Review Article, J Pharm Sci Emerg Drugs Vol: 6 Issue: 1
Evolution of Cancer Stem Cells in Acute Myelogenous Leukemia and Targeting Via Novel Nanotechnology Approaches
*Corresponding Author : Sharad B Murdande
Worldwide Safety and Regulatory-Global Chemistry, Manufacturing and Controls, Pfizer Worldwide R&D, Groton, USA
E-mail: [email protected]
Received: September 08, 2017 Accepted: January 23, 2018 Published: January 30, 2018
Citation: Murdande SS, Murdande SB (2018) Evolution of Cancer Stem Cells in Acute Myelogenous Leukemia and Targeting Via Novel Nanotechnology Approaches. J Pharm Sci Emerg Drugs 6:1 doi: 10.4172/2380-9477.1000123
The cancer stem cell model is a hierarchical representation of the asymmetric division of cancer stem cells to form transit-amplifying cells, and ultimately differentiated cancer cells. The model can be applied to Acute Myelogenous Leukemia (AML), a hematopoieticderived cancer. A single tumor population of AML is composed of a minor cancer stem cell subpopulation as well as the majority transit-amplifying cell population. Following treatment of AML with chemotherapy and radiation, the tumors repopulate, as the cancer stem cells remain to regrow the transit-amplifying cell population. This is supported by evidence of an increased number of cancer stem cell markers following relapse of AML, such as CD34, CD38, and CD45 surface markers. Cancer stem cells are therefore the focus of targeted cancer therapies, such as novel nanotechnology drug approaches, which improve speed and accuracy of drug delivery.
Keywords: Stem cells; Cancer; Acute Myelogenous leukemia; Nanotechnology
Cancer is a disease of malfunctioning cells, particularly uninhibited cell proliferation and tissue abnormality. The primary causes of cancer are environment and hereditary factors. Environmental factors include an individual’s physical environment and lifestyle choices while genetic mutations are the hereditary causes of cancer . Further genomic causes of cancer are attributed to the rapid expression of oncogenes and the mutations of tumor suppressor genes. Both genomic alterations lead to rapid, uncontrolled cell proliferation. Therefore, cancer is primarily a disease of malfunctioning cells .
There exist multiple stages in the progression of tissue abnormality from normal to metastatic cancerous tissue. Hyperplasia is the first step of abnormal tissue growth, characterized by an excessive growth in the number of cells. The next stage is metaplasia, which is the transdifferentiation of cell types from one region of the body to another. Polyps and papillomas are the subsequent phase and are benign growths that do not invade the underlying stromal tissue beneath the cell. Dysplasia is next and is abnormal cell and tissue structure . Finally, there is metastatic cancer, in which the cancer cells express proteases to break through the underlying basement membrane and invade the supporting stromal connective tissue, becoming malignant. The stromal connective tissue components may even hyperproliferate in response to the invading cancer. Histological analyses can determine the founding or primary tumor from the differentiated tumor tissue because cancer cells also retain some of the properties of their founding tumor .
Cancer cells are marked by their ability to form tumors, known as tumorigenicity. This property has been established by studying the ability of transformed (cancerous) cells to create tumors in immuno-compromised mouse models. Cancer cells evolve from normal cells and their transformation elicits a number of distinctive characteristics. Altered morphology (rounded shape); anchorage independence, minimized dependence on growth factors, indefinite proliferation (immortalization), tumorigenicity, and inability to cease proliferation without growth factors are all properties of evolved cancer cells .
Cancer stem cells
Cancer stem cells (CSC) are a subject of much recent interest in the cancer research field. In order to win the battle against cancer, researchers should learn more about the evolution of these cells in various types of cancers. Therefore, researchers have proposed the cancer stem cell theory with supporting evidence. The theory states that in a population of tumor cells in any given cancer, there exists a heterogeneous mixture of different cell types. Cancer stem cells compose the small subpopulation. They are the parental cells for all of the progeny cancer cells present in that particular tumor . The other subpopulations of cells in the tumor are non-cancer stem cells (non-CSC). The tumor heterogeneity can be attributed to both the heredity of the patient and the microenvironment of the tumor that supports its excessive proliferation .
