Search

New concepts on cancer- and metastasis-initiating cells suggest that these immature cells endowed with a high self-renewal potential and aberrant multilineage differentiation ability can provide critical functions for tumor initiation, metastases at distant tissues and organs, treatment resistance and disease relapse. The malignant transformation of multipotent tissue-resident adult stem/progenitor cells or their early progenies endowed with a self-renewal capacity is generally associated with the accumulation of different genetic and/or epigenetic alterations concomitant with the changes in their local microenvironment, niches. Particularly, the cancer progression to locally invasive and metastatic stages is often accompanied by a down-regulation of tumor suppressor genes combined with a sustained activation of distinct growth factor signaling pathways during the epithelial-mesenchymal (EMT) transition program that provide critical functions in the stringent regulation of self-renewal and/or differentiation of tissue-resident adult stem/progenitor cells. The signaling cascades that are often deregulated in highly tumorigenic cancer- and metastasis-initiating cells include hedgehog, epidermal growth factor receptor (EGFR), Wnt/β-catenin, NOTCH, polycomb gene product BMI-1 and/or stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4). The cooperation between these signal transduction elements may play a major role for their sustained proliferation, survival, invasion and metastasis. Importantly, the unique intrinsic properties of cancer stem/progenitor cells, including their high expression levels of DNA repair and detoxifying enzymes, anti-apoptotic factors, and ATP-binding cassette (ABC) multidrug transporters, may also be associated with their resistance to the current clinical cancer therapies and disease recurrence. Therefore, the molecular targeting of distinct deregulated signaling elements in cancer- and metastasis-initiating cells and their progenies is of immense therapeutic interest to overcome the treatment resistance. These novel targeting approaches should eliminate the total cancer cell mass, and thereby improve the efficacy of the current therapeutic regimens against aggressive, metastatic, recurrent and lethal cancers. [ABSTRACT FROM AUTHOR]