**Multi-Role of Cancer Stem Cell in Children Acute Lymphoblastic Leukemia**

Dong-qing Wang, Hai-tao Zhu, Yan-fang Liu, Rui-gen Yin, Liang Zhao, Zhi-jian Zhang, Zhao-liang Su, Yan-Zhu, Hui-qun Lu, Juan Hong and Jie Zhang

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55075

**1. Introduction**

Acute lymphoblastic leukemia (ALL) is a malignant proliferation of lymphoid precursor cells in the bone marrow blood. It is an age related tumor, with a peak between the ages of 2 and 10 and a second peak after the age of 5. Among children younger than 15 years, ALL represents 23% of cancer that was diagnosed. The children aged 2 to 3 years were a sharp peak in ALL incidence (>80 per million per year).The rates of the ALL among children aged 8 to 10 years incidence decreasing to 20 per million. Moreover, there has been a gradual increase in the incidence of ALL in the past 25 years.

With the development of the medicine, considerable advances have been made in the treatment of childhood ALL. In the 1980's, relapsed ALL was regarded as an incurable disease. However, about 85% of childhoods ALL can hope to achieve a second remission over the last years. Meanwhile, around 40% of these can hope to achieve long term cure. On the other hand, despite optimal therapy, long term survival rate still limited to 30–40% of patients and about 15-20% children will sustain relapse. Because of the high relapse rate, refractoriness to conventional treatment protocols, the incidence of chemotherapy-related deaths, the complete remission rate, numerous challenges remained in the management of ALL, especially the children with re‐ lapsedALL.Also,thediseasemechanismismulti-factorialsandinvolvesindifferentgeneticand environmental factors. So, ALL is still a problem that clinic must face up to. However, the emergency of cancer stem cell seems give us a new direction for deeper recognize this disease.

© 2013 Wang et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Despite the clone origin of many cancers, a notable characteristic of primary tumors is a marked degree of cellular heterogeneity. The hypothesis that human cancers comprise a heterogeneous population of cells that differ in marker expression, morphology, proliferation, and tumori‐ genicity has existed for over a century. Every tumor can be viewed as an abnormal organ that harbors a stem cell compartment. Emerging evidence has confirmed that the capacity of a tumor to grow and propagate depends on a small subset of cells within the tumor, which are most specifically referred to as "cancer stem cells" (CSCs), but have also been referred to as "progenitor cells" or "tumor initiating cells" (TICs) to distinguish them from the rest of the neoplastic cells that are unable to regenerate tumors. CSCs are defined to be a distinct population but variable subpopulation of the total tumor mass with stem cell characteristics that are essential for the initiation, development of human cancers, multi-drug resistance and metastases.

survival and proliferation advantages. In the primary tumour, selection is proposed to take place continuously which giving rise to heterogeneity that simply reflects the coexistence of cell populations evolving independently and displaying distinct oncogenic potentials. The environment that the tumor exists was thought to be an important factor that impacts the selection procedure. The theory above mentioned denominates the cancer research one century and might be sufficient to interpret the cell diversity observed in tumors. However, it fails to explain how individual disseminated cancer cells escaping from primary tumours yield secondary tumours with similar diversity. An alternative model assumes that primary and secondary tumours arise from cancer cells displaying both self-renewal and differentiation capabilities, namely cancer stem cell. Recently, it became apparent that the different subpo‐ pulations have different degrees of proliferative and self-renewing abilities and only a small subpopulation can regenerate all the other tumor cell subpopulations of the original tumor when injected into immuno-compromised mice. This model seems not exclusive of the above

Multi-Role of Cancer Stem Cell in Children Acute Lymphoblastic Leukemia

http://dx.doi.org/10.5772/55075

77

**Figure 1.** Craig T Jordan.Cancer stem cell biology: from leukemia to solid tumors. Current Opinion in Cell Biology

At present, on the basis of expression of a particular cell surface marker, Cancer stem cells that sorted by FACE in children ALL are suggested to be have the most superior ability to form a new tumourinaninvivoxenograftassayandgreatabilitytoformcellspheresnamelyclonogenicwhen plated at low density in non-adherent culture. These two models were beloved to be the golden

2004, 16:708–712.

theory, but more suitable to explain the origination of the tumor.

