Hypothesis suggesting origin of cancer stem cells
T1 - Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy
Neural Stem Cells and the Origin of Gliomas — NEJM
N2 - With the advent of the cancer stem cell hypothesis, the field of cancer research has experienced a revolution in how we think of and approach cancer. The discovery of "brain tumor stem cells" has offered an explanation for several long-standing conundrums on why brain tumors behave the way they do to treatment. Despite the great amount of research that has been done in order to understand the molecular aspects of malignant gliomas, the prognosis of brain tumors remains dismal. The slow progress in extending the survival of patients with malignant CNS neoplasms is very likely due to poor understanding of the cell of origin in these tumors. This review article discusses the progress in our understanding of brain tumor stem cells as the cell of origin in brain cancers. We review the different proposed mechanisms of how brain tumor stem cells may originate, the intracellular pathways disrupted in the pathogenesis of BTSCs, the molecular markers used to identify BTSCs, the molecular mechanisms of cancer initiation and progression, and finally the clinical implications of this research.
It is believed, that in most cancers therapy targeted to cancer stem cells might be curative. However, multiple evidence has recently indicated that GCSCs may not represent a restricted and infrequent GBM component; rather, they might constitute most cells within the tumor bulk (Mazzoleni and Galli, 2012; Kondo et al., 2004; Zheng et al., 2007; Zhou et al., 2009).
Development of novel chemotherapeutic agents targeted to glioblastoma stem cells is of great interest. It is likely that all agents molecularly targeted to GCSCs will have cytostatic, but not cytotoxic inhibitory effects. Obviously, the combination of targeted cytostatic effects together with toxic effects to GCSCs and to the vascular niche would be necessary to achieve the elimination of those highly resistant non-diving cells. Some examples of inhibitors mainly acting on pathways important for GCSCs survival have been mentioned. Sai et al. 2012 found that a novel small molecule inhibitor of the JAK2/STAT3 pathway, WP1193, induced cell-cycle arrest and apoptosis in glioblastoma stem-like cells. WP1193 significantly decreased the proliferation of established glioma cell lines in vitro and inhibited the growth of glioma in vivo. Zhuang et al., 2012 reported that curcumin, a natural compound with low toxicity to normal cells, significantly induced differentiation of GCsCs in vivo and in vitro by inducing autophagy.
The Notch1-mediated signaling pathway has a central role in the maintenance of neural stem cells and contributes to growth and progression of glioblastomas. Fassl et al., 2011 demonstrated that the receptor promotes survival of glioblastoma cells by regulation of the anti-apoptotic Mcl-1 protein. They have shown that inhibition of the Notch1 pathway overcomes apoptosis resistance and sensitizes glioblastoma cells to apoptosis induced by ionizing radiation. Similar observations were reported by Wang et al., 2010. Inhibition of Sonic hedgehog and Notch pathways enhances sensitivity of CD133+ glioma stem cells to temozolomide therapy (Ulasov et al., 2011). Glioblastoma cells grown in neural stem cell medium, supplemented with epidermal growth factor and form spheroids are regarded as GCSCs . Ledur et al., 2012 reported that human U87 glioma form spheroids expressing the markers of glioma cancer stem cells CD133, Oct-4, and . However, messenger RNAs for several purinergic receptors were differently expressed in spheroids when compared to a cell monolayer not containing spheroids. Treatment of human gliomas U87 or U343, as well as rat C6 gliomas, with 100 µM ATP reduced the number of tumor spheroids in a dose-dependent manner. ATP also reduced the expression of Nanog, CD133 and Oct-4 showing that the purinergic system affects GCSC biology.
To block brain tumor stem cell self renewal and promote differentiation particularly if terminally differentiated cell types can be generated, such as neurons, may be another useful strategy for glioblastoma treatment (for a review see Dirks, 2010). Piccirillo and Vescovi, 2006 have shown that promotion of bone morphogenic protein 4 signaling can enhance GCSCs differentiation and attenuate tumorigenic phenotype. Thus the differentiation therapy being successful in treatment of acute promyelocytic leukemia might be another approach worth to be studied.