The CSC is of vital importance to understand and treat cancer because chemotherapy and radiation therapies target cancer stem cell progeny cells (i.e. non-CSC) instead of the original cancer stem cells in the tumor. Therefore, the CSC maintains the ability to grow and proliferate in spite of these treatments, form new tumors, and metastasize to different organs . The CSC theory contrasts with another prevalent theory in the cancer research field: the clonal evolution theory.
The clonal evolution theory is a stochastic model that emphasizes that the progeny cells of an initially mutated cell are subjected to an increasing number of mutations. The primary tumor-initiating cell divides symmetrically to form equipotent cancer cells . The combination of gene mutations that are most advantageous to the proliferating cancer cell will be continued in subsequent cell generations so that the cancer cells may continue to survive and replicate themselves. While the clonal evolution theory has gained recognition in the scientific community, the cancer stem cell model proves useful in developing novel methods for cancer therapy and treatment, as cancer stem cells play a vital role in the evolution of cancer cells, and their daughter cells are prevalent within a tumor cell population.
The cancer stem cell model is a hierarchical tumor model of asymmetric cell division. An initiating cancer stem cell divides to produce the first transit-amplifying or progenitor cell as well as another cancer stem cell. The cancer stem cell further divides into another transit-amplifying cell and a cancer stem cell, while the first transit-amplifying cell divides into two transit-amplifying cells. These cells further divide with the transit-amplifying cells dividing into differentiated cancer cells . The cancer stem cells maintain an asymmetric cell division pattern, thereby existing in lower frequency in relation to the transit-amplifying progenitor cells. The evolution of cancer stem cells is critical to tumor formation, as cancer stem cells may form tumors when cultured ex vivo . They possess a greater replicative capacity than the transit-amplifying cells, which are the bulk of the tumor . This indicates the proliferative, anchorageindependent growth capability of the cancer stem cells.
Numerous studies investigate the existence of cancer stem cells. Although there is no definitive evidence for the existence of cancer stem cells in all cancer phenotypes, cancer stem cells have been identified in various cancers, such as glioblastoma and multiple mouse cancer cell lines. Furthermore, cancer stem cells have yet to be discovered in advanced tumors, although there is supporting evidence for their existence in early stage tumors . The existence of cancer stem cells provides an effective target for cancer therapies, which typically target the differentiated progenitor cells in the tumor tissue. Targeting cancer stem cells for destruction would eliminate all cancer cells of the tumor as well as the re-emergence of the tumor following therapy.
In the mouse cell line experiment, the cancers that were cultured were Lewis lung carcinoma (LLC), mouse embryonal carcinoma (P19), mouse melanoma (B16) and mouse mammary carcinoma. In one significant approach, researchers studied glioblastoma in mouse models. The mice carried homozygous recessive mutations of multiple tumor suppressor genes, which led to the formation of cancer. In the experiment, the glioblastoma-prone mice were treated with NES-dTK-GFP transgene that marked adult neural stem cells. The experimenters tested to observe if the transgene also marked internally originating glioma cells in the mice. These cells would serve as the cancer stem cells. The mice with glioblastoma were then treated with TMZ, which is a chemotherapy agent. The transit-amplifying progenitor cells of the glioblastoma tumor were destroyed, while the endogenous cells remained, as indicated by the presence of NESdTK- GFP transgene in the endogenous cells .
The cells that remained after TMZ chemotherapy treatment were able to form a new tumor and self-replicate once more, thereby forming a relapse. Therefore, the TMZ treatment targeted the transitamplifying progenitor cells and not the cancer stem cells themselves. The results of this experiment provided substantial evidence for the existence of cancer stem cells, although the existence of cancer stem cells in all cancer phenotypes has not been identified .
