FIGURE 1.

Proposed model of cancer initiation, progression, and metastasis and treatment resistance mediated through cancer- and metastasis-initiating cells. This scheme shows the malignant transformation of adult stem/progenitor cells into tumorigenic cancer stem/progenitor cells, also known as ‘cancer-initiating cells’, which may be induced through genetic and/or epigenetic alterations in these immature cells and changes in their local microenvironments, including the activated stromal cells. The symmetric or asymmetric division of cancer stem cells (CSCs) into transit-amplifying (TA) also designated as intermediate cells that, in turn, may generate the bulk mass of poorly, moderately, and highly differentiated cancer cells is also illustrated. Moreover, the acquisition of a migratory phenotype by tumorigenic cancer-initiating cells, which may be induced by the sustained activation of distinct oncogenic signaling pathways during the epithelial–mesenchymal transition (EMT) program, is shown. The possible invasion of certain tumorigenic and migrating cancer-initiating cells in the activated stroma, which might lead to their dissemination through the peripheral circulation at distant tissues and organs, is also illustrated. Moreover, the possible loss of the migratory phenotype of metastasis-initiating cells via the occurrence of mesenchymal–epithelial transition (MET) at secondary tumor sites is indicated. The dormancy phenomenon of metastasis-initiating cells and their possible reactivation associated with the formation of secondary tumor formation under specific microenvironmental conditions at distant sites is also illustrated. New cancer therapies, which use molecular targeting of cancer- and metastasis-initiating cells to counteract cancer progression and metastases at distant tissues and organs, are also indicated.