In the last two decades, with the wide spread utilization of fluorescence activated cell sorting (FACS) or magnetic activated cell sorting (MACS),the application of these technology to isolate and characterize of distinct cell populations of hematopoietic stem (HSC) or progenitor cell populations has become available. Using the same methodologies that employed to character‐ ize normal hematopoietic stem cells,Cancer stem cells were first identified in haematopoietic malignancies and later in a broad spectrum of solid tumors including those of the breast, pancre‐ atic, colon and brain. So, the malignant stem cell population that has been identified from ALL have been analyzed in most detail. These leukemia initiating, or leukemia stem cells (LSC) reside at the apex of a hierarchy of malignant cells that is analogous to the hierarchy found in normal hematopoietic. Thus, a hierarchical development structure for the leukemic population can be envisaged that originates from the malignant stem cell and is similar to normal hematopoietic processes. Importantly, these subpopulation of leukemic stem cells maintain the key stem cells properties of self-renewal, extensive proliferative potential and differentiate potential, highly resistant to chemo- and radio-therapy, driven metastasis, especially special organ metastases.

Apart from the method of FACS, LSCs may be sorted by various other characteristics.With the characteristic of limit less self-renewal in vitro, LSCs can be enriched in spheres when these cells are cultured in serum-free medium supplemented with the basic fibroblast growth factor (bFGF),epidermal growth factor (EGF),B27, insulin, and transferring. With the characteristic of expressing ABC transporters, these cells are able to pump the fluorescent dye hoechst-33342 out of the cell, namely identify unlabelled "side population" (SP) which highly enriched in stem cells.

With the deeper study of cancer stem cell, the role of it in ALL was believed to be more and more important. These functions include the following aspects.

## **2. Cancer stem cell may the origination of children Acute lymphoblastic leukemia**

The development of the tumour is always believed to be the result of a succession of epigenetic/ genetic alterations and selection steps which leading to the emergence of cells accumulating survival and proliferation advantages. In the primary tumour, selection is proposed to take place continuously which giving rise to heterogeneity that simply reflects the coexistence of cell populations evolving independently and displaying distinct oncogenic potentials. The environment that the tumor exists was thought to be an important factor that impacts the selection procedure. The theory above mentioned denominates the cancer research one century and might be sufficient to interpret the cell diversity observed in tumors. However, it fails to explain how individual disseminated cancer cells escaping from primary tumours yield secondary tumours with similar diversity. An alternative model assumes that primary and secondary tumours arise from cancer cells displaying both self-renewal and differentiation capabilities, namely cancer stem cell. Recently, it became apparent that the different subpo‐ pulations have different degrees of proliferative and self-renewing abilities and only a small subpopulation can regenerate all the other tumor cell subpopulations of the original tumor when injected into immuno-compromised mice. This model seems not exclusive of the above theory, but more suitable to explain the origination of the tumor.

Despite the clone origin of many cancers, a notable characteristic of primary tumors is a marked degree of cellular heterogeneity. The hypothesis that human cancers comprise a heterogeneous population of cells that differ in marker expression, morphology, proliferation, and tumori‐ genicity has existed for over a century. Every tumor can be viewed as an abnormal organ that harbors a stem cell compartment. Emerging evidence has confirmed that the capacity of a tumor to grow and propagate depends on a small subset of cells within the tumor, which are most specifically referred to as "cancer stem cells" (CSCs), but have also been referred to as "progenitor cells" or "tumor initiating cells" (TICs) to distinguish them from the rest of the neoplastic cells that are unable to regenerate tumors. CSCs are defined to be a distinct population but variable subpopulation of the total tumor mass with stem cell characteristics that are essential for the initiation, development of human cancers, multi-drug resistance and

