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target for antibody-drug conjugates (ADC), which was proven by binding mouse anti-human CD133
monoclonal antibody to highly cytotoxic monomethyl auristatin F, ultimately inducing apoptosis in cancer
[56]
cells with high levels of CD133 expression . However, a recent study demonstrated that the hierarchical
organization that involves CSCs and non-CSCs may be reversible through epigenetic gene regulation, which
suggests that therapeutic strategies that target GCSCs themselves might be insufficient to eliminate cancer
[57]
cells .

CONCLUSION
Molecular-targeted agents have been developed as a new treatment strategy and have been applied to
various types of solid tumors. These developed agents have been assessed in diverse combinations with
conventional chemotherapy as a treatment against advanced tumors including GC. However, the success
of molecular-targeted agents for GC has been limited, and the prognosis of patients with advanced GC is
still poor. Based on accumulating evidence, GCSCs are deeply involved in GC progression. Moreover, the
tumor microenvironment that surrounds GCSCs forms the CSC niche and allows the stem cells to give rise
to a hierarchy of proliferative and non-GCSC cells. Targeting the critical pathways and molecules between
GCSCs and their environment may therefore represent a promising therapeutic strategy, and may provide a
complementary approach to conventional therapies that target the malignant cells themselves. This review
describes recent progress and evidence concerning the markers of GCSCs, related molecules within the
GCSC niche and treatment targets. Further elucidation of the molecular mechanisms of GCSC regulation
may lead to the development of novel treatment strategies that target GCSCs.

DECLARATIONS
Authors’ contributions
Writing manuscript: Uchihara T, Ishimoto T, Yonemura A, Baba H
Organized data: Uchihara T, Ishimoto T

Financial support and sponsorship
None.

Conflicts of interest
There are no conflicts of interest.

Patient consent
Not applicable.

Ethics approval
Not applicable.

Copyright
© The Author(s) 2018.

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