Glioblastomas are highly vascular tumors. Therefore, it was expected that agents targeting angiogenesis may have efficacy. Recent preclinical and clinical investigations have revealed that agents targeting angiogenesis did not fulfill these expectations. Reasons for failure and new strategies based on molecular mechanisms of tumor vessel formation have been discussed by Tokano, 2012. Using patient derived specimens of glioblastoma, a subpopulation of GCSCs was identified being enriched for (high)/Id1(high) cells, which tend to be located in a perivascular niche. It was found that growth of the CD44(high)/Id1(high) cells was inhibited by TGF-β inhibitors. Repression of DNA-binding protein (Id)-1 and -3 transcription factors decreased the GCSCs population that might inhibit the capacity of cells to initiate tumors (Anido et al., 2010).
Cellular origin of cancer: differentiation or stem cell maturation ..
AB - A major advance in recent cancer research is the identification of tumor cells with stem cell-like properties. Cancer stem cells (CSCs) often represent a rare population in the tumor mass and possess the exclusive ability to initiate the growth of a heterogeneous tumor. The origin of CSCs remains elusive and is likely to be cancer type specific. One possible but under-appreciated potential mechanism for the generation of CSCs is through fusion between stem cells and differentiated cells. The cell fusion hypothesis of CSCs adds an important functional underpinning to the potential multifaceted roles of cell fusion in the initiation and progression of cancer.
The idea that cancers are driven by cells with “embryonic features” is an old one. Many cancers regress to a less differentiated state, expressing proteins that are usually expressed only in the embryo or during early development. It is only in the past 20 years or so, however, that additional observations led to the hypothesis that these embryonic-like cells were a separate subpopulation that fueled tumor expansion, much the same way that stem cells churn out the cells that make up a particular organ.
Implications of the cancer stem-cell hypothesis for …
Antiangiogenic agents are another treatment whose administration may need to be rethought in light of what we now know about CSC biology. The development of antiangiogenic agents such as bevacizumab (Avastin) and sunitinib (Sutent) represented an area of significant promise in cancer. However, recent clinical trials have produced relatively disappointing results. Although these agents delay tumor progression, they do not significantly increase patient survival. Our group has demonstrated that in mouse models, these antiangiogenic agents actually increase CSC populations through generation of tumor hypoxia, or low oxygenation,which drives the proliferation of CSCs by triggering the Akt and Wnt pathways.[10. S.J. Conley et al., “Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia,” , 109:2784-89, 2012.] This suggests that, to be clinically effective, these agents may require additional therapies capable of targeting CSC populations.
Statistic data of cancer patient survival revealed that the most successful cancer therapy is surgery when applied early. Elimination of both dividing tumor cells and cancer stem cells before they can spread could provide a cure. This is usually not possible with high-grade brain tumors. At present, the standard therapy for GBM patients, consisting of tumor debulking, followed by radiotherapy and chemotherapy, is not a curative approach. There is increasing evidence that cytotoxic therapies select for more aggressive GTSCs. Recently developed tumor targeting therapy, driven by mesenchymal (stromal) stem cells (MSCs ) possessing tumor tropic properties, brought hope for a novel therapeutic modality (Studeny et al., 2002; Studeny et al., 2004; Kucerova et al., 2007; Kucerova et al., 2008; Kucerova et al., 2010; Cavarretta et al., 2010; for a review see Altaner, 2008a). Prodrug cancer gene therapy mediated by MSCs transduced with yeast CD::UPRT might be one of several treatments with potential for curative therapy of high-grade brain tumors (Altanerova et al., 2012). The stem cell driven cytosine deaminase/5-FC system represents an attractive tool for activating the prodrug directly within the tumor mass, resulting in high local 5-FU concentrations without systemic toxicity. Expression of the yeast CD::UPRT fused gene (Kievit et al., 2000) and formation of 5-FU cause inhibition of both DNA and RNA synthesis, consequently leading to death of dividing and non-dividing cells, thus attacking GCSCs. In addition, mesenchymal stem cells transduced with cytosine deaminase induce the expression of pro-apoptopic genes in tumor cells (Cihova et al., 2011).
