In words quite clear,"our thought is that we should recognize it before the Nobel Prize did" Dr. Shaul G. Massry, a professor emeritus of medicine at the University of Southern California has predicted the future Nobel Laureate trio of Dr. James A. Thomson, Dr. Shinya Yamanaka and Dr. Rudolf Jeanich who shared the Massry Prize for the year 2008.
Eight of its 21 recipients, since its establishment in 1996, have gone on to win the Nobel Prize. That highlights the significant contribution to science that this prize recognizes.
The three recipients reversed the differentiated skin cells to obtain iPS cells. Dr. Jeanich, however, has used these cells to successfully treat Parkinson's disease in mouse model.
The full story can be read here.
There is much hope in this science of transdifferentiation. A team of researchers from University of Bath, center for Regenerative Medicine that includes Dr. Jonathan Slack who is currently the head of the Stem cell Institute at University of Minnesota have already used the technique to transdifferentiate liver cells to pancreatic Beta-cells that carries the promise of helping diabetic patients.
Sunday, January 25, 2009
Saturday, January 03, 2009
Cancer Stem Cells
The much talked about paper by Quintana et al (Nature 2008(Dec 4); 456(7222): 593-8.) brings into question the rarity of existence of cancer stem cells and a detailed analysis of this publication has been made on various sites, including the Nature Publishing Group's blog, "The Niche". Jim Till, who is a member of the Board of Directors of the Cancer Stem Cell Consortium (CSCC), based in Ottawa, Canada, does a comprehensive review of literature on the topic and the implication of this particular study. Another comprehensive blog run by Alexey Bersenev of Children's Hospital of Philadephia summarizes the findings on the topic with a stem cells perspective in hematological malignancies.
There are few points that emerge from these discussions:
Cancer stem cells don't necessarily have to be rare.
The results of this particular study can not be generalized to all malignancies.
The most important point that emerges from these exhaustive discourses of the subject is that there is a need to identify and understand that population of cells which is resistant to therapy. This unequivocally points towards cells which we now label as cancer stem cells, be it the hematological malignancies or of solid tumors like breast or brain tumors.
This particular study doesn't imply in any way to reject the well established stem cell hypothesis, for example, in the case of brain tumors. It would not have any implications what so ever, admits Dr. Peter Dirks whose team first identified brain tumor stem cells. He professes that the results in the case of brain malignancies would not change much as immune responses are already crippled in brain milieu against tumors. Further readings about lowered immune reactivity against malignant cells, from an earlier, though unethical, study are available here.
In case of brain tumors, the question is not whether CD-133 is a marker for brain tumor stem cells but it is more of this marker being necessary and sufficient. There is little doubt about it being sufficient as xenografting of cells expressing CD-133 were able to recapitulate tumor characteristics at numbers as low as 100 whereas even 100,000 of CD133 negative cells were not able to initiate tumors. It is not by chance that the same cells expressing this marker happen to be resistant to chemotherapy and radiotherapy. It is also not serendipitous for these cells to be present at lower proportions in low grade gliomas and at higher numbers in high grade tumors like glioblastomas. So from a purely translational-research perspective, and borrowing from Jim Till's argument and from Jenny Chang's argument that in the clinical setting, the only importance is ‘what are the characteristics of the resistant population that appear to be able to make new cancers, we can conclude that this should be our main point of focus.
All these observations point towards, though an obvious, fact that cancers comprise of very heterogeneous population of cells. A recent BMC article by Zhang et al (J Exp Clin Cancer Res. 2008 Dec 24;27(1):85.) addresses their significance by using a combination makers such as Nestin and CD-133 by employing immunohistochemistry to positively identify brain tumor stem cells. The use of more than one marker should suffice in addressing the controversy surrounding any single marker, and there should be an active search for newer more specific markers.
Finally, coming to the debate of "cells of origin" and CSCs, many points have been made in both of these blogs about not confusing the two, though indirectly hardly any ambiguity remains as to what would the cells of origin for tumors and of stem cells present in these tumors be. Much indirect evidence comes from studies in mouse models and Dr. Alvarez-Buylla and Dr. Luis F. Parada just published their finding in Cancer Cell. 2009 Jan 6;15(1):45-56, lending further support to the already accumulating evidence that tries to answer the cells of origin question, at least in part for brain tumors. Here is what John Dick, who identified for the first time human CSCs from leukemic patients, says about the "cells of origin" dilemma that should clarify some of the ambiguity:
"As a final point, we would like to re-iterate the distinction between the concepts of CSCs (cells within a tumor that possess stem-like properties) and “cell of origin” (the normal cell type in which the tumorigenic process is initiated, whether a stem cell or progenitor). The CSC model does not make any assumptions regarding the origins of CSCs – indeed, there is now abundant evidence that CSCs in mice may arise from either normal stem or progenitor cells depending on the specific transforming events, although evidence in human cancers is still lacking."
