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Tumour-initiating cells vs. cancer ‘stem’ cells and CD133: What’s in the name?
Biochemical and Biophysical Research Communications 355 (2007) 855–859 www.elsevier.com/locate/ybbrc
Mini review
Tumour-initiating cells vs. cancer ‘stem’ cells and CD133: What’s in the name? Jiri Neuzil a,b,*, Marina Stantic a, Renata Zobalova a,b, Jaromira Chladova b, Xiufang Wang a, Lubomir Prochazka a,c, Lanfeng Dong a, Ladislav Andera d, Stephen J. Ralph e a Apoptosis Research Group, School of Medical Science, Griffith University, Southport, Qld, Australia Molecular Therapy Group, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic c Veterinary Research Institute, Brno, Czech Republic Laboratory of Apoptosis and Cell Signalling, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic e Genomics Research Centre, School of Medical Science, Griffith University, Southport, Qld, Australia b
d
Received 22 January 2007 Available online 6 February 2007
Abstract Recent evidence suggests that a subset of cells within a tumour have ‘stem-like’ characteristics. These tumour-initiating cells, distinct from non-malignant stem cells, show low proliferative rates, high self-renewing capacity, propensity to differentiate into actively proliferating tumour cells, resistance to chemotherapy or radiation, and they are often characterised by elevated expression of the stem cell surface marker CD133. Understanding the molecular biology of the CD133+ cancer cells is now essential for developing more effective cancer treatments. These may include drugs targeting organelles, such as mitochondria or lysosomes, using highly efficient and selective inducers of apoptosis. Alternatively, agents or treatment regimens that enhance sensitivity of these therapy-resistant ‘‘tumour stem cells’’ to the current or emerging anti-tumour drugs would be of interest as well. Ó 2007 Published by Elsevier Inc. Keywords: Tumour-initiating cells; CD133; Resistance to treatment
Over the last decade, improvements in cancer therapies have prolonged the lives of cancer patients. However, after apparently successful initial therapy and recovery, there is often development of secondary tumours leading to the relapse of the disease. It is well established that primary tumours are clonally derived and arise after sequential DNA mutations in key genes regulating growth, which are largely a result of genetic instability [1]. The hallmarks of most cancer cells include: (i) self-sufficiency for growth signals; (ii) insensitivity to growth-inhibitory (anti-growth) signals; (iii) evasion of programmed cell death (apoptosis); (iv) unlimited replicative potential; (v) sustained angiogenesis; and (vi) tissue invasion and metastasis [1]. While these * Corresponding author. Address: Apoptosis Research Group, School of Medical Science and Griffith Institute of Health and Medical Research, Griffith University, Southport, 9716 Qld, Australia. Fax: +61 2 555 28444. E-mail address: j.neuzil@griffith.edu.au (J. Neuzil).
0006-291X/$ - see front matter Ó 2007 Published by Elsevier Inc. doi:10.1016/j.bbrc.2007.01.159
features may be inherent to the majority of cells in a tumour, tumours also contain a small sub-population of cells that have characteristics of somatic stem cells capable of self-renewal, asymmetric division and multilineage differentiation [2,3]. Often this small sub-population is referred to as side-population because these tumour stem cells can actively exclude fluorescent DNA staining dyes [4]. These tumour-initiating cells (TICs) have been identified in leukemias [5,6], multiple myelomas [7], neoplasias of the nervous system [3,8–10], colorectal, prostate or hepatocellular carcinomas [11–15], and tissues prone to cancer development. The precise identity of the TICs and their relationship to stem cells is currently uncertain. The existence of normal stem cells is well established, and these cells may undergo mutations and give rise to tumours [16,17]. In addition, there are also cells or cellular structures that promote tumour development by inducing angiogenesis [18]. In this
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communication, we focus on the small resident population of cells within a tumour mass that can give rise to secondary tumours as it is likely that these cells are a major source of cancer recurrence after apparently successful therapy. Since these stem-like cells cause induction (initiation) of tumours in immunocompromised mice, we will refer to them as TICs [3,19]. Since the presence of tumour-initiating cells within a cancerous mass greatly impairs long-term survival after therapy, it is imperative to understand the characteristics of such cells, including their specific markers, bioenergetics, and the molecular mechanism for their resistance to chemotherapy in order to design more efficient ways to eradicate them during the treatment of primary malignancies and to prevent tumour recurrence [20–22]. CD133, a marker of tumour-initiating cells A variety of markers have been