76 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

In the last two decades, with the wide spread utilization of fluorescence activated cell sorting (FACS) or magnetic activated cell sorting (MACS),the application of these technology to isolate and characterize of distinct cell populations of hematopoietic stem (HSC) or progenitor cell populations has become available. Using the same methodologies that employed to character‐ ize normal hematopoietic stem cells,Cancer stem cells were first identified in haematopoietic malignancies and later in a broad spectrum of solid tumors including those of the breast, pancre‐ atic, colon and brain. So, the malignant stem cell population that has been identified from ALL have been analyzed in most detail. These leukemia initiating, or leukemia stem cells (LSC) reside at the apex of a hierarchy of malignant cells that is analogous to the hierarchy found in normal hematopoietic. Thus, a hierarchical development structure for the leukemic population can be envisaged that originates from the malignant stem cell and is similar to normal hematopoietic processes. Importantly, these subpopulation of leukemic stem cells maintain the key stem cells properties of self-renewal, extensive proliferative potential and differentiate potential, highly resistant to chemo- and radio-therapy, driven metastasis, especially special organ metastases. Apart from the method of FACS, LSCs may be sorted by various other characteristics.With the characteristic of limit less self-renewal in vitro, LSCs can be enriched in spheres when these cells are cultured in serum-free medium supplemented with the basic fibroblast growth factor (bFGF),epidermal growth factor (EGF),B27, insulin, and transferring. With the characteristic of expressing ABC transporters, these cells are able to pump the fluorescent dye hoechst-33342 out of the cell, namely identify unlabelled "side population" (SP) which highly enriched in

With the deeper study of cancer stem cell, the role of it in ALL was believed to be more and

**2. Cancer stem cell may the origination of children Acute lymphoblastic**

The development of the tumour is always believed to be the result of a succession of epigenetic/ genetic alterations and selection steps which leading to the emergence of cells accumulating

more important. These functions include the following aspects.

metastases.

stem cells.

**leukemia**

**Figure 1.** Craig T Jordan.Cancer stem cell biology: from leukemia to solid tumors. Current Opinion in Cell Biology 2004, 16:708–712.

At present, on the basis of expression of a particular cell surface marker, Cancer stem cells that sorted by FACE in children ALL are suggested to be have the most superior ability to form a new tumourinaninvivoxenograftassayandgreatabilitytoformcellspheresnamelyclonogenicwhen plated at low density in non-adherent culture. These two models were beloved to be the golden standard to test whether the cells own the characteristic of stemness.Meanwhile, it demonstrat‐ ed that the Leukemic stem cells may be the origination of children ALL.

chemotherapeuticagents,especiallythatarespecialforthecyclepopulationagentswerecytostatic

to completely destroy the tumor population permanently.On the other hand, new threpy agent desperatelyneededtobeexploredtopromotethequiescentLSCsintotheactivestate.Second,the second key property of LSCs is their abnormal expression of certain pumps which are absent in their compartment of non-LSC. These proteins included ATP-binding cassette (ABC) transport‐ ers super family, multidrug resistance-associated protein (MRP) family, breast cancer resist‐ anceprotein(BCRP),lungresistanceprotein(LRP)andsoon.Theyarepromiscuoustransporters of both hydrophobic and hydrophilic compounds and can help the cell extruding several drugs out of the cells. The exact physiological role of these pumps is not yet fully understood, but it is known that they are involved in cellular protection against exogenous products and in resist‐ ance to hypoxic stress, mediated by an increased ability to consume hydrogen peroxide and a reducedaccumulationoftoxicmetabolites.So,withthehelpoftheseabnormalproteins,LSCscan display the great ability to promptly eliminate or degrade toxic compounds even though the concentration of the drug at a very high level. Once the treatment stopped, LSCs may selfrenewalanddifferentiateintomultipledistinctcelltypeswhichledtotherelapse.Third,themost important key property is resistance to apoptosis, which can be limited to CSC initially, is often rapidly acquired also by the bulk of tumor cells at relapse, perhaps due to the genetic instability which distinguishes tumor from normal cells. Activation of programmed cell death or apopto‐ sisisapromisingstrategyforthetreatmentofcancer,andthebalancebetweenanti-apoptoticand pro-apoptotic members is a key factor in the regulation of cell death. In order to maintain the progenitor pool from which differentiated cells derive, cancer stem cells are programmed to be long-lived. For this purpose, cancer stem cells activate some protective mechanisms that protect them from senescence and/or cellular stress. These mechanisms include: (I) The current results showed that cancer stem cells expressed high levels of the anti-apoptotic protein such as Bcl-2, andlowlevelsofthepro-apoptoticproteincaspase3,comparedtononcancerstemcells.Enhance‐ ment of their anti-apoptosis ability means that tumor cells survival becomes more dependent on anti-apoptotic-pathway activation, and standard therapeutic approaches may thus fail to kill cancer stem cells; (II) activation of some self-renewal pathways, such as TGF-β, Sonic Hedge‐ hog(SHH), Wnt/β-catenin or BMI-1; (III) generation of auto-crine loops through the production of growth factors like epidermal growth factor (EGF), basic fibroblast growth factor (bFGF); and (IV) enhanced capability to repair DNA damage after genotoxic stress.As a consequence of this, chemotherapy invariably causes bone marrow toxicity due to its effects on trans-amplifying, progenitor and even more differentiated cells, whereas tumors may initially regress but subse‐ quently become completely resistant to chemotherapy. By these natures, it was easy found that CSCs are biologically distinct from other cancer cell types. Moreover, certain natural properties of CSCs are likely to increase their resistance to standard chemotherapy agents. So, if cancer therapies do not effectively target the CSC population during initial treatment, then relapse may occur as a consequence of CSC driven tumor expansion. This is almost certainly the case in many instances of ALL, where standard drugs are unlikely to target the LSCs population effectively. Therefore, in developing new cancer therapeutics, analyses that directly assess toxicity towards

