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Figure 1: Novel therapeutic strategies for targeting cancer stem cells
of the Notch pathway has been implicated particularly SILENCING ONCOGENES
in breast CSCs, possibly by influencing the EMT and
contributing to the invasiveness of the CSCs. One RNAi is biological processes in which small interfering
[26]
group investigated the effects of the bioactive compound RNAs (siRNA) cause complementary target mRNA to be
psoralidin on Notch signaling in a breast cancer model. The degraded, thereby silencing the gene. While there are many
plant-derived drug inhibited Notch signaling in both bulk RNAi-based strategies which target bulk tumor cells, fewer
tumor and CSCs, resulting in decreased mammosphere studies have shown CSC-specific RNAi. One group used
formation, upregulation of pro-apoptotic proteins, and lentiviral short hairpin RNA (shRNA) to silence the human
inhibition of CSC proliferation. Other studies have papillomavirus gene E6 in CSC-enriched cervical cancers.
[27]
demonstrated that inhibiting Notch signaling resensitizes They discovered that after shRNA exposure, CSC growth
breast cancer cells to doxorubicin and docetaxel. [28] and sphere formation were dramatically inhibited. E6 is
upregulated in cervical CSCs, and E6 silencing also led to
The Hedgehog signaling pathway may also contribute decreased CSC self-renewal through TGF-β modulation.
[35]
to CSC formation. Hedgehog signaling controls cell fate Another study also used shRNA to silence HMGA1, an
and proliferation in embryonic SCs, but dysregulation of oncogene overexpressed in CD133 colon CSCs. HMGA1
+
the pathway has been associated with CSC generation. knockdown restored normal SC properties to CSCs,
Cyclopamine was the first Hedgehog antagonist to be including quiescence, increased asymmetric division, and
identified and its effects have been studied in many decreased self-renewing division. HMGA1 silencing was
cancers. Cyclopamine depleted CSCs and induced also linked to increased p53 expression. Both E6 and
[29]
[36]
tumor regression in a chronic myeloid leukemia model, HMGA1 may be viable targets for anti-CSC therapy.
[30]
decreased tumor growth rate in a medulloblastoma
model, and inhibited proliferation of pancreatic CSCs. [32] The application of RNAi in the clinic has been hampered
[31]
by the inability to deliver high enough doses to the tumor
Hedgehog abnormalities are linked to aberrant Wnt site. One group has used targeted siRNAs to downregulate
pathway activity. It is believed that Wnt plays a role in CSC oncogenes in vivo. They used PEGylated EpCAM
maintaining the self-renewal capabilities of CSCs. CD44, aptamers to guide siRNA to EpCAM-overexpressing
a CSC marker, is an important target for Wnt signaling, and breast CSCs. The siRNA accumulated at the tumor site and
CD44 knockdown resulted in decreased tumor formation in resulted in an 80% knockdown of the survivin gene, which
an intestinal cancer model. Another group tested several inhibits apoptosis and promotes chemoresistance in CSCs.
[33]
small molecule antagonists of Wnt and reported reduced When combined with doxorubicin, the aptamer-siRNA
mammosphere formation in vitro and halted tumor growth chimera improved survival rates of tumor-bearing mice,
[37]
in vivo in a breast cancer model. [34] demonstrating the effectiveness of anti-CSC RNAi in vivo
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ July 8, 2016 ¦ 235