used to characterise the stem-like tumour-initiating cells. For example, in leukemias, TICs feature the CD44+/CD38 phenotype [5]. The prostate cancer TICs have been characterised by the þ CD44þ =a2 bhi 1 =CD133 phenotype [13]. About 0.1% of cells within prostate tumours expressed this phenotype, and they had the capacity for self-renewal, although their number did not correlate with the tumour grade or the metastatic state. Brain TICs often feature the CD133+/ musashi-1+/nestin+ or similar phenotypes, which suggests the ‘stemness’ of the cells and their propensity to differentiate [23–25]. In breast tissue, a side-population exists that has been phenotypically characterised as Lin/CD29hi/ CD24+ [26,27]. A single normal mammary epithelial cell with this phenotype, when implanted into the mammary tissue of the MMTV-wnt-1 mice, could reconstitute a complete mammary gland in vivo, which may have important implications for tumorigenesis. A side-population has been discovered within hematopoietic cells with the Lin/ CD34/CD38 phenotype capable of repopulating the non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice [6]. While TICs specific for various tissues differ in their phenotype, various TICs, in particular those of the epithelial origin, share a unifying phenotype with high levels of CD133 expression [28,29]. CD133, also known as prominin-1 [30], is a cell-surface glycoprotein comprising five trans-membrane domains and two large glycosylated extracellular loops. It was first isolated from hematopoietic stem cells and was found to localise to membrane protrusions [31]. The function of CD133 has not been established thus far but it could participate in the regulation of membrane topology [30]. CD133/prominin-1 is enriched in cholesterol rich membrane microdomains and its mutations cause human retinal degeneration [32,33]. Its transcription can be initiated at five tissuespecific promoters, yielding formation of alternatively spliced transcripts [34,35]. The prominin family also comprises prominin-2 that is a cholesterol binding pro-
tein also enriched in membrane microdomains and expressed at plasma membrane prorusions of epithelial cells [35,36]. High levels of CD133 expression is now accepted as an important marker for a number of different cell lineages [30], and expression of CD133 in peripheral blood correlates with bone metastasis in cancer patients [29]. Recent data revealed that CD133 is highly expressed in TIC populations, including medulloblastomas [8], glioblastomas [37,38], as well as prostate [13,28] and colon carcinomas [11,12]. Other reports, confirming that it is possible to preserve CD133+ cells in culture and use them for tumour generation in immunocompromised mice, should enable further molecular characterisation of TICs, including those from hepatocarcinoma cell lines [14,15]. Of the liver cancer cell lines tested, the Huh-7 cells were reported to contain as much as 50% CD133+ cells [14]. Huh-7 cells are, however, very low in the expression of CD34, CD29, CD44 and CD117 [14], and in our hands, the Huh-7 cell line only contained about 25% CD133+ cells [M. Stantic et al., unpublished data]. Subcutaneous implantation of the Huh-7 CD133+ cells in NOD/SCID mice, following their separation, resulted in the formation of tumours in the animals, whereas the Huh-7 CD133 cells failed to form tumours [14]. By comparison, the hepatocarcinoma cell line SMMC7721 contains only about 0.1–1% CD133+ cells [15]. As did the Huh-7 cells, the CD133+ SMMC7721 cells also formed carcinomas after injection into the liver of NOD/SCID mice. Interestingly, it was reported that 107 CD133+ Huh-7 cells were required for subcutaneous injection to form tumours, whereas as few as 103 CD133+ SMMC7721 cells were sufficient to form tumours in NOD/SCID mice [14,15]. It is possible that the higher number of the CD133+ Huh-7 cells needed was due to the location of the xenograft in the skin rather than the liver, which might indicate that tumorigenicity is more efficient when cancer cells are growing within their normal tissue. The above results raise the possibility that in xenograft models of cancer, i.e., implantation of cancer cells in immunocompromised mice, the tumours formed are due to the presence of a sub-population of CD133+ cells, perhaps comprising <1% of the total number of injected cells. This could explain why injecting between 106 and 107 of in vitro cultured cells is commonly required to ensure that tumours are reformed see, e.g., Refs. [39– 41]. This conclusion is further supported by the report [15] that some 99% of hepatocarcinoma SMMC7721 cells deficient in CD133, failed to form tumours when injected into the livers of NOD/SCID mice. Thus it is plausible that very low sub-population existing within the total population is responsible for tumour formation in immunocompromised mice while the vast majority of the tumour cell population does not form tumours. In summary, CD133 appears to be, thus far, the most important marker inherent to a number of types of TICs identified to date.