Further evidence for the existence of cancer stem cells was derived from mouse models. Mouse induced pluripotent stem cells (miPS) were cultured along with cancer cell lines to study Lewis lung carcinoma, mouse embryonal carcinoma, mouse melanoma, and mouse mammary carcinoma . The cells were treated with Nanog markers to mark the cancer stem cells. Subsequent to the formation of tumor spheres in culture, the cell suspensions were placed in immunofluorescent staining for Nanog. The Nanog stain was observed in the miPS cells. Nanog is a genetic promoter element that is necessary for the survival of the cancer stem cells in this particular cancer cell population. Therefore, the preservation of Nanog indicated that the cells that remained in the tumor were cancer stem cells .
With exposure to cancer therapy, the cancer stem cells are not targeted for destruction and thus remain to differentiate during the relapse period. In the instance of cancer stem cell destruction, the daughter cells are able to dedifferentiate or express reversal properties to revert to a prior cancer stem cell state. This property of dedifferentiation creates more difficulty in targeting and eliminating cancer stem cells. Therefore, it is crucial to understand the properties of cancer stem cells in order to most effectively understand the evolution of cancer. Cancer stem cells typically express low levels of CD34 surface antigens on their cell membranes and do not express CD38 antigens . Through an experiment in severe combined immunodeficient (SCID) mice, cells that have CD34 markers were shown to express tumor-forming abilities . Following cancer treatment, the CD34 markers were still expressed in low amounts, indicating that the cancer therapy targeted and destroyed the progeny cancer cells and not the parent CSCs . Thus, the cancer stem cells remained to proliferate and differentiate into additional types of cancer cells.
It has also been shown that cancer stem cells may be eliminated and their progeny cells may adopt the characteristics of cancer stem cells and return to a cancer stem cell state. The cancer stem cells therefore have a strong lasting impact on their progeny cells. Cancer stem cells furthermore exhibit resistance to cancer therapy and thus must be targeted for novel cancer treatment methods. This topic will be further examined in the section, Cancer Stem Cells and Chemotherapy Resistance.
Acute myelogenous leukemia
Acute Myelogenous Leukemia (AML) or Acute Myeloid Leukemia is a hematopoietic-derived cancer of the white blood cells that affects both adults and children. AML is a liquid tumor that is found throughout the blood circulation and affects the myeloid cells of the body. Myeloblasts, the precursors of the myeloid cells, do not differentiate into myeloid cells in this disease, but instead remain as undifferentiated, immature, or ectopic condition. Myeloblasts multiply rapidly in the blood circulation . As a result, fewer effective red blood cells, platelets, and white blood cells are produced for normal body function. This severely compromises immune functions, such as the ability to form a correct response to disease and foreign pathogens . Furthermore, the progression of AML has been linked to chromosomal variations, primarily chromosomal fusion in AML transformed cells . The tumors of AML are able to metastasize to other organs as well.
In over 40% of patients with AML, relapse occurs within the span of two years . This is believed to be due to the role of cancer stem cells that are present in AML and their consequent role in reinitiating tumor formation during and subsequent to relapse of the disease. The focus of this review is the evolution of cancer stem cells in AML and the progression of the AML disease as well as the consequent tumor regrowth and metastases after radiation and chemotherapy.
Evolution of CSC in acute myelogenous leukemia
The cancer stem cell model can be applied for the treatment of AML. An AML tumor population includes the founding clonal cells and a population of subclonal cells. The evolution of AML cells closely follows that of the cancer stem cell model, in which there is a population of founding cancer stem cells and the progeny or daughter cancer cells make up the subpopulation. There are few genomic mutations that result in AML, with one particular mutation being the primary identifying factor for the disease . Researchers have deduced that the mutations take place in the hematopoietic stem cells that differentiate into the myeloid lineage . The evolution of AML tumor cells has been studied by conducting genetic sequencing of the tumor . The mutations that occur in the myeloid precursor cells can be classified as single nucleotide variants (SNVs). Single nucleotide mutations significantly alter the structure and function of the cell-encoded protein .
