In a previous post I tried to summarize the major points underlying the Cancer Stem Cell Hypothesis, which states that tumors are hierarchically structured and that a particular subpopulation of cells, cancer stem cells (CSCs), are capable of initiating and sustaining the growth of the tumor [Cancer Stem Cells: the root of all evil?]. This has obvious clinical implications since eliminating these cells would lead to the definitive disappearance of the tumor.A recent issue of Cell featured an article addressing one of the major questions in cancer biology nowadays: can we selectively target cancer stem cells within the whole tumor?
This paper tries to answer this question by developing a high-throughput screening method to identify chemical agents that could selectively target the CSC population within the tumor. This is a technically challenging matter to address since CSCs have been reported to be a very small subpopulation within the tumor and hard to maintain in culture.
To circumvent these problems, the authors sought to enrich CSCs in a cultured breast cancer cell line. They performed this by inducing a mesenchymal phenotype on the cells, a phenomenon known as epithelial to mesenchymal transition (EMT). This was based on a previous publication from the same group (Mani et al, 2008), where they showed that EMT-induced cells are enriched in all the phenotypical features of CSCs.
After setting this "CSC culture" up, they screened ~16,000 compounds for their effects on these cells and control ones (that is, EMT-induced and control cells).
The screen revealed that about 10% of the compounds had an effect on the viability of both cell populations. Interestingly, they found that 32 compounds showed selective toxicity on the CSC population and had no effect on the control cells (which could be considered as “bulk” population, see Cancer Stem Cells: the root of all evil?). From these 32, only 4 showed consistent evidence of selective toxicity on these cells and they decided (mainly because of availability issues ,as they claim) to continue their work with only one of these compounds: salinomycin. It's noteworthy that the authors state that upon further retesting of the libraries, more compounds exhibited EMT-specific toxicity, thus suggesting that more thorough screenings using different compound libraries should be done.
Notably, salinomycin treatment indeed decreased the CSC subpopulation (defined as CD44high/CD24low cells) within breast cancer cells, while paclitaxel (a commonly used chemotherapeutic drug) treatment led to an enrichment of these cells, thus showing that in their system, the use of conventional chemotherapy can only effectively target the bulk of the tumoral population.
If these results hold true, it could mean that current therapies are effectively targeting the non-CSC population, thus slowing the tumoral progression, however not stopping it in the long run (it’s widely known that cancer recurrance is one of the major issues in cancer treatment). This relapse could be due to the enrichment of CSCs led to by conventional therapies. It is then possible that the use of selective inhibitors of CSCs as therapeutical adjuvants could then lead to better treatments (i.e. a combination of paclitaxel and salinomycin for breast cancer, for example).
It still remains to be seen whether the findings shown in this study are applicable in clinical settings, which takes me to the caveats of this paper: my main criticism regards the lack of validation in human samples. Every single experiment, (which as everyone knows in a Cell paper means a lot of data) is done with cell lines. The authors could have exploited their findings to analyze how xenografts of human breast tumors behave when mice are treated with the drug, for example. Furthermore, they could have analyzed if spontaneously generated breast tumors (such as the MMTV-PyMT model) respond to salinomycin alone or in combination with paclitaxel. Both the use of primary human breast tumors and spontaneous models of breast cancer would give much more insight into the potential of this compound in targeting CSCs in vivo.
The authors conclude:
The field of CSCs is moving quite fast these days and exciting new findings are being published regularly. To conclude this post I just want to give a word of caution to most people outside the field (or even misinformed people in the field), regarding the conclusions that can be drawn from all the research being done. Only time will tell if the CSC hypothesis holds true for all or certain types of tumors and whether if this has any clinical relevance. Despite this warning and all of the issues raised, these are very interesting times to be involved in biomedicine.
To circumvent these problems, the authors sought to enrich CSCs in a cultured breast cancer cell line. They performed this by inducing a mesenchymal phenotype on the cells, a phenomenon known as epithelial to mesenchymal transition (EMT). This was based on a previous publication from the same group (Mani et al, 2008), where they showed that EMT-induced cells are enriched in all the phenotypical features of CSCs.