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Expression of CD133 and resistance to therapy A major problem with cancer cells that have stem-like characteristics and are capable of tumour initiation is their resistance to current therapies such as chemo- or radiotherapy [41–44]. It has been implied that during cancer therapy a low percentage of cells with stem-like features escapes the killing efficacy of established anti-cancer drugs. These cells can then give rise to secondary tumours that are highly resistant to further treatment since they were positively selected by the original therapy. CD133+ TICs are resistant to therapy [38], consistent with their stem-like nature as reported both for chemotherapy [41,42] and radiation treatment [43,44]. However, since the function of CD133 is unknown, it is not clear if CD133 is just a marker of resistant cells or whether high expression of CD133 in TICs could contribute to the resistance to therapy. A recent paper claimed that the ‘stemness’ of medulloblastoma-derived CD133+ cells was associated with the Notch signalling pathway [44]. The authors documented that blocking the Notch pathway by inhibiting c-secretase resulted in inhibition of expression of Hes1 and in induction of apoptosis in medulloblastoma [46]. Further, the more differentiated Notch-inhibited cell lines, while remaining viable, failed to form tumour xenografts when injected into NOD/SCID mice. Notch blockade also resulted in 5-fold loss in the CD133+ sub-population and in elimination of the CD133+ side-population featuring high Hoechst dye exclusion. In the highly aggressive brain tumour, glioblastoma multiforme, the HEDGEHOG (HH)-GLI pathway has been shown to regulate the self-renewal of the CD133+ cells and, importantly, expression of the ‘stemness signature’-associated genes, which include CD133, OLIG2, BMI1, BCAN, OCT.4, NANOG, PTEN, ABCG2, PDGFR-A, SOX2 and NRD1 [47]. Of these genes, most were over-expressed in the gliomasphere cultures. The HH pathway includes several signalling mediators, such as SMOOTHENED (SMO), that activates the GLI transcription factors [48]. Inhibition of the HH-GLI pathway using SMO shRNA reduced the proliferative rate of the CD133+ cells as well as their capacity to form gliomaspheres, and increased survival of mice with glioblastoma xenografts. Also, the anti-glioma drug temozolomide, while efficient in suppressing proliferation and survival of glioblastoma cell lines, failed to block the glioma cell self-renewal. On the other hand, the pharmacological inhibitor of the HHGLI pathway, cyclopamine, reduced the number of spheres, leading to the suggestion that combinatorial treatment might be used to eradicate the TICs in these cancers [47]. Liu et al. [38] studied the gene expression profile in CD133+ glioblastoma cell lines prepared from patients, and found that CD133+ cells expressed much higher levels of markers of neural precursors CD90, CD44, CXCR4, nestin, MsiI and MELK compared to their CD133 counterparts. Also, the CD133+ cells were found to express high levels of the anti-apoptotic genes Bcl-2, Bcl-xL, FLIP,
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c-IAP2, XIAP, NAIP and survivin by a factor of up to 150, while the expression of the pro-apoptotic Bax was depressed by 5-fold when compared to the corresponding CD133 cells. The CD133+ cells were resistant to etoposide, paclitaxel, temozolomide and carboplatin. Since CD133+ cells express high levels of the caspase-8 inhibitor FLIP, they can be expected to be resistant to induction of the extrinsic apoptotic signalling pathway. Moreover, expression of CD133 was much higher in the recurring glioblastoma multiforme than in newly diagnosed gliomas, again pointing to the critical importance of CD133 [38]. Several reports have highlighted upregulation of the ATPase pump ABCG5 in CD133+ cells, including the progenitor cells of human epidermal melanocytes and a subpopulation of malignant melanoma cells [49]. Frank et al. [43] recently showed that CD133+/ABCG5+ melanoma cells were resistant to doxorubicin treatment and that melanoma tissue isolated from patients expressed high levels of both CD133 and ABCG5. They suggested that ABCG5 could be used as a marker of chemoresistance and that it represented a useful target for therapy. CD133+ glioma cells are also resistant to radiation therapy [41]. These authors showed that following radiation, glioma cells acquired higher level of resistance, associated with increased CD133 expression, and that inhibiting the cell cycle checkpoint kinases Ch1 and Ch2 