ThisresultssupportedtheconceptthatablationoftheLSCisnecessary

Multi-Role of Cancer Stem Cell in Children Acute Lymphoblastic Leukemia

http://dx.doi.org/10.5772/55075

79

butnotcytotoxictotheLSCs.

tumor stem cells are an important priority.

The Leukemic stem cells (LSCs) appear to retain many characteristics of normal hematopoietic stem cells (HSCs). This observation indicates that the malignant stem cell population can arise in two possible ways. One possibility is that normal HSCs are the direct target of mutations that cause conversion to an LSCs phenotype. Alternatively, more differentiated cell types might acquire mutations that confer stem-cell-like properties on cells that typically would not display stem cell characteristics. Normal stem cells intrinsically possess three hallmark features: first, the potential to undergo self-renewal; second, the potential to undergo extensive proliferation; third, the potential to differentiate into multiple distinct cell types. Like normal stem cells, LSCs own the ability of asymmetric division and symmetric division. Leukemic stem cells undergo symmetric division and expand the stem cell compartment. Conversely, via asymmetric division, CSCs give rise to the variety of differentiated cells in the tumor mass. They are stringently defined by functional attributes including the ability to instigate, maintain and serially propagate leukemia in vivo while retaining capacity to differentiate into commit‐ ted progeny that lack these properties.

So, LSCs not only sustain the tumor but maintain the number of cancer stem cell in the tumor tissue. One contribution to our understanding of tumor initiation and growth comes from considering the developmental biology of stem cell systems.

#### **3. Cancer stem cells are the main factor of drug resistance and relapse**

SubsequentstudieshavefurtherrefinedtheimmunophenotypeofALLstemcellsandsubstantial‐ lyaddedtoourunderstandingoftheirbiology.Oneofthemostimportantcharacteristicsofcancer stem cells is highly resistant to chemo- and radio-therapy. Because of the resistant to chemo- and radio-therapy, cancer stem cells further led to the relapse of the tumor. With the deeper re‐ search, it had make out of that resistance could depend on certain features that LSCs share with normal stem cells. First, this property concerns cell proliferation. A lot of research showed that ALL stem cells reside mostly in a quiescent cell cycle state in the absence of specific stimulation from the microenvironment which is analogous to their normal hematopoietic stem cell counter‐ parts.Thisobservationhasagreatsignificantinunderstandingtheroleofcancerstemcellsindrug resistant. Because most therapeutic agents which rely on cycling cells in order to cause lethal cellular damage approaches to leukemia are directed towards actively cycling populations. The quiescent nature of LSCs indicates that standard chemotherapy drugs will not generally be effective against ALL stem cells. Notably, while treatment of ALL children with the drug that specially towards actively cycling sub-populations, it has been highly effective for inducing remission. However, Because of the existence of the quiescent cells, the patients would recur‐ rence in the short time. This evidence indicates the disease is suppressed rather than eradicated. For example, 5-FU which is special for the S stage have obvious effect in the patient who was first diagnose of ALL. However, once the drug was retreat, the tumor may relapse. FACS analyze displayed that the existence cells mostly display the stemness cell characteristic. So, most