After setting this "CSC culture" up, they screened ~16,000 compounds for their effects on these cells and control ones (that is, EMT-induced and control cells).
The screen revealed that about 10% of the compounds had an effect on the viability of both cell populations. Interestingly, they found that 32 compounds showed selective toxicity on the CSC population and had no effect on the control cells (which could be considered as “bulk” population, see Cancer Stem Cells: the root of all evil?). From these 32, only 4 showed consistent evidence of selective toxicity on these cells and they decided (mainly because of availability issues ,as they claim) to continue their work with only one of these compounds: salinomycin. It's noteworthy that the authors state that upon further retesting of the libraries, more compounds exhibited EMT-specific toxicity, thus suggesting that more thorough screenings using different compound libraries should be done.
Notably, salinomycin treatment indeed decreased the CSC subpopulation (defined as CD44high/CD24low cells) within breast cancer cells, while paclitaxel (a commonly used chemotherapeutic drug) treatment led to an enrichment of these cells, thus showing that in their system, the use of conventional chemotherapy can only effectively target the bulk of the tumoral population.
If these results hold true, it could mean that current therapies are effectively targeting the non-CSC population, thus slowing the tumoral progression, however not stopping it in the long run (it’s widely known that cancer recurrance is one of the major issues in cancer treatment). This relapse could be due to the enrichment of CSCs led to by conventional therapies. It is then possible that the use of selective inhibitors of CSCs as therapeutical adjuvants could then lead to better treatments (i.e. a combination of paclitaxel and salinomycin for breast cancer, for example).
It still remains to be seen whether the findings shown in this study are applicable in clinical settings, which takes me to the caveats of this paper: my main criticism regards the lack of validation in human samples. Every single experiment, (which as everyone knows in a Cell paper means a lot of data) is done with cell lines. The authors could have exploited their findings to analyze how xenografts of human breast tumors behave when mice are treated with the drug, for example. Furthermore, they could have analyzed if spontaneously generated breast tumors (such as the MMTV-PyMT model) respond to salinomycin alone or in combination with paclitaxel. Both the use of primary human breast tumors and spontaneous models of breast cancer would give much more insight into the potential of this compound in targeting CSCs in vivo.
The authors conclude:
“The importance of targeting CSCs derives from the multiple observations showing that CSCs, in addition to having increased tumor-seeding potential, are resistant to a variety of chemotherapy drugs and radiation treatment. As is shown here and elsewhere (Fillmore and Kuperwasser, 2008), treatment with paclitaxel actually imposes a strong selection for CSC survival and expansion. This suggests that in cases where chemotherapy or radiation treatment fail to completely eradicate the disease, the residual cancer cells will be highly enriched for cells that persist in a CSC/mesenchymal state. This notion is supported by recent clinical observations showing that after conventional chemotherapy, breast tumors have an increased proportion of cells with a CD44hi/CD24lo marker profile and increased tumorsphere- forming ability (Li et al., 2008). Collectively, these considerations indicate that to be effective in the long-term, cancer therapies should include agents that target CSCs to prevent the regrowth of neoplastic cell populations”
The field of CSCs is moving quite fast these days and exciting new findings are being published regularly. To conclude this post I just want to give a word of caution to most people outside the field (or even misinformed people in the field), regarding the conclusions that can be drawn from all the research being done. Only time will tell if the CSC hypothesis holds true for all or certain types of tumors and whether if this has any clinical relevance. Despite this warning and all of the issues raised, these are very interesting times to be involved in biomedicine.
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Gupta, P., Onder, T., Jiang, G., Tao, K., Kuperwasser, C., Weinberg, R., & Lander, E. (2009). Identification of Selective Inhibitors of Cancer Stem Cells by High-Throughput Screening Cell, 138 (4), 645-659 DOI: 10.1016/j.cell.2009.06.034
MANI, S., GUO, W., LIAO, M., EATON, E., AYYANAN, A., ZHOU, A., BROOKS, M., REINHARD, F., ZHANG, C., & SHIPITSIN, M. (2008). The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells Cell, 133 (4), 704-715 DOI: 10.1016/j.cell.2008.03.027
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