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closeSummary of reviewers' comments
Posted by dyjin on 16 Mar 2007 at 07:17 GMT
All reviewers agreed that this is an interesting study and that the authors have made a good effort to address the issues raised in two rounds of review. However, some reviewers still had significant concerns over the existence of precancerous stem cells (PCSC) and other issues as summarized below. This interesting paper is recommended for publication with the hope that critical issues can be openly discussed at a new and more advanced level among readers and authors.
1) The differentiation of "PCSC" into either normal or neoplastic tissues might reflect the heterogeneity of cell populations in the clones. To support the existence of PCSC, it is crucially important to demonstrate of the ability of single cells to achieve both modes of differentiation.
2) According to the authors, PCSC should be uncommitted stem cells with incomplete multipotency, but the clones described here are predetermined to specific types of cancer tissues in immunodeficient mice. How can PCSC trans-differentiate into other tissues?
3) The level of normal cell engraftment in both adult mice and blastocysts is too low.
RE: Summary of reviewers' comments
jxgao replied to dyjin on 25 Dec 2008 at 19:50 GMT
1) The differentiation of "PCSC" into either normal or neoplastic tissues might reflect the heterogeneity of cell populations in the clones. To support the existence of PCSC, it is crucially important to demonstrate of the ability of single cells to achieve both modes of differentiation.
As we have indicated in the discussion, we have used clonal pCSCs for cell transplantation. Thus, it is unlikely that the bi-potency of pCSC differentiation reflects the contaminated populations in the clones. Ideally, using a single cell transplantation to achieve both modes of differentiation is most convincing. However, unlike normal stem cells that can expand in normal stem cell niches, pCSCs transplanted into normal recipients may not expand, because normal stem cell niches may not be adaptable for the singly-transplanted pCSCs. In fact, the success rate of single normal stem cell transplantation is still very low at present.
2) According to the authors, PCSC should be uncommitted stem cells with incomplete multipotency, but the clones described here are predetermined to specific types of cancer tissues in immunodeficient mice. How can PCSC trans-differentiate into other tissues?
The concept of uncommitted pCSCs is different from that of uncommitted normal stem cells. Compared to normal stem cells, first, pCSC is injured in self-renewal and multipotency of differentiaiton; second, pCSC can develop from a progenitor cell that has acquired the stemness of a stem cell but may retain the predetermined property of a progenitor. This does not exclude the potentiality of a predetermined or a specific cancer tissue-derived pCSC to differentiate into other types of caner tissue. This is observed in more pCSC lines developed in our laboratory (unpublished). The capability of pCSC trans-differentiation depends on whether and where embryonic stem (ES) cell genes are activated in pCSCs. ES cell genes may guide the pCSC to differentiate into a cell type of the tissue where it resides (1), such as tumor vascular progenitor cells in the vasculogenic environments (2, 3).
3) The level of normal cell engraftment in both adult mice and blastocysts is too low.
It is predictable that the level of “normal” cell engraftment in both adult mice and blasocyst chimera is low, because the “normal” is not real “normal” but benign. The pCSC-derived benign cells may not be as “normal” as a normal cell, and thus most of the benignly differentiating pCSCs may undergo differentiation-induced cell death (DICD) (1). This is supported by fact that most of the pCSC-derived red blood cells in the blastocyst chimera mice are morphologically abnormal (4).
1. Gao, J. X. 2008. Cancer stem cells: the lessons from precancerous stem cells. J Cell Mol Med 12:67-96.
2. Shen, R., Y. Ye, L. Chen, Q. Yan, S. H. Barsky, and J. X. Gao. 2008. Precancerous stem cells can serve as tumor vasculogenic progenitors. PLoS ONE 3:e1652.
3. Bussolati, B., C. Grange, A. Sapino, and G. Camussi. 2008. Endothelial Cell Differentiation of Human Breast Tumor Stem/Progenitor Cells. J Cell Mol Med.
4. Chen, L., R. Shen, Y. Ye, X. A. Pu, X. Liu, W. Duan, J. Wen, J. Zimmerer, Y. Wang, Y. Liu, L. C. Lasky, N. A. Heerema, D. Perrotti, K. Ozato, S. Kuramochi-Miyagawa, T. Nakano, A. J. Yates, W. E. Carson Iii, H. Lin, S. H. Barsky, and J. X. Gao. 2007. Precancerous Stem Cells Have the Potential for both Benign and Malignant Differentiation. PLoS ONE 2:e293.