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Review
. 2014 Feb;23(2):234-54.
doi: 10.1158/1055-9965.EPI-13-0785. Epub 2013 Nov 22.

Molecular biomarkers of cancer stem/progenitor cells associated with progression, metastases, and treatment resistance of aggressive cancers

Murielle Mimeault  1 , Surinder K Batra
Affiliations
Review

Molecular biomarkers of cancer stem/progenitor cells associated with progression, metastases, and treatment resistance of aggressive cancers

Murielle Mimeault et al. Cancer Epidemiol Biomarkers Prev. 2014 Feb.

Abstract

The validation of novel diagnostic, prognostic, and predictive biomarkers and therapeutic targets in tumor cells is of critical importance for optimizing the choice and efficacy of personalized therapies. Importantly, recent advances have led to the identification of gene-expression signatures in cancer cells, including cancer stem/progenitor cells, in the primary tumors, exosomes, circulating tumor cells (CTC), and disseminated cancer cells at distant metastatic sites. The gene-expression signatures may help to improve the accuracy of diagnosis and predict the therapeutic responses and overall survival of patients with cancer. Potential biomarkers in cancer cells include stem cell-like markers [CD133, aldehyde dehydrogenase (ALDH), CD44, and CD24], growth factors, and their cognate receptors [epidermal growth factor receptor (EGFR), EGFRvIII, and HER2], molecules associated with epithelial-mesenchymal transition (EMT; vimentin, N-cadherin, snail, twist, and Zeb1), regulators of altered metabolism (phosphatidylinositol-3' kinase/Akt/mTOR), and drug resistance (multidrug transporters and macrophage inhibitory cytokine-1). Moreover, different pluripotency-associated transcription factors (Oct3/4, Nanog, Sox2, and Myc) and microRNAs that are involved in the epigenetic reprogramming and acquisition of stem cell-like properties by cancer cells during cancer progression may also be exploited as molecular biomarkers to predict the risk of metastases, systemic treatment resistance, and disease relapse of patients with cancer.

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Figures

Figure 1
Figure 1
Schematic representation of functions of cancer stem/progenitor cells during cancer progression and metastasis and characterization of their biomarkers. The scheme shows cancer stem/progenitor cells endowed with stem cell–like properties and which can generate the total cancer cell population at the primary and secondary tumors. Moreover, the exosomes released by cancer cells, which may contribute to the malignant transformation of other cancer cells via the transfer of oncogenic products and drug resistance–associated molecules such as EGFRvIII and P-glycoprotein, are also illustrated. The possibility to perform the characterization of molecular gene signature and biomarkers of cancer cells, exosomes, and CTCs, including cancer stem/progenitor cells expressing stem cell–like markers, is also indicated.
Figure 2
Figure 2
Schematic representation of functions of exosomes released by cancer cells in cancer progression, metastasis, angiogenesis, and treatment resistance and their potential therapeutic applications. A, the oncogenic molecules such as EGFR or EGFRvIII, which can be shed from cancer cells via exosome secretion and transferred to other adjacent cancer cells and/or endothelial cells. Hence, the activated EGFR or EGFRvIII may stimulate MAPK and Akt pathways and expression of their targeted genes, including VEGF, in host cancer cells and endothelial cells in their surrounding tumor microenvironment. VEGF released by endothelial cells in turn can activate in an autocrine manner the VEGFR2 cascade and tumor angiogenesis. Of therapeutic interest, the inhibition of exosome secretion from cancer cells carried by shRNA silencing of Rab27a/b, using an inhibitor of sphingomyelinase (GW4869) or annexin/diannexin and which represent potential strategies to prevent the promoting effects of exosomes on tumor progression, angiogenesis, and metastasis is indicated. B, the elimination of tumor cell–derived exosomes from the entire circulatory system, which can be performed by extracorporeal hemofiltration using novel medical devices such as an affinity plasmapheresis platform designated as Aethlon ADAPT system is illustrated. C, the systemic delivery of therapeutic agents incorporated in cellular or synthetic exosomes and which are able to inhibit the functions of tumor-specific mRNAs, miRNAs such as spherical nucleic acid constructs, and/or oncogenic products in target cancer cells is also illustrated.
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