Another experiment that was conducted utilized the KG1a cancer cell line of AML. The KG1a cancer cell line was cultured and the cells in the line expressed CD34 surface antigen markers, however, they did not express CD38 markers. CD34 and CD38 cell surface markers are among the most common surface markers expressed on leukemic stem cells. The KG1a cell line were stained with CD34 and CD38 antibodies that served for identification of the CD34 and CD38 markers after flow cytometry. Following the flow cytometry analysis, it was determined that many of the cells in the KG1a cell line had CD34 and CD38 markers . These markers were indicative of the presence of leukemic stem cells in the cell population.
Additionally, the KG1a cancer cell line was able to initiate Acute Myelogenous Leukemia disease in non-severe immune compromised (SCID) mice . This was determined due to the presence of CD34 and CD38 markers in the non-SCID mice when the KG1a cultured cancer cell line was injected into the mice. Therefore, it was further deduced that due to the self-renewal and proliferative properties of cancer stem cells, the cancer stem cells in AML led to the transitamplifying or differentiated progenitor cells of the tumor. In order to test the self-renewing capacity of AML cancer stem cells, the stem cells from the KG1a cancer cell line were cultured and injected into SCID or severe immunocompromised mice through their tails and the CD34 and CD38 markers were observed in the mice. The markers were found in other locations of the mice body, along with various other cancer cell markers that appeared, indicating that the cancer stem cells self-renewed and harbored the potential to replicate themselves in vivo .
In another experiment that was performed, AML leukemic stem cells were found to carry CD34 surface markers and the existence of the CD34 surface markers subsequent to chemotherapy treatment indicated that the AML leukemic stem cells were involved in the progression of the disease during relapse. Furthermore, it was also discovered that there exists a phase that is prior to relapse and following cancer treatment that is referred to as minimal residual disease (MRD) . This phase that precedes the major relapse phase is additionally indicated by the presence of CD34 and CD38 cell surface antigen markers.
Additional cancer genome studies revealed that Acute Myelogenous Leukemia tumor cells may become resistant to drug therapies. Current therapy for AML includes chemotherapy, radiation therapy, and drug therapy. In an experiment that was conducted, five AML tumor cells were extracted from bone marrow and one clonal population of cells that grew resistant to the Acute Myelogenous Leukemia therapy treatments. Further analysis showed that the individual cells in that particular population displayed a SNV mutation in one of each pair of homologous chromosomes. The mutation substituted an adenine base pair for a guanosine base pair nucleotide in 4 out of 5 cells . Therefore, it can be deduced that the single nucleotide variant mutations are the primary contributors to the resistance to tumor therapy.
Additionally, the leukemic cancer stem cells displayed greater diversity in their surface antigen markers after therapy, indicating that the cancer stem cells have the ability to proliferate with more diversity and success than before therapy . The surface markers that were present prior to relapse and during diagnosis of Acute Myelogenous Leukemia increased in frequency as well as diversity. The surface markers that increased in diversity include CD34, CD38, CD45, and various other markers . It is thereby postulated that the cancer therapies and treatments that are currently in use for the eradication of cancers such as Acute Myelogenous Leukemia are contributing to the diversity of the cancer stem cells. One research study reports that a 9-90-fold increase in leukemic stem cells appeared after chemotherapy . This indicates to scientists that the cancer therapy itself may be a catalyzing factor in the increased growth and differentiation of cancer cells after therapy treatment that potentially leads to an increase in the number of mutations in the cancer cells as well as the heterogeneity of the tumor cell populations . Therefore, it is critical to study and understand the role and function of cancer stem cells in Acute Myelogenous Leukemia in order to prevent relapse and the cancer, as well.
Cancer stem cells and chemotherapy resistance
While chemotherapy treatment primarily eliminates the progenitor cells of the cancer stem cells to shrink the tumor, the cancer stem cells in the tumor population remain to grow following treatment. The progenitor or transit-amplifying cells release chemicals that signal and function as recruiters of the AML cancer stem cells. The cancer stem cells can thereby repopulate the residual tumors and eventually become unresponsive to various cancer therapies. In Acute Myelogenous Leukemia, the cancer stem cells are present at a much higher number during relapse of the cancer than during the initial stages of the disease.
