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Hedgehog and Epithelial to Mesenchymal Transition: Partners in Crime in Cancer Drug Resistance

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Review of “Twist1 and snail link Hedgehog signaling to tumor-initiating cell-like properties and acquired chemoresistance independently of ABC transporters” from Stem Cells by Stuart P. Atkinson

Drug-based cancer treatments are often limited by the phenomenon of acquired chemoresistance which researchers believe is mediated through the actions of tumor‐initiating cells or cancer stem cells (CSC) [1]. A new study from the laboratory of Wenfu Tan (Fudan University, Shanghai, China) has uncovered a novel mechanism through which cells can gain tumor-initiating capabilities and chemoresistance at the same time: elevated Hedgehog (Hh) pathway activity in the presence of factors which promote an epithelial to mesenchymal transition (EMT). Published this month in Stem Cells, this new finding may uncover new targets to combat resistance in the treatment of many forms of cancer [2]. 

Initial experiments uncovered a higher tumor-initiating potential in the multidrug resistant cancer cell sublines, as compared to their chemosensitive parental cancer cell lines. Previous studies by the same group had established the existence of high Hh signaling in these resistant sublines [3], and the researchers discovered that inhibiting Hh signaling through knockdown of Smo or Gli1 expression led to a reduction in this heightened tumor-initiating potential. EMT-associated transcription factor expression is linked to the development of tumor‐initiating cells [4] and researchers additionally found that of all tested transcription factors, the drug resistant sublines expressed elevated levels of both Snail and Twist1. Knockdown of these two transcription factors reduced the tumor-initiating properties in the sublines, and together with the previous data, suggests that acquired chemoresistant cancer cells requires both Hh pathway activity and the expression of EMT transcription factors to maintain heightened tumor‐initiating cell potential. Interestingly, the group then found that Hh pathway activation led to the upregulation of Snail and Twist1 expression, and the demonstration of Gli1 binding the promoter regions of the Twist1 suggested that Hh signaling may directly initiate Twist1 expression. Finally, Kong et al demonstrated that either inhibition of Hh signaling or reduced Snail and Twist1 expression also greatly reduced the chemoresistant nature of the cancer cell sublines, linking tumor initiating potential to chemotherapeutic drug resistance.  ABC transporters normally control drug efflux from cells [5], and are therefore of great interest in studies of chemoresistance, but in this case Hh signaling and EMT-mediated chemoresistance did not specifically require these transporters, so pointing to another drug resistance mechanism at play.

Overall, the data firmly suggests that Hh signaling in cancer cells may lead to chemoresistance through the promotion of tumor-initiating cell properties mediated by Twist1 and Snail expression (See the adjoined figure for a graphical representation of this mechanism). This should allow the identification of further druggable targets towards combating chemotherapeutic resistance, although, as the authors note, this mechanism requires confirmation in in vitro cultured cancer cell lines or clinical tumor tissues. Additionally, further study towards deciphering how chemoresistance is effected without using the well-known ABC transporters may provide further therapeutic targets.

References

  1. Dean M, Fojo T, and Bates S Tumour stem cells and drug resistance. Nat Rev Cancer 2005;5:275-284.
  2. Kong Y, Peng Y, Liu Y, et al. Twist1 and snail link Hedgehog signaling to tumor-initiating cell-like properties and acquired chemoresistance independently of ABC transporters. Stem Cells 2015;
  3. Zhan X, Wang J, Liu Y, et al. GPCR-like signaling mediated by smoothened contributes to acquired chemoresistance through activating Gli. Mol Cancer 2014;13:4.
  4. Mani SA, Guo W, Liao MJ, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008;133:704-715.
  5. Gottesman MM, Fojo T, and Bates SE Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002;2:48-58.