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Neural stem/progenitors and glioma stem-like cells have differential sensitivity to chemotherapy

  • Marc C Chamberlain, Provider, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliancechambemc@u.washington.edu
Submitted August 08, 2011

Gong et al. compared the sensitivity of embryonic neural stem cells (NSC) and adult glioma stem cells (GSC) to chemotherapy. [1] Temozolomide (TMZ)— the most common treatment of adult gliomas—and the rarely-used cisplatin (CDDP) were studied. Erlotinib and bortezomib were also included.

The clinical relevance of the particular agents selected is unclear given the lack of single agent activity in recurrent adult gliomas with the exception of TMZ. GSC are relatively quiescent, radiation- and chemotherapy-resistant, multi-potent, and able to self-renew. [2-5] GSC exists in brain tumors although their relative abundance and relationship with normal NSC is unclear. [2-5] GSC are genomically unstable and the acquisition of stemness does not imply a relationship with normal NSC. The authors should have described the relationship between NSC and GCS. In addition, Gong et al. should have explained if GSC exist as a rare subpopulation within a glioma and if the cell of origin for different types of glioma affects response.

The role of NSC in adults is controversial. Gong et al. reported TMZ and CDDP injure NSC while minimally affecting GSC and postulate that TMZ may result in cognitive injury and specifically memory loss. [1] There are no current data to support this hypothesis in adults treated only with TMZ. GSC have a number of mechanisms by which resistance to therapy is manifested including: active and up-regulated DNA damage repair systems; up-regulated anti-apoptotic pathways; increased expression of multi-drug transporters; and residence in microvascular niches. [2-5] It is unclear whether NSC have similar therapy-resistant mechanisms.

It is also uncertain whether the NSC sensitivity to DNA damaging agents reflects a paucity of DNA repair following genotoxic injury. The lack of correlation with MGMT and mismatch repair system seems counterintuitive as TMZ cytotoxicity is a function of cellular MGMT activity as well as proficient mismatch repair. The correlation of NSC drug sensitivity with low expression of the drug transporter system (multidrug resistance gene) is also unclear because neither TMZ nor CDDP are exported by this system.

Regarding targeted therapy, GSC showed increased drug sensitivity compared to NSC. A variety of cell signaling pathways have been characterized for GSC (Notch, ErbB1 and 2, hedgehog, Wnt/B-catenin, IL6/STAT3, and CXCR1/2) although less is known regarding NSC. [5] Erlotinib, an ErbB1 inhibitor, preferentially affected GSC with relative sparing of NSC presumably due to overexpression of ErbB1 on GSC. In lieu of the lack of single agent activity for ErbB1 inhibitors in adult glioma is the relevance of this finding that may reflect the failure of in vitro chemosensitivity assays to predict in vivo responses in cancer and specifically glioma. The increased sensitivity of GSC to the bortezomib was postulated to reflect a paucity of proteasomes in GSC.

Peripheral nerve injury is dose limiting. This suggests that if proteasome inhibitors easily entered the CNS—none do at present—CNS-related drug injury would likely manifest. Lastly, does embryonic NSC as used by Gong et al. reflect adult NSC behavior with respect to function as well as treatment sensitivity?

References

2. Zhou B, Zhang H, Damelin M, et al. Tumor initiating cells: challenges and opportunities for anticancer drug discovery. Nature Rev 2009;8:806-823.

3. Liu G, Yuan X, Zeng Z, et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 2006;5:67-70.

4. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer 2005;5:275-284.

5. Liu S, Wicha MS. Targeting breast cancer stem cells. J Clin Oncol 2010;28:4006-4012.

Disclosure: The author reports no disclosures.

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