Additionally, the diversity of the phenotypes of the cancer stem cells in AML is greater during relapse than prior to relapse. The CD34 and CD38 markers that are typically present on AML cancer stem cells were observed. Subsequent to relapse, the frequency of the cancer stem cell population of AML increased and this was supported by the increased expression of AML cancer stem cell markers . The markers that increased, however, were not the CD34 and CD38 markers. Instead, different markers had to be tested in order to determine if the number of AML cancer stem cells increased in direct relation to the number of cancer stem cell markers.
Therefore, markers such as CD32, CD47, CD33, CD123, CD97, TIM-3, and CD99 were observed. Many of these additional markers were found to exist in increased frequency following relapse of AML. While some of the markers even reported to have increased 25 times more than the original population number, some of the markers were not present in the leukemic stem cell population at all prior to relapse and then abruptly appeared after relapse. This was the CD34 marker in one particular patient. Therefore, the genetic instability of the cancer stem cell markers cannot be a reason for the alterations in the number of markers before and after relapse . This study demonstrates the evolution of different cancer stem cell phenotypes that allow the cells to alter and persist following therapy. Based on these results, the researchers concluded that the cancer stem cells present in the AML population of the patients matched the requirements for cancer stem cells in most other cancers .
Furthermore, the researchers postulated that the AML cancer stem cells underwent mutations and alterations in genotype that resulted in their increased population number following relapse. In the total seven patients who were tested for the AML cancer stem cell properties, four patients were reported to have developed additional genetic changes in their cancer stem cell populations. This finding can be attributed to genetic instability . In the following experiment, the genomic alteration that occurred in the leukemic stem cells was studied. It was found that DNMT3A, an enzyme that is present as a denovo DNA methyl transferase enzyme in its isoform of 3A and is also present during embryogenesis and various tumor types, was present and active in epigenetically modifying the DNA of the nonleukemic stem cell population as well as the DNA of the leukemic stem cell population. It was reported that the cell populations that did not exhibit DNMT3A before relapse or during diagnosis, acquired the DNMT3A mutations, following relapse .
DNA methyl transferase 3A is critical to cancer development. DNMT3A methylates the DNA strands of the cells where cytosine and guanine base pairs are found to be in position directly next to each other. This position is referred to as a CpG dinucleotide. When the dinucleotide is present near a DNA region that codes for a gene promoter, such as a tumor suppressor gene, methylation of the DNA by DNA methyltransferase 3A can inactivate the region and thereby shut down the tumor suppressor gene, leading to the formation of the tumor . Therefore, DNA methyltransferase enzyme down regulates the tumor suppressor gene expression.
The methylation pattern of CpG dinucleotides varies in normal cells versus in cancer cells. In normal cells, there are CpG dinucleotide islands that exist in an unmethylated form and are most often located next to a tumor suppressor gene promoter region. The CpG dinucleotides surrounding the islands are methylated in normal cells. In cancer cells, this methylation profile switches and the CpG islands are methylated while the surrounding CpG dinucleotides are unmethylated, which can be seen through mass cytometry .
Overall, the changes in tumor cell population number are determined by the genetic and epigenetic alterations that occur to the DNA strands in the cells that encompass the tumor. The resistance to cancer therapy derives from the evolution of cancer stem cells into differentiated progenitor cells along with their development of different marker phenotypes. This allows the cancer stem cell populations to survive and adapt to new threats or treatments and maintain its self-renewal capacity and proliferate during relapse of the disease.