Mesenchymal stem cells have many attributes that support their use as a tumor specific therapeutic vehicle in clinical practice. It has been shown that MSCs share some characteristics with pericytes (Bexell et al., 2009; Bexell et al., 2010). This property might facilitate the migration of MSCs to highly vascularised glioblastomas. MSCs lack major histocompatibility complex MHC-II and show only minimal MHC-I expression (LeBlanc, 2003; Koppula et al., 2009; Griffin et al., 2010). Thanks to their non imunogenic character, allogeneic MSCs can substitute for autologous stem cells. We and others (Danks et al., 2007; Nakamura et al., 2004; Nakamizo et al., 2005) are encouraged by the results of stem cell driven enzyme prodrug therapy experiments to treat glioblastoma multiforme, a tumor with fatal prognosis. Our experiments took the advantage of the fact that human AT-MSCs are not immunogenic in treatment of rat glioblastoma C6 growing intracebroventriculary. The cell population of C6 rat glioblastoma has been shown to be composed primarily of cancer stem cells. Therapeutic experiments were designed to simulate scenarios for future clinical applications for high-grade glioblastoma therapy by direct injections of therapeutic stem cells into the tumor. The results revealed that genetically modified therapeutic stem cells labeled with super paramagnetic iron nanoparticles still have the tumor tropism when injected to a distant intracranial site and effectively inhibited glioblastoma growth after 5-FC therapy (Altanerova et al., 2012). Intratumoral administration of therapeutic stem cells improved the survival in a cell dose-dependent manner. Furthermore, the repeated administration of therapeutic cells and continuous intracerebroventricular delivery of 5-FC led to an increased number of animals being completely cured.
and we would hypothesis that the germ cell cancer stem cells ..
05/11/2013 · Cell of origin and cancer stem cells ..
20/12/2017 · Basal cell carcinoma: Cell of origin, cancer stem cell hypothesis and stem cell markers
The theory of a stem-cell origin of cancer is ..
The prevalence of stem-ness in cancer suggests that cancer has a stem-cell origin and is a stem-cell ..
on a tumor's "cell of origin"
Doug Melton and Nadia Rosenthal are leaders in stem cell research, working primarily with mouse and human tissue
Thus, the question, "Are stem cells involved in cancer?"
According to the cancer stem cell hypothesis, only cancer stem cells have self-renewal ability and the rest of the tumor cells would die out without being replenished from the cancer stem cells. One of the predictions of this hypothesis is that tumor progression-driving genetic events may only accumulate in cancer stem cells, since other cells are presumed to be evolutionary ‘dead ends’. A major problem with this hypothesis is that it assumes stability within the tumor and does not consider the possibility that the cancer stem cell phenotype can be acquired. However, several studies have demonstrated that more differentiated cancer cells can acquire mutation (eg, β-catenin mutation) or activate a transcription factor (eg, FOXC2 or some other stem cell phenotype-inducing transcription factor) and become cancer stem cells (). Thus, essentially we are back to where we were and what we knew for decades: tumors are diverse, genetically unstable, and evolve due to the intra-tumoral diversity of cellular genotypes and phenotypes. Recent papers by several groups have shown that even a normal human differentiated cell can be converted to a functional pluripotent embryonic stem cell just by expressing the right combination of transcription factors in them. Thus, the question is what would prevent a ‘differentiated’ cancer cell from acquiring similar changes and become a cancer stem cell?
Presentation of the hypothesis.
While there are many similarities, there also are differences between cancer and normal stem cells. Unlike normal stem cells that represent a very small population of cells in the tissue they reside in, putative cancer stem cells can make a rather significant portion of tumor cells. In breast cancer, putative cancer stem cells with CD24−/low/CD44+ phenotype constituted 12–60% of the tumor cells, whereas in colon cancer, CD133+ putative cancer stem cells ranged from 3.8 to 24.6% of total tumor cells;,, thus, it is possible that in poorly differentiated tumors, cancer stem cells constitute the majority of tumor cells. In fact, based on recent mathematical calculations determining the probability of tumor growth after treatment, the assumption that cancer stem cells represent a small fraction of all cancer cells in an advanced stage tumor does not appear to be correct.
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