sensitised the resistant cells to radiation-induced killing. The research summarised above strongly links high expression of the surface marker CD133, tumour-initiating capacity of cancer cells and their greater resistance to radiotherapy, while suggesting potential methods for selectively eradicating the TICs by targeting associated signalling pathways [45,47], the cell cycle machinery [41], or using siRNA [50]. An alternative approach to eliminating tumour-initiating cells might be by targeting their mitochondria using mitocans, drugs that induce apoptosis by destabilising mitochondria [51,52]. There is preliminary evidence that sesquiterpene lactones or parthenolides may target mitochondria of TICs resulting in their death [53]. However it remains to be determined whether mitochondria in slow proliferating tumour-initiating cells are different from those in fast-proliferating non-tumour-renewing cancer cells or normal cells. Thus, it can be envisaged that mitocans will become useful for killing TICs either used alone or in combination with other approaches, such as diminishing the ‘stemness’ of these cells. While mitochondria may be different in the relatively slow-proliferating TICs compared with the high-proliferating more differentiated cancer cells, it can be anticipated that other organelles, such as lysosomes, may be unchanged, and can be utilised as an excellent target for killing cancer cells regardless of the CD133 status, providing development of cancer cellspecific lysosomotrophic agents [54,55]. In summary, a better understanding of the molecular mechanisms of resistance of TICs to anti-cancer drugs could provide novel ways to eradicate TICs within tumours and prevent the recurrence of cancers.
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Mini review
Tumour-initiating cells vs. cancer ‘stem’ cells and CD133: What’s in the name? Jiri Neuzil a,b,*, Marina Stantic a, Renata Zobalova a,b, Jaromira Chladova b, Xiufang Wang a, Lubomir Prochazka a,c, Lanfeng Dong a, Ladislav Andera d, Stephen J. Ralph e a Apoptosis Research Group, School of Medical Science, Griffith University, Southport, Qld, Australia Molecular Therapy Group, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic c Veterinary Research Institute, Brno, Czech Republic Laboratory of Apoptosis and Cell Signalling, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic e Genomics Research Centre, School of Medical Science, Griffith University, Southport, Qld, Australia b
d
Received 22 January 2007 Available online 6 February 2007
Abstract Recent evidence suggests that a subset of cells within a tumour have ‘stem-like’ characteristics. These tumour-initiating cells, distinct from non-malignant stem cells, show low proliferative rates, high self-renewing capacity, propensity to differentiate into actively proliferating tumour cells, resistance to chemotherapy or radiation, and they are often characterised by elevated expression of the stem cell surface marker CD133. Understanding the molecular biology of the CD133+ cancer cells is now essential for developing more effective cancer treatments. These may include drugs targeting organelles, such as mitochondria or lysosomes, using highly efficient and selective inducers of apoptosis. Alternatively, agents or treatment regimens that enhance sensitivity of these therapy-resistant ‘‘tumour stem cells’’ to the current or emerging anti-tumour drugs would be of interest as well. Ó 2007 Published by Elsevier Inc. Keywords: Tumour-initiating cells; CD133; Resistance to treatment
Over the last decade, improvements in cancer therapies have prolonged the lives of cancer patients. However, after apparently successful initial therapy and recovery, there is often development of secondary tumours leading to the relapse of the disease. It is well established that primary tumours are clonally derived and arise after sequential DNA mutations in key genes regulating growth, which are largely a result of genetic instability [1]. The hallmarks of most cancer cells include: (i) self-sufficiency for growth signals; (ii) insensitivity to growth-inhibitory (anti-growth) signals; (iii) evasion of programmed cell death (apoptosis); (iv) unlimited replicative potential; (v) sustained angiogenesis; and (vi) tissue invasion and metastasis [1]. While these * Corresponding author. Address: Apoptosis Research Group, School of Medical Science and Griffith Institute of Health and Medical Research, Griffith University, Southport, 9716 Qld, Australia. Fax: +61 2 555 28444. E-mail address: j.neuzil@griffith.edu.au (J. Neuzil).
