkers. Identifying molecular and cell surface biomarkers is important for diagnosis, decision-making, and determining clinical outcomes. Furthermore, CSCs promote cancer initiation, development, advancement, relapse, and therapeutic resistance by altering the tumor microenvironment (TME). Cancer-favoring molecular signaling pathways may contribute to differentiating CSCs into TME components that create favorable conditions conducive to cancer progression. In turn, different TME components may differentially stimulate CSCs, prompting proliferation into diverse cancer cell phenotypes. This review describes the mechanisms of CSCs in promoting CRC and elucidates how the TME and CSCs work synergistically to sustain cancer development, evoke relapse, and promote therapeutic resistance. These cancer-promoting mechanisms can be antagonized by identifying different CSC phenotypes and targeting them for cancer therapy.