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Figure 1. Models that explain pancreatic cancer tumor development and roles of cancer stem cells (CSCs) in tumor initiation and progression. A: stochastic model shows that every cell has the potential to be the tumor initiator; B: CSC model shows that CSCs originate from normal stem cells (NSCs) through mutations and tumorigenic transformation of several potential pathways including Hh: hedgehog, epithelial-to-mesenchymal transition (EMT), and the reverse process mesenchymal-to-epithelial transition (MET). CSCs are also generated by de-differentiation of differentiated malignant cells by chemotherapeutic agents, ionizing radiation, and hypoxia. CSCs and drug-induced CSCs (Di-CSCs) are enriched following conventional chemotherapy treatment; C: the model of long-term tumor growth in PDAC states that a succession of CSC or tumor initiating cells (TIC) clones and drives tumor progression in serial xenotransplantation. Individual TICs contribute to tumor formation transiently and generate mainly non-tumorigenic progeny expressing little or no self-renewal