chemotherapeuticagents,especiallythatarespecialforthecyclepopulationagentswerecytostatic butnotcytotoxictotheLSCs. ThisresultssupportedtheconceptthatablationoftheLSCisnecessary to completely destroy the tumor population permanently.On the other hand, new threpy agent desperatelyneededtobeexploredtopromotethequiescentLSCsintotheactivestate.Second,the second key property of LSCs is their abnormal expression of certain pumps which are absent in their compartment of non-LSC. These proteins included ATP-binding cassette (ABC) transport‐ ers super family, multidrug resistance-associated protein (MRP) family, breast cancer resist‐ anceprotein(BCRP),lungresistanceprotein(LRP)andsoon.Theyarepromiscuoustransporters of both hydrophobic and hydrophilic compounds and can help the cell extruding several drugs out of the cells. The exact physiological role of these pumps is not yet fully understood, but it is known that they are involved in cellular protection against exogenous products and in resist‐ ance to hypoxic stress, mediated by an increased ability to consume hydrogen peroxide and a reducedaccumulationoftoxicmetabolites.So,withthehelpoftheseabnormalproteins,LSCscan display the great ability to promptly eliminate or degrade toxic compounds even though the concentration of the drug at a very high level. Once the treatment stopped, LSCs may selfrenewalanddifferentiateintomultipledistinctcelltypeswhichledtotherelapse.Third,themost important key property is resistance to apoptosis, which can be limited to CSC initially, is often rapidly acquired also by the bulk of tumor cells at relapse, perhaps due to the genetic instability which distinguishes tumor from normal cells. Activation of programmed cell death or apopto‐ sisisapromisingstrategyforthetreatmentofcancer,andthebalancebetweenanti-apoptoticand pro-apoptotic members is a key factor in the regulation of cell death. In order to maintain the progenitor pool from which differentiated cells derive, cancer stem cells are programmed to be long-lived. For this purpose, cancer stem cells activate some protective mechanisms that protect them from senescence and/or cellular stress. These mechanisms include: (I) The current results showed that cancer stem cells expressed high levels of the anti-apoptotic protein such as Bcl-2, andlowlevelsofthepro-apoptoticproteincaspase3,comparedtononcancerstemcells.Enhance‐ ment of their anti-apoptosis ability means that tumor cells survival becomes more dependent on anti-apoptotic-pathway activation, and standard therapeutic approaches may thus fail to kill cancer stem cells; (II) activation of some self-renewal pathways, such as TGF-β, Sonic Hedge‐ hog(SHH), Wnt/β-catenin or BMI-1; (III) generation of auto-crine loops through the production of growth factors like epidermal growth factor (EGF), basic fibroblast growth factor (bFGF); and (IV) enhanced capability to repair DNA damage after genotoxic stress.As a consequence of this, chemotherapy invariably causes bone marrow toxicity due to its effects on trans-amplifying, progenitor and even more differentiated cells, whereas tumors may initially regress but subse‐ quently become completely resistant to chemotherapy. By these natures, it was easy found that CSCs are biologically distinct from other cancer cell types. Moreover, certain natural properties of CSCs are likely to increase their resistance to standard chemotherapy agents. So, if cancer therapies do not effectively target the CSC population during initial treatment, then relapse may occur as a consequence of CSC driven tumor expansion. This is almost certainly the case in many instances of ALL, where standard drugs are unlikely to target the LSCs population effectively. Therefore, in developing new cancer therapeutics, analyses that directly assess toxicity towards tumor stem cells are an important priority.

standard to test whether the cells own the characteristic of stemness.Meanwhile, it demonstrat‐

The Leukemic stem cells (LSCs) appear to retain many characteristics of normal hematopoietic stem cells (HSCs). This observation indicates that the malignant stem cell population can arise in two possible ways. One possibility is that normal HSCs are the direct target of mutations that cause conversion to an LSCs phenotype. Alternatively, more differentiated cell types might acquire mutations that confer stem-cell-like properties on cells that typically would not display stem cell characteristics. Normal stem cells intrinsically possess three hallmark features: first, the potential to undergo self-renewal; second, the potential to undergo extensive proliferation; third, the potential to differentiate into multiple distinct cell types. Like normal stem cells, LSCs own the ability of asymmetric division and symmetric division. Leukemic stem cells undergo symmetric division and expand the stem cell compartment. Conversely, via asymmetric division, CSCs give rise to the variety of differentiated cells in the tumor mass. They are stringently defined by functional attributes including the ability to instigate, maintain and serially propagate leukemia in vivo while retaining capacity to differentiate into commit‐

