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

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.

Integrins in prostate cancer progression

“…The mechanisms by which integrins are regulated need to be characterized by focusing on modulators of integrin expression. Yet another promising avenue of research is to elucidate the role of integrins in promoting proliferation of prostate cancer stem cells, in particular, a 2 b 1 appears to be interesting since it is highly expressed in these cells (Collins et al 2005, Mimeault et al 2007. Finally, an under-investigated area in prostate cancer research is the cross talk between bone microenvironment and metastasis (Mohla 2004), to which the interactions between integrins and their ECM ligands are likely to contribute significantly.…”

γ-Secretase inhibitor, DAPT inhibits self-renewal and stemness maintenance of ovarian cancer stem-like cells in vitro

“…Zhang et al [4] demonstrated that CD44+CD117+ cells are ovarian cancer-initiating cells. CD133 is also a surface marker for CSCs, including those in the brain, prostate, pancreas, liver, colon, and skin cancers [30,31] . Some recent studies indicated that CD133 expression defined a tumor-initiating cell population in human ovarian cancer [8,32] .…”

“…OCSCs are characterized by 11111111111  their capacity to survive and organize suspended spheroid structures in serum-free medium, overexpression of several stem cell markers (ABCG2, Nanog, Nestin, and Oct4) [4,10] , CD44+, CD117+, CD133+, as well as resistance to conventional chemotherapies, resistance to apoptosis, and the ability to recapitulate the original tumor in vivo [4,[6][7][8]11] .…”

Antitumor efficacy induced by a B16F10 tumor cell vaccine treated with mitoxantrone alone or in combination with reserpine and verapamil in mice

“…Here, we report the safety and immunogenicity of an apoptotic B16F10 tumor cell vaccine in a controlled study of C57BL/6 mice. 5 wild-type B16F10 cells as control. In the antitumor effect experiment, C57BL/6 mice were randomly divided into the experimental, the B16F10 cell and the PBS control groups.…”

“…In the antitumor effect experiment, C57BL/6 mice were randomly divided into the experimental, the B16F10 cell and the PBS control groups. Each mouse was immunized s.c. in the abdominal region, respectively, with a vaccine of 5x10 5 B16F10 tumor cells treated with MIT in combination with RP and VP for 12 h or 1x10 5 wild-type B16F10 cells inactivated with mitomycin C or 100 µl PBS. The same immunization was repeated twice at an interval of 2 weeks.…”