0006-291X/$ - see front matter Ó 2007 Published by Elsevier Inc. doi:10.1016/j.bbrc.2007.01.159
features may be inherent to the majority of cells in a tumour, tumours also contain a small sub-population of cells that have characteristics of somatic stem cells capable of self-renewal, asymmetric division and multilineage differentiation [2,3]. Often this small sub-population is referred to as side-population because these tumour stem cells can actively exclude fluorescent DNA staining dyes [4]. These tumour-initiating cells (TICs) have been identified in leukemias [5,6], multiple myelomas [7], neoplasias of the nervous system [3,8–10], colorectal, prostate or hepatocellular carcinomas [11–15], and tissues prone to cancer development. The precise identity of the TICs and their relationship to stem cells is currently uncertain. The existence of normal stem cells is well established, and these cells may undergo mutations and give rise to tumours [16,17]. In addition, there are also cells or cellular structures that promote tumour development by inducing angiogenesis [18]. In this
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communication, we focus on the small resident population of cells within a tumour mass that can give rise to secondary tumours as it is likely that these cells are a major source of cancer recurrence after apparently successful therapy. Since these stem-like cells cause induction (initiation) of tumours in immunocompromised mice, we will refer to them as TICs [3,19]. Since the presence of tumour-initiating cells within a cancerous mass greatly impairs long-term survival after therapy, it is imperative to understand the characteristics of such cells, including their specific markers, bioenergetics, and the molecular mechanism for their resistance to chemotherapy in order to design more efficient ways to eradicate them during the treatment of primary malignancies and to prevent tumour recurrence [20–22]. CD133, a marker of tumour-initiating cells A variety of markers have been used to characterise the stem-like tumour-initiating cells. For example, in leukemias, TICs feature the CD44+/CD38 phenotype [5]. The prostate cancer TICs have been characterised by the þ CD44þ =a2 bhi 1 =CD133 phenotype [13]. About 0.1% of cells within prostate tumours expressed this phenotype, and they had the capacity for self-renewal, although their number did not correlate with the tumour grade or the metastatic state. Brain TICs often feature the CD133+/ musashi-1+/nestin+ or similar phenotypes, which suggests the ‘stemness’ of the cells and their propensity to differentiate [23–25]. In breast tissue, a side-population exists that has been phenotypically characterised as Lin/CD29hi/ CD24+ [26,27]. A single normal mammary epithelial cell with this phenotype, when implanted into the mammary tissue of the MMTV-wnt-1 mice, could reconstitute a complete mammary gland in vivo, which may have important implications for tumorigenesis. A side-population has been discovered within hematopoietic cells with the Lin/ CD34/CD38 phenotype capable of repopulating the non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice [6]. While TICs specific for various tissues differ in their phenotype, various TICs, in particular those of the epithelial origin, share a unifying phenotype with high levels of CD133 expression [28,29]. CD133, also known as prominin-1 [30], is a cell-surface glycoprotein comprising five trans-membrane domains and two large glycosylated extracellular loops. It was first isolated from hematopoietic stem cells and was found to localise to membrane protrusions [31]. The function of CD133 has not been established thus far but it could participate in the regulation of membrane topology [30]. CD133/prominin-1 is enriched in cholesterol rich membrane microdomains and its mutations cause human retinal degeneration [32,33]. Its transcription can be initiated at five tissuespecific promoters, yielding formation of alternatively spliced transcripts [34,35]. The prominin family also comprises prominin-2 that is a cholesterol binding pro-