Transcriptomic, proteomic, bioinformatics, nanotechnology or systems biology etc, whatever the means may be, a better understaning of the resistant population of cells is necessary if only we are to eradicate brain tumors. Equally important is the understanding of approaches, for example immunological, pharmacological, osmotic, oncolytic viruses, gene therapy, microRNA or nanotechnology based approaches that employ various combinations of available technique, in order to get rid of brain tumors, after all responses tend to stall after some time following exposure to these therapeutic strategies. The goal is to ameliorate human suffering, decrease morbidity and mortality, improve quality of life, and increase longevity with the ultimate aim to cure the disease. What, therefore, matters is the end, not the means to an end but equally important are the resources that remain limited, thus dictating us further in allocating them wisely.
There are few points that emerge from these discussions:
Cancer stem cells don't necessarily have to be rare.
The results of this particular study can not be generalized to all malignancies.
The most important point that emerges from these exhaustive discourses of the subject is that there is a need to identify and understand that population of cells which is resistant to therapy. This unequivocally points towards cells which we now label as cancer stem cells, be it the hematological malignancies or of solid tumors like breast or brain tumors.
This particular study doesn't imply in any way to reject the well established stem cell hypothesis, for example, in the case of brain tumors. It would not have any implications what so ever, admits Dr. Peter Dirks whose team first identified brain tumor stem cells. He professes that the results in the case of brain malignancies would not change much as immune responses are already crippled in brain milieu against tumors. Further readings about lowered immune reactivity against malignant cells, from an earlier, though unethical, study are available here.
In case of brain tumors, the question is not whether CD-133 is a marker for brain tumor stem cells but it is more of this marker being necessary and sufficient. There is little doubt about it being sufficient as xenografting of cells expressing CD-133 were able to recapitulate tumor characteristics at numbers as low as 100 whereas even 100,000 of CD133 negative cells were not able to initiate tumors. It is not by chance that the same cells expressing this marker happen to be resistant to chemotherapy and radiotherapy. It is also not serendipitous for these cells to be present at lower proportions in low grade gliomas and at higher numbers in high grade tumors like glioblastomas. So from a purely translational-research perspective, and borrowing from Jim Till's argument and from Jenny Chang's argument that in the clinical setting, the only importance is ‘what are the characteristics of the resistant population that appear to be able to make new cancers, we can conclude that this should be our main point of focus.
All these observations point towards, though an obvious, fact that cancers comprise of very heterogeneous population of cells. A recent BMC article by Zhang et al (J Exp Clin Cancer Res. 2008 Dec 24;27(1):85.) addresses their significance by using a combination makers such as Nestin and CD-133 by employing immunohistochemistry to positively identify brain tumor stem cells. The use of more than one marker should suffice in addressing the controversy surrounding any single marker, and there should be an active search for newer more specific markers.
Finally, coming to the debate of "cells of origin" and CSCs, many points have been made in both of these blogs about not confusing the two, though indirectly hardly any ambiguity remains as to what would the cells of origin for tumors and of stem cells present in these tumors be. Much indirect evidence comes from studies in mouse models and Dr. Alvarez-Buylla and Dr. Luis F. Parada just published their finding in Cancer Cell. 2009 Jan 6;15(1):45-56, lending further support to the already accumulating evidence that tries to answer the cells of origin question, at least in part for brain tumors. Here is what John Dick, who identified for the first time human CSCs from leukemic patients, says about the "cells of origin" dilemma that should clarify some of the ambiguity:
"As a final point, we would like to re-iterate the distinction between the concepts of CSCs (cells within a tumor that possess stem-like properties) and “cell of origin” (the normal cell type in which the tumorigenic process is initiated, whether a stem cell or progenitor). The CSC model does not make any assumptions regarding the origins of CSCs – indeed, there is now abundant evidence that CSCs in mice may arise from either normal stem or progenitor cells depending on the specific transforming events, although evidence in human cancers is still lacking."
Transcriptomic, proteomic, bioinformatics, nanotechnology or systems biology etc, whatever the means may be, a better understaning of the resistant population of cells is necessary if only we are to eradicate brain tumors. Equally important is the understanding of approaches, for example immunological, pharmacological, osmotic, oncolytic viruses, gene therapy, microRNA or nanotechnology based approaches that employ various combinations of available technique, in order to get rid of brain tumors, after all responses tend to stall after some time following exposure to these therapeutic strategies. The goal is to ameliorate human suffering, decrease morbidity and mortality, improve quality of life, and increase longevity with the ultimate aim to cure the disease. What, therefore, matters is the end, not the means to an end but equally important are the resources that remain limited, thus dictating us further in allocating them wisely.
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