Figure 2.

Clonal evolution of pancreatic carcinogenesis and progression. Red arrows indicate the lineage of the index metastasis from its origin in a normal cell. Carcinogenesis begins with an initiating alteration (M) in a normal cell that provides a selective advantage. Before the establishment of fixed cancer cells that are referred to as parental clones, clones with mutations that are beneficial for adapting to the environment are selected by selection pressure and survive. This clonal expansion is expected to generate more than one subclone within a cancer, one of which will give rise to the founder cell (blue clone) that will eventually become the parental clone and hence initiate the infiltrating carcinoma. Once parental clones are established, various spontaneous mutations seem to be accumulated. Even mutations that are not necessarily beneficial in the microenvironment are accumulated. This state refers to intratumor heterogeneity (ITH), which is observed clinically. While abnormal genes are accumulated, subclones that can adapt to the microenvironment at metastatic sites appear and metastasize (black clone). M: Gene mutation. This figure is adapted from Yachida S. et al. [22].