Abstract
Human gastrointestinal malignancies are highly heterogeneous cancers. Clinically, heterogeneity largely contributes to tumor progression and resistance to therapy. Heterogeneity within gastrointestinal cancers is defined by molecular subtypes in genomic and transcriptomic analyses. Cancer stem cells (CSCs) have been demonstrated to be a major source of tumor heterogeneity; therefore, assessing tumor heterogeneity by CSC trait-guided classification of gastrointestinal cancers is essential for the development of effective therapies. CSCs share critical features with embryonic stem cells (ESCs). Molecular investigations have revealed that embryonic genes and developmental signaling pathways regulating the properties of ESCs or cell lineage differentiation are abnormally active and might be oncofetal drivers in certain tumor subtypes. Currently, multiple strategies allow comprehensive identification of tumor subtype-specific oncofetal signatures and evaluation of subtype-specific therapies. In this review, we summarize current knowledge concerning the molecular classification of gastrointestinal malignancies based on CSC features and elucidate their clinical relevance. We also outline strategies for molecular subtype identification and subtype-based therapies. Finally, we explore how clinical implementation of tumor classification by CSC subtype might facilitate the development of more effective personalized therapies for gastrointestinal cancers.