tein also enriched in membrane microdomains and expressed at plasma membrane prorusions of epithelial cells [35,36]. High levels of CD133 expression is now accepted as an important marker for a number of different cell lineages [30], and expression of CD133 in peripheral blood correlates with bone metastasis in cancer patients [29]. Recent data revealed that CD133 is highly expressed in TIC populations, including medulloblastomas [8], glioblastomas [37,38], as well as prostate [13,28] and colon carcinomas [11,12]. Other reports, confirming that it is possible to preserve CD133+ cells in culture and use them for tumour generation in immunocompromised mice, should enable further molecular characterisation of TICs, including those from hepatocarcinoma cell lines [14,15]. Of the liver cancer cell lines tested, the Huh-7 cells were reported to contain as much as 50% CD133+ cells [14]. Huh-7 cells are, however, very low in the expression of CD34, CD29, CD44 and CD117 [14], and in our hands, the Huh-7 cell line only contained about 25% CD133+ cells [M. Stantic et al., unpublished data]. Subcutaneous implantation of the Huh-7 CD133+ cells in NOD/SCID mice, following their separation, resulted in the formation of tumours in the animals, whereas the Huh-7 CD133 cells failed to form tumours [14]. By comparison, the hepatocarcinoma cell line SMMC7721 contains only about 0.1–1% CD133+ cells [15]. As did the Huh-7 cells, the CD133+ SMMC7721 cells also formed carcinomas after injection into the liver of NOD/SCID mice. Interestingly, it was reported that 107 CD133+ Huh-7 cells were required for subcutaneous injection to form tumours, whereas as few as 103 CD133+ SMMC7721 cells were sufficient to form tumours in NOD/SCID mice [14,15]. It is possible that the higher number of the CD133+ Huh-7 cells needed was due to the location of the xenograft in the skin rather than the liver, which might indicate that tumorigenicity is more efficient when cancer cells are growing within their normal tissue. The above results raise the possibility that in xenograft models of cancer, i.e., implantation of cancer cells in immunocompromised mice, the tumours formed are due to the presence of a sub-population of CD133+ cells, perhaps comprising <1% of the total number of injected cells. This could explain why injecting between 106 and 107 of in vitro cultured cells is commonly required to ensure that tumours are reformed see, e.g., Refs. [39– 41]. This conclusion is further supported by the report [15] that some 99% of hepatocarcinoma SMMC7721 cells deficient in CD133, failed to form tumours when injected into the livers of NOD/SCID mice. Thus it is plausible that very low sub-population existing within the total population is responsible for tumour formation in immunocompromised mice while the vast majority of the tumour cell population does not form tumours. In summary, CD133 appears to be, thus far, the most important marker inherent to a number of types of TICs identified to date.
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Expression of CD133 and resistance to therapy A major problem with cancer cells that have stem-like characteristics and are capable of tumour initiation is their resistance to current therapies such as chemo- or radiotherapy [41–44]. It has been implied that during cancer therapy a low percentage of cells with stem-like features escapes the killing efficacy of established anti-cancer drugs. These cells can then give rise to secondary tumours that are highly resistant to further treatment since they were positively selected by the original therapy. CD133+ TICs are resistant to therapy [38], consistent with their stem-like nature as reported both for chemotherapy [41,42] and radiation treatment [43,44]. However, since the function of CD133 is unknown, it is not clear if CD133 is just a marker of resistant cells or whether high expression of CD133 in TICs could contribute to the resistance to therapy. A recent paper claimed that the ‘stemness’ of medulloblastoma-derived CD133+ cells was associated with the Notch signalling pathway [44]. The authors documented that blocking the Notch pathway by inhibiting c-secretase resulted in inhibition of expression of Hes1 and in induction of apoptosis in medulloblastoma [46]. Further, the more differentiated Notch-inhibited cell lines, while remaining viable, failed to form tumour xenografts when injected into NOD/SCID mice. Notch blockade also resulted in 5-fold loss in the CD133+ sub-population and in elimination of the CD133+ side-population featuring high Hoechst dye exclusion. In the highly aggressive brain tumour, glioblastoma multiforme, the HEDGEHOG (HH)-GLI pathway has been shown to regulate the self-renewal of the CD133+ cells and, importantly, expression of the ‘stemness signature’-associated genes, which include CD133, OLIG2, BMI1, BCAN, OCT.4, NANOG, PTEN, ABCG2, PDGFR-A, SOX2 