Therapeutic Targeting Strategies of Cancer Stem Cells in Gastrointestinal Malignancies

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Abstract

Cancer stem cells (CSCs) are thought to be a distinct population of cells within a tumor mass that are capable of asymmetric division and known to have chemoresistant characteristics. The description and identification of CSC models in cancer growth and recurrence has inspired the design of novel treatment strategies to overcome treatment resistance by targeting both CSCs and non-CSC tumor cells. Several cellular signaling pathways have been described as playing a role in the induction and maintenance of stemness in CSCs, such as the Wnt/β-catenin, Notch, STAT3, and Hedgehog pathways. In this review, we aim to review some of the ongoing CSC therapeutic targeting strategies in gastrointestinal malignancies.

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Most cited references 29

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Wnt signalling and its impact on development and cancer.

Alexandra Klaus, Walter Birchmeier (2008)

The Wnt signalling pathway is an ancient system that has been highly conserved during evolution. It has a crucial role in the embryonic development of all animal species, in the regeneration of tissues in adult organisms and in many other processes. Mutations or deregulated expression of components of the Wnt pathway can induce disease, most importantly cancer. The first gene to be identified that encodes a Wnt signalling component, Int1 (integration 1), was molecularly characterized from mouse tumour cells 25 years ago. In parallel, the homologous gene Wingless in Drosophila melanogaster, which produces developmental defects in embryos, was characterized. Since then, further components of the Wnt pathway have been identified and their epistatic relationships have been defined. This article is a Timeline of crucial discoveries about the components and functions of this essential pathway.

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Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance.

Jiangbing Zhou, Julia Wulfkuhle, Hao Zhang … (2007)

Side-population (SP) cells within cancers and cell lines are rare cell populations known to enrich cancer stem-like cells. In this study, we characterized SP cells from the human breast cancer cell line MCF7 as a model for cancer stem-like cells. Compared with non-SP cells, MCF7 SP cells had higher colony-formation ability in vitro and greater tumorigenicity in vivo, suggesting that MCF7 SP cells enrich cancer stem-like cells. cDNA microarray analysis of the SP cells indicated higher expression of ATP-binding cassette transporters and genes involved in quiescence, which were confirmed by quantitative RT-PCR and flow cytometry cell cycle analysis. To identify signal pathways important for cancer stem-like cells, we analyzed cDNA microarray data and identified nine pathways that were altered in the SP cells. To analyze the protein signaling networks, we used reverse-phase signaling pathway protein microarray technology and identified three signaling proteins that are significantly different between MCF7 SP and non-SP cells. Notably, signaling of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR), signal transduction and activator of transcription (STAT3), and phosphatase and tensin homolog (PTEN) was confirmed to be critical for MCF7 SP cell survival and proliferation by pathway specific inhibitors, selected gene knockdown, and in vivo tumorigenicity assay. The STAT3 pathway was found to be positively regulated by mTOR signaling, whereas PTEN served as a negative regulator of both STAT3 and mTOR signaling. This study suggests the existence of prosurvival signaling pathways critical for cancer stem-like cell maintenance, which could be selectively targeted for inhibiting cancer stem-like cells for improved treatment.

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Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway.

Zhiwei Wang, Yiwei Li, Dejuan Kong … (2009)

Despite rapid advances in many fronts, pancreatic cancer (PC) remains one of the most difficult human malignancies to treat due, in part, to de novo and acquired chemoresistance and radioresistance. Gemcitabine alone or in combination with other conventional therapeutics is the standard of care for the treatment of advanced PC without any significant improvement in the overall survival of patients diagnosed with this deadly disease. Previous studies have shown that PC cells that are gemcitabine-resistant (GR) acquired epithelial-mesenchymal transition (EMT) phenotype, which is reminiscent of "cancer stem-like cells"; however, the molecular mechanism that led to EMT phenotype has not been fully investigated. The present study shows that Notch-2 and its ligand, Jagged-1, are highly up-regulated in GR cells, which is consistent with the role of the Notch signaling pathway in the acquisition of EMT and cancer stem-like cell phenotype. We also found that the down-regulation of Notch signaling was associated with decreased invasive behavior of GR cells. Moreover, down-regulation of Notch signaling by siRNA approach led to partial reversal of the EMT phenotype, resulting in the mesenchymal-epithelial transition, which was associated with decreased expression of vimentin, ZEB1, Slug, Snail, and nuclear factor-kappaB. These results provide molecular evidence showing that the activation of Notch signaling is mechanistically linked with chemoresistance phenotype (EMT phenotype) of PC cells, suggesting that the inactivation of Notch signaling by novel strategies could be a potential targeted therapeutic approach for overcoming chemoresistance toward the prevention of tumor progression and/or treatment of metastatic PC.

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Journal

Journal ID (nlm-ta): Biomedicines

Journal ID (iso-abbrev): Biomedicines

Journal ID (publisher-id): biomedicines

Title: Biomedicines

Publisher: MDPI

ISSN (Electronic): 2227-9059

Publication date (Electronic): 10 March 2019

Publication date Collection: March 2019

Volume: 7

Issue: 1

Electronic Location Identifier: 17

Affiliations

Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, AZ 85054, USA; Sonbol.mohamad@ 123456mayo.edu (M.B.S.); ahn.daniel@ 123456mayo.edu (D.H.A.)

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[* ]Correspondence: bekaii-saab.tanios@ 123456mayo.edu

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Mohamad B. Sonbol https://orcid.org/0000-0002-6931-242X

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Publisher ID: biomedicines-07-00017

DOI: 10.3390/biomedicines7010017

PMC ID: 6466109

PubMed ID: 30857342

SO-VID: a036e970-0d57-4e9c-9a2c-e0faaf868d72

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Therapeutic Targeting Strategies of Cancer Stem Cells in Gastrointestinal Malignancies

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Karger: Oncology

Most cited references 29

Wnt signalling and its impact on development and cancer.

Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance.

Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway.

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