So, LSCs not only sustain the tumor but maintain the number of cancer stem cell in the tumor tissue. One contribution to our understanding of tumor initiation and growth comes from

**3. Cancer stem cells are the main factor of drug resistance and relapse**

SubsequentstudieshavefurtherrefinedtheimmunophenotypeofALLstemcellsandsubstantial‐ lyaddedtoourunderstandingoftheirbiology.Oneofthemostimportantcharacteristicsofcancer stem cells is highly resistant to chemo- and radio-therapy. Because of the resistant to chemo- and radio-therapy, cancer stem cells further led to the relapse of the tumor. With the deeper re‐ search, it had make out of that resistance could depend on certain features that LSCs share with normal stem cells. First, this property concerns cell proliferation. A lot of research showed that ALL stem cells reside mostly in a quiescent cell cycle state in the absence of specific stimulation from the microenvironment which is analogous to their normal hematopoietic stem cell counter‐ parts.Thisobservationhasagreatsignificantinunderstandingtheroleofcancerstemcellsindrug resistant. Because most therapeutic agents which rely on cycling cells in order to cause lethal cellular damage approaches to leukemia are directed towards actively cycling populations. The quiescent nature of LSCs indicates that standard chemotherapy drugs will not generally be effective against ALL stem cells. Notably, while treatment of ALL children with the drug that specially towards actively cycling sub-populations, it has been highly effective for inducing remission. However, Because of the existence of the quiescent cells, the patients would recur‐ rence in the short time. This evidence indicates the disease is suppressed rather than eradicated. For example, 5-FU which is special for the S stage have obvious effect in the patient who was first diagnose of ALL. However, once the drug was retreat, the tumor may relapse. FACS analyze displayed that the existence cells mostly display the stemness cell characteristic. So, most

ed that the Leukemic stem cells may be the origination of children ALL.

78 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

ted progeny that lack these properties.

considering the developmental biology of stem cell systems.

**4. LSCs solely are capable of driving tumor metastases**

bloodstream environment and, eventually formed the second tumor.

LSCs to form macroscopic metastases

It has even been proposed that cancer cells adopt stem cell features only upon undergoing EMT. Indeed, induction of EMT in immortalized human mammary epithelial cells resulted in the expression of stem cell markers, and phenotypes associated with CSCs. These findings illustrated a direct link between EMT and gain of properties characteristic for migratory stem cells. So,it can be concluded that LSCs acquired the property of EMT which is essential for the

CD44 has been proposed as one such marker. CD44 may play a crucial role in developing of metastasis in ALL, especially metastasis to special organ. Additionally, LSCs may express higher levels of cell-surface receptors than their non-LSCs counterparts so that they may fully

colonization or akinosis.

With the deeper research, it was well understanding that the cancer metastasis was viewed as a series of distinct steps that comprise the "invasion-metastasis-cascade" on the biological level [30-31]. The first step, cancer cells in the primary tumor acquire the ability to invade into the surrounding tissue such as the basement membrane. Next, tumor cells must gain access to blood and/or lymphatic vessels, enter into these vessels (intravasation), survive transport through these vessels, and exit from the vasculature (extravasation). Finally, small cell clumps or singly disseminated tumor cells must acquire the ability to survive and proliferate in the microenvironment of a foreign tissue in order to form macroscopic metastases, namely

Multi-Role of Cancer Stem Cell in Children Acute Lymphoblastic Leukemia

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81

In the procedure of the tumor metastasis, EMT represents a crucial step and plays important role in mediated invasiveness sand metastasis, also is strongly associated with poor clinical outcome in many tumour types [32]. EMT termed epithelio–mesenchymal transformation was first described in a model of chick primitive streak formation. Nowadays, EMT is defined as a biologic process that allows a polarized epithelial cell, which normally interacts with the basement membrane via its basal surface, to undergo multiple biochemical changes that enable it to assume a mesenchymal cell phenotype, which includes enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly increased production of extracel‐ lular matrix components [33-35]. Due to reorganization of epithelial intercellular junctions, EMT weakens cell-cell cohesion. Further-more cell-cell adhesion complexes and their tran‐ scriptional repressors are strongly regulated by a number of classical EMT-regulated pathways which including TGF-β, PDGF, Notch, Wnt, many of which also seem to play key role in skeletal metastasis. Moreover,EMT stimulates focal, proteolytic degradation of extracellular natrices, thus favoring invasion of stroma and intravasation. The modification of the cytoske‐ leton during EMT also contributes to migration. Intermediate filaments of epithelial cells such as cytokeratins are responsible for maintaining cell structure, stiffness and integrity. Apart from invasiveness, EMT also contributes to angiogenesis and intravasation. In addition to stimulating neovascularization, migratory carcinoma cells that have undergone EMT have acquired a number of specific properties that allow them to interact with endothelial cells and to enhance trans-endothelial migration. At last, EMT renders enhanced resistance to apoptotic signals and may contribute to the survival of circulating tumor cells (CTCs) in the hostile