and NRD1 [47]. Of these genes, most were over-expressed in the gliomasphere cultures. The HH pathway includes several signalling mediators, such as SMOOTHENED (SMO), that activates the GLI transcription factors [48]. Inhibition of the HH-GLI pathway using SMO shRNA reduced the proliferative rate of the CD133+ cells as well as their capacity to form gliomaspheres, and increased survival of mice with glioblastoma xenografts. Also, the anti-glioma drug temozolomide, while efficient in suppressing proliferation and survival of glioblastoma cell lines, failed to block the glioma cell self-renewal. On the other hand, the pharmacological inhibitor of the HHGLI pathway, cyclopamine, reduced the number of spheres, leading to the suggestion that combinatorial treatment might be used to eradicate the TICs in these cancers [47]. Liu et al. [38] studied the gene expression profile in CD133+ glioblastoma cell lines prepared from patients, and found that CD133+ cells expressed much higher levels of markers of neural precursors CD90, CD44, CXCR4, nestin, MsiI and MELK compared to their CD133 counterparts. Also, the CD133+ cells were found to express high levels of the anti-apoptotic genes Bcl-2, Bcl-xL, FLIP,
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c-IAP2, XIAP, NAIP and survivin by a factor of up to 150, while the expression of the pro-apoptotic Bax was depressed by 5-fold when compared to the corresponding CD133 cells. The CD133+ cells were resistant to etoposide, paclitaxel, temozolomide and carboplatin. Since CD133+ cells express high levels of the caspase-8 inhibitor FLIP, they can be expected to be resistant to induction of the extrinsic apoptotic signalling pathway. Moreover, expression of CD133 was much higher in the recurring glioblastoma multiforme than in newly diagnosed gliomas, again pointing to the critical importance of CD133 [38]. Several reports have highlighted upregulation of the ATPase pump ABCG5 in CD133+ cells, including the progenitor cells of human epidermal melanocytes and a subpopulation of malignant melanoma cells [49]. Frank et al. [43] recently showed that CD133+/ABCG5+ melanoma cells were resistant to doxorubicin treatment and that melanoma tissue isolated from patients expressed high levels of both CD133 and ABCG5. They suggested that ABCG5 could be used as a marker of chemoresistance and that it represented a useful target for therapy. CD133+ glioma cells are also resistant to radiation therapy [41]. These authors showed that following radiation, glioma cells acquired higher level of resistance, associated with increased CD133 expression, and that inhibiting the cell cycle checkpoint kinases Ch1 and Ch2 sensitised the resistant cells to radiation-induced killing. The research summarised above strongly links high expression of the surface marker CD133, tumour-initiating capacity of cancer cells and their greater resistance to radiotherapy, while suggesting potential methods for selectively eradicating the TICs by targeting associated signalling pathways [45,47], the cell cycle machinery [41], or using siRNA [50]. An alternative approach to eliminating tumour-initiating cells might be by targeting their mitochondria using mitocans, drugs that induce apoptosis by destabilising mitochondria [51,52]. There is preliminary evidence that sesquiterpene lactones or parthenolides may target mitochondria of TICs resulting in their death [53]. However it remains to be determined whether mitochondria in slow proliferating tumour-initiating cells are different from those in fast-proliferating non-tumour-renewing cancer cells or normal cells. Thus, it can be envisaged that mitocans will become useful for killing TICs either used alone or in combination with other approaches, such as diminishing the ‘stemness’ of these cells. While mitochondria may be different in the relatively slow-proliferating TICs compared with the high-proliferating more differentiated cancer cells, it can be anticipated that other organelles, such as lysosomes, may be unchanged, and can be utilised as an excellent target for killing cancer cells regardless of the CD133 status, providing development of cancer cellspecific lysosomotrophic agents [54,55]. In summary, a better understanding of the molecular mechanisms of resistance of TICs to anti-cancer drugs could provide novel ways to eradicate TICs within tumours and prevent the recurrence of cancers.
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