Recent advances in cancer stem/progenitor cell research: therapeutic implications for overcoming resistance to the most aggressive cancers

Abstract

• Introduction • Functions of cancer progenitor cells in the cancer initiation and progression ‐ New model of carcinogenesis based on the cancer progenitor cells ‐ Isolation and ex vitro and in vivo characterization of functional properties of cancer progenitor cells ‐ Functions of cancer progenitor cells in the cancer development ‐ Influence of local tumour microenvironment on the behavior of cancer progenitor cells • Cancer types originating from cancer progenitor cells ‐ New concepts of the heterogeneity of cancers derived from distinct cancer progenitor cells ‐ Implication of cancer progenitor cells in bone marrow‐derived cancers ‐ Leukaemias ‐ Sarcomas ‐ Implication of cancer progenitor cells in pediatric and adult brain tumors ‐ Implication of cancer progenitor cells in other cancer types • Novel cancer therapies by molecular targeting of cancer progenitor cells and their microenvironment ‐ New concepts on the functions of cancer progenitor cells in the resistance to current cancer therapies ‐ New combination therapies against the aggressive and recurrent cancers ‐ Targeting cancer progenitor cells ‐ Targeting the local microenvironment of cancer progenitor cells • Conclusions • Future directions and perspectives Abstract Overcoming intrinsic and acquired resistance of cancer stem/progenitor cells to current clinical treatments represents a major challenge in treating and curing the most aggressive and metastatic cancers. This review summarizes recent advances in our understanding of the cellular origin and molecular mechanisms at the basis of cancer initiation and progression as well as the heterogeneity of cancers arising from the malignant transformation of adult stem/progenitor cells. We describe the critical functions provided by several growth factor cascades, including epidermal growth factor receptor (EGFR), platelet‐derived growth factor receptor (PDGFR), stem cell factor (SCF) receptor (KIT), hedgehog and Wnt/β ‐catenin signalling pathways that are frequently activated in cancer progenitor cells and are involved in their sustained growth, survival, invasion and drug resistance. Of therapeutic interest, we also discuss recent progress in the development of new drug combinations to treat the highly aggressive and metastatic cancers including refractory/relapsed leukaemias, melanoma and head and neck, brain, lung, breast, ovary, prostate, pancreas and gastrointestinal cancers which remain incurable in the clinics. The emphasis is on new therapeutic strategies consisting of molecular targeting of distinct oncogenic signalling elements activated in the cancer progenitor cells and their local microenvironment during cancer progression. These new targeted therapies should improve the efficacy of current therapeutic treatments against aggressive cancers, and thereby preventing disease relapse and enhancing patient survival.