**Figure 2.** Lara Lacerda,Lajos Pusztai,et al.The role of tumor initiating cells in drug resistance of breast cancer:Implica‐ tions for future therapeutic approaches. Drug Resistance Updates, 2010,13: 99–108

**Figure 3.** Malcolm R. Alison,Wey-Ran Lin,et al.Cancer stem cells: In the line of fire. Cancer Treatment Reviews, 2012,38:589-598.

## **4. LSCs solely are capable of driving tumor metastases**

**Figure 2.** Lara Lacerda,Lajos Pusztai,et al.The role of tumor initiating cells in drug resistance of breast cancer:Implica‐

**Figure 3.** Malcolm R. Alison,Wey-Ran Lin,et al.Cancer stem cells: In the line of fire. Cancer Treatment Reviews,

2012,38:589-598.

tions for future therapeutic approaches. Drug Resistance Updates, 2010,13: 99–108

80 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

With the deeper research, it was well understanding that the cancer metastasis was viewed as a series of distinct steps that comprise the "invasion-metastasis-cascade" on the biological level [30-31]. The first step, cancer cells in the primary tumor acquire the ability to invade into the surrounding tissue such as the basement membrane. Next, tumor cells must gain access to blood and/or lymphatic vessels, enter into these vessels (intravasation), survive transport through these vessels, and exit from the vasculature (extravasation). Finally, small cell clumps or singly disseminated tumor cells must acquire the ability to survive and proliferate in the microenvironment of a foreign tissue in order to form macroscopic metastases, namely colonization or akinosis.

In the procedure of the tumor metastasis, EMT represents a crucial step and plays important role in mediated invasiveness sand metastasis, also is strongly associated with poor clinical outcome in many tumour types [32]. EMT termed epithelio–mesenchymal transformation was first described in a model of chick primitive streak formation. Nowadays, EMT is defined as a biologic process that allows a polarized epithelial cell, which normally interacts with the basement membrane via its basal surface, to undergo multiple biochemical changes that enable it to assume a mesenchymal cell phenotype, which includes enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly increased production of extracel‐ lular matrix components [33-35]. Due to reorganization of epithelial intercellular junctions, EMT weakens cell-cell cohesion. Further-more cell-cell adhesion complexes and their tran‐ scriptional repressors are strongly regulated by a number of classical EMT-regulated pathways which including TGF-β, PDGF, Notch, Wnt, many of which also seem to play key role in skeletal metastasis. Moreover,EMT stimulates focal, proteolytic degradation of extracellular natrices, thus favoring invasion of stroma and intravasation. The modification of the cytoske‐ leton during EMT also contributes to migration. Intermediate filaments of epithelial cells such as cytokeratins are responsible for maintaining cell structure, stiffness and integrity. Apart from invasiveness, EMT also contributes to angiogenesis and intravasation. In addition to stimulating neovascularization, migratory carcinoma cells that have undergone EMT have acquired a number of specific properties that allow them to interact with endothelial cells and to enhance trans-endothelial migration. At last, EMT renders enhanced resistance to apoptotic signals and may contribute to the survival of circulating tumor cells (CTCs) in the hostile bloodstream environment and, eventually formed the second tumor.

It has even been proposed that cancer cells adopt stem cell features only upon undergoing EMT. Indeed, induction of EMT in immortalized human mammary epithelial cells resulted in the expression of stem cell markers, and phenotypes associated with CSCs. These findings illustrated a direct link between EMT and gain of properties characteristic for migratory stem cells. So,it can be concluded that LSCs acquired the property of EMT which is essential for the LSCs to form macroscopic metastases

CD44 has been proposed as one such marker. CD44 may play a crucial role in developing of metastasis in ALL, especially metastasis to special organ. Additionally, LSCs may express higher levels of cell-surface receptors than their non-LSCs counterparts so that they may fully harness the soluble growth factors present at secondary sites, conferring a growth advantage and permitting successful colonization.

