New Concepts on the Critical Functions of Cancer- and Metastasis-Initiating Cells in Treatment Resistance and Disease Relapse: Molecular Mechanisms, Signaling Transduction Elements and Novel Targeting Therapies

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