Targeting cancer stem cells: a new therapy to cure cancer patients

Abstract

Cancer stem cells (CSCs) have been defined as cells within tumor that possess the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. They have been identified in blood, breast, brain, colon, melanoma, pancreatic, prostate, ovarian, lung cancers and so on. It is often considered to be associated with chemo-resistance and radio-resistance that lead to the failure of traditional therapies. Most therapies are directed at the fast growing tumor mass but not the slow dividing cancer stem cells. Eradicating cancer stem cells, the root of cancer origin and recurrence, has been thought as a promising approach to improve cancer survival or even to cure cancer patients. Understanding the characteristics of cancer stem cells will help to develop novel therapies to eliminate the initiating cancer stem cell, and the relevant patents on the cancer stem cell and cancer therapy by cancer stem cells will be discussed.

Keywords: Cancer stem cell; Mesenchymal stem cells; biomarker; differentiation therapy; drug resistance; natural compound; signal pathway.

Figure 1

The Wnt/β-Catenin signaling pathway and their inhibitors. A: In the off-state, Wnt ligands usually bind with Soluble frizzled-related proteins (SFRP) and Wnt inhibitory factor-1 (WIF-1) which prevent them from interact with frizzled (Fz) receptors. Dickkopf (Dkk) interacts with low density lipoprotein receptor-related protein 5/6 (LRP5/6) to inhibit binding of Wnt ligands. β-Catenin that is not bound with cadherin is phosphorylated by a complex formed by casein kinase 1α (CK1α), glycogen synthase kinase-3β (GSK3β), adenomatous polyposis coli (APC), and Axin, then it is identified by β-TrCP and lead to the ubiquitin-proteasome pathway. B: In the on state, Wnts bind to and activate FZD (Frizzled) and LRP (LDL-related receptor protein) receptors on target cells. Phosphorylation of β-Catenin is suppressed and β-Catenin escapes from the degradation. Free cytoplasmic β-Catenin translocates to the nucleus, forms a complex with TCF/LEF, and activates the transcription of target genes, such as cyclin D1, c-myc, c-Jun, and fibronectin. The coupounds vitamiD3, PRI-724, CWP232291 inhibit the β-Catenin that lead to the inhibition of Wnt/β-Catenin signaling pathway, and Celecoxi worked through promoting degradation of TCF.

Figure 2

The Notch signaling pathway and their inhibitors. Notch proteins (and ligands) contain extracellular EGF-like repeats, which interact with the DSL domain of ligands. Activation of Notch upon ligand binding is accompanied by proteolytic processing that releases an intracellular domain of Notch (NICD) from the membrane. The NICD contains the RAM23 domain (RAM), which enhances interaction with CSL protein, NLS (Nuclear Localization Signals), a CDC10/Ankyrin repeat domain ANK. Upon release, the NICD translocates to the nucleus and associates with the CSL family of DNA-binding proteins to form a transcriptional activator, that activate the expression of a set of target genes, including the E (spl) (Enhancer of Split) group and others. The compounds, DAPT, MK0752, RO4929097, PF-03084014, inhibit the Notch signaling pathways through the inhibition of γ-secretase.

Figure 3

The Hh signaling pathway and their inhibitors. The Hh-signaling pathway comprises three main components: the Hh ligand; a transmembrane receptor circuit composed of the negative regulator Ptc, and the an activator Smo; and finally a cytoplasmic complex that regulates the Ci or Gli family of transcriptional effectors. Ptc, a twelve-pass membrane protein binds Hh ligand, and in the absence of ligand, Ptc interacts with and inhibits Smo, a sevenpass membrane protein. When Hh binds Ptc, its interactions with Smo are altered, leads to Ci/Gli protein entering the nucleus and acting as a transcriptional activator for the same genes. Cur-61414, GDC-0449, BMS-833923 and IPI-926 could antagonize the smo that lead to the inhibiton of Hh-signaling pathway.

Figure 4

Schematic diagram of the mechanisms leading to cancer stem cell resistance to chemo- and radiation therapy.