**Author details**

Dong-qing Wang1

Zhenjiang, China

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3 Department of Immunology & Laboratory Immunology, Jiangsu University, Zhenjiang,

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Multi-Role of Cancer Stem Cell in Children Acute Lymphoblastic Leukemia

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**Figure 4.** Christina Scheel, Robert A. Weinberg. Cancer stem cells and epithelial–mesenchymal transition: Concepts and molecular links. Seminars in Cancer Biology,2102.

In a world, although LSCs accounting for only a few distinct populations, it is the most important factors that mediated the biology of the ALL. LSCs may play a great role in the origination, drug-resistance and metastases. In the future, LSCs may be the sole target for treatment. A detailed consideration of stem cell biology principles will be useful in better understanding tumor pathogenesis and in designing strategies for more effective therapies.

### **Acknowledgements**

This work was supported by Natural Science Foundation of Jiangsu Province (Grant No. BK2011487) and Social Development Foundation of Zhenjiang City (Grant No. SZC201130128).

## **Author details**

harness the soluble growth factors present at secondary sites, conferring a growth advantage

82 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

**Figure 4.** Christina Scheel, Robert A. Weinberg. Cancer stem cells and epithelial–mesenchymal transition: Concepts

In a world, although LSCs accounting for only a few distinct populations, it is the most important factors that mediated the biology of the ALL. LSCs may play a great role in the origination, drug-resistance and metastases. In the future, LSCs may be the sole target for treatment. A detailed consideration of stem cell biology principles will be useful in better understanding tumor pathogenesis and in designing strategies for more effective therapies.

This work was supported by Natural Science Foundation of Jiangsu Province (Grant No. BK2011487) and Social Development Foundation of Zhenjiang City (Grant No. SZC201130128).

and permitting successful colonization.

and molecular links. Seminars in Cancer Biology,2102.

**Acknowledgements**

Dong-qing Wang1 , Hai-tao Zhu1 , Yan-fang Liu2 , Rui-gen Yin1 , Liang Zhao1 , Zhi-jian Zhang3 , Zhao-liang Su3 , Yan-Zhu1 , Hui-qun Lu1 , Juan Hong1 and Jie Zhang4

1 Department of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, China

2 Department of Central Laboratory, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, China

3 Department of Immunology & Laboratory Immunology, Jiangsu University, Zhenjiang, China

4 Department of Ultrasound, Xuzhou Children's Hospital, Xuzhou, China

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**Chapter 5**

**Adult T-Cell Leukemia/Lymphoma (ATL):**

Adult T-cell leukemia/lymphoma (ATL) was first described in 1977 as a distinct clinico‐ pathological entity with a suspected viral etiology. Subsequently, a RNA retrovirus, hu‐ man T-cell leukemia /lymphotropic virus type 1 (HTLV-1) was isolated as a carcinogenic

HTLV-1 infects approximately 15 to 20 million people worldwide, with endemic areas in Japan,

After prolonged latency periods, approximately 3 to 5% of HTLV-1 infected individuals will develop either ATL or other disorders such as HTLV-1-associated myelopathy/tropical spastic

The three major routes of HTLV-1 transmission are, 1)mother-to-child infections via breast milk, 2)sexual intercourse, and 3)blood transfusions. HTLV-1 infection early in life, presuma‐

HTLV-1 infects CD4+ and CD8+ T lymphocytes and can also efficiently infect dendritic

and reproduction in any medium, provided the original work is properly cited.

© 2013 Kobayashi and Iwasaki; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

bly from breast feeding, is crucial in the development of ATL [2].

**Pathogenesis, Treatment and Prognosis**

Shoko Kobayashi and Shigeki Iwasaki

http://dx.doi.org/10.5772/54776

**1. Introduction**

pathogens [1].

the Caribbean, and Africa.

paraparesis (HAM/TSP).

**3. Initial infection**

cells [3].

**2. Transmission and spread**

Additional information is available at the end of the chapter

**Chapter 5**
