Therapeutic Targeting of Signaling Pathways Related to Cancer Stemness

Abstract

The theory of cancer stem cells (CSCs) proposes that the different cells within a tumor, as well as metastasis deriving from it, are originated from a single subpopulation of cells with self-renewal and differentiation capacities. These cancer stem cells are supposed to be critical for tumor expansion and metastasis, tumor relapse and resistance to conventional therapies, such as chemo-and radiotherapy. The acquisition of these abilities has been attributed to the activation of alternative pathways, for instance, WNT, NOTCH, SHH, PI3K, Hippo, or NF-κB pathways, that regulate detoxification mechanisms; increase the metabolic rate; induce resistance to apoptotic, autophagic, and senescence pathways; promote the overexpression of drug transporter proteins; and activate specific stem cell transcription factors. The elimination of CSCs is an important goal in cancer therapeutic approaches because it could decrease relapses and metastatic dissemination, which are main causes of mortality in oncology patients. In this work, we discuss the role of these signaling pathways in CSCs along with their therapeutic potential.

Emerging agents that target signaling pathways to eradicate colorectal cancer stem cells

“…These data indicate that the Wnt/β‐catenin signaling pathway is a critical pathway to eradicate CRC‐SCs. On the other hand, crosstalk among pathways can lead to resistance to single‐pathway inhibitors and maintenance of the CSC phenotype [ 127 , 128 ]. Therefore, multiple cellular pathways must be targeted to effectively eradicate CRC‐SCs.…”

Combinatorial Strategies to Target Molecular and Signaling Pathways to Disarm Cancer Stem Cells

“…The combinatorial strategies herein reported foresee the targeting of developmental and oncogenic signaling pathways that are key players in defining several features of CSCs biology, including self-renewal, stemness, EMT, CSCs dormancy, as well as drug resistance, radio-resistance, tumor initiation and dedifferentiation, widely discussed in many published reviews (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

“…Developmental signaling pathways [including Wnt, Sonic Hedgehog (Shh) and Notch] and oncogenic cascades (including transforming growth factor-beta (TGF-b), Janus kinase/signal transducer and activator of transcription 3 (JAK/ STAT3), phosphatidylinositol 3-kinase/V-Akt murine thymoma viral oncogene/mammalian target of rapamycin (PI3K/AKT/ mTOR), Mitogen-activated protein kinase (MAPK) and V-SRC avian sarcoma (Src) have been identified as key players both in CSCs biology maintenance and in cancer therapy resistance (17,18). The description of these signaling pathways and their roles in defining the biology of CSCs will not be tackled herein and the reader is invited to refer to reviews that widely discuss these topics (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Although several targeted approaches relying on monotherapy have been developed to affect these pathways, they have shown limited efficacy due to the activation of bypass pathway(s) and to the complexity of signaling networks containing feedback loops and cross-talk.…”

Aberrant Signaling Pathways in Cancer Cells: Application of Nanomaterials

“…CSCs have self-renewal capacity and differentiation potential, and contribute to several tumor malignancies, such as recurrence, metastasis, heterogeneity, and multidrug/ radiation resistance. Besides other factors, intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Hedgehog, and PI3K/AKT/mTOR, are the prime regulators of CSCs [43,44]. Here, we have briefly discussed Wnt and PI3K/ AKT/mTOR signaling pathways in CSCs.…”