Targeting cancer stem cells via novel nanotechnology drug therapy
Nanotechnology is a scientific and medicinal field that has been studied and investigated over the last couple of decades. Nanotechnology involves using vectors or nano-sized objects as carriers for drugs as a drug delivery system. Nanotechnologybased drug delivery has a variety of benefits to the patient, as the drug need only be present in minute amounts. Therefore, there are fewer side effects associated with the drug delivery. Nanoparticles are increasingly being applied within this arena to optimize drug targeting and bioavailability. Some of the examples of these nano particles include polymeric nanoparticles, solid lipid nanoparticles, gold nanoparticles, silica based nanoparticles and RNA nanoparticles that are all utilized in order to target anticancer drugs directly to the cancer cells as well as to the cancer stem cells . Nanotechnology is a cutting edge field that would be of great significance to the effectiveness of treating cancers that involve cancer stem cells such as Acute Myelogenous Leukemia. The field offers a novel method for targeting cancer stem cells while minimizing harm to the patient.
In one experiment that utilizes nanotechnology in cancer, lipid nanoparticles were used in order to deliver the microRNA-200c to breast cancer stem cells . Breast cancer stem cells serve the same function as the cancer stem cells in many other cancers in that they are a small subset of the population of tumor cells and are able to grow and proliferate following the elimination of transit-amplifying cells or differentiated progenitor cells. The breast cancer stem cells have a self-renewing capacity and are able to regenerate themselves as well as the entire tumor population. MicroRNA-200c, which served as a molecular enhancer to the drug paclitaxel, was delivered to the breast tissue . Paclitaxel is a drug that treats breast cancers as a part of chemotherapy regimen. The microRNA-200c was transmitted to patients using solid lipid nanoparticles .
The lipid nanoparticles were an effective method of transferring the microRNA-200c paclitaxel drug enhancer, as the nanoparticles are of miniscule size and also the microRNA-200c suppresses the expression of class III beta-tubulin molecules, which are crucial to the uncontrolled proliferation of breast cancer stem cells . The experiment was conducted by placing the breast cancer cells in culture order to separate the breast cancer stem cells from the surrounding cells in the culture line. These breast cancer stem cells formed mammospheres that were the target of the microRNA-200c that enhanced the paclitaxel drug delivery. A series of scientific procedures and techniques were utilized subsequent to the mammosphere formation. These techniques included PCR analysis, in vitro cytotoxicity, western blotting, gel retardation assay, as well as statistical analyses . These procedures characterized and analyzed the release of microRNA-200c from the solid lipid nanoparticle.
The data from the experiment was further quantified using these methods listed above, including the release rate of the microRNA- 200c enhancer which was a critical observation in order to determine the effectiveness of the nanoparticle drug delivery system . It was discovered that the primary eight hours of the release of the microRNA-200c resulted in the most effective as well as efficient drug delivery method that yielded positive drug delivery results. The microRNA-200c was easily released from the nanoparticle and could be spread throughout the mammosphere in a highly rapid manner . Elimination of the breast cancer stem cell population would likely eliminate the breast cancer in its entirety. The same techniques can be applied to Acute Myelogenous Leukemia, using in vivo nanoparticles.
Cancer stem cells are of vital relevance in the cancer research field, as they provide novel insight into the existence and proliferation of cancer cells as well as the targeting of cancer for destruction and permanent elimination. The cancer stem cell model describes the population of cells in a tumor as consisting of two subsets of cell types. The first type of cell is the cancer stem cell that is present in a smaller frequency than the second subset of cells, which are the transit-amplifying or differentiated progenitor cells. They are present in a higher frequency than the cancer stem cells. Typically, cancer therapies treat transit-amplifying cells, resulting in the shrinkage of the tumor, yet the cancer stem cells remain to self-renew and proliferate once more, leading to relapse of the disease .
However, researchers are investigating the potential benefits of targeting cancer stem cells and the effects that they might carry in the treatment of many types of cancers, including Acute Myelogenous Leukemia. Acute Myelogenous Leukemia is a hematopoietic-derived cancer that severely affects the white blood cells of the body as well as the myeloid cells of the body. The leukemia is a liquid tumor that is present in circulation throughout the body and is found to be able to metastasize to other regions of the body, as well. The disease is also associated with a strong relapse occurrence . Cancer stem cells arise from genetic and epigenetic alterations in the DNA sequences found in the cells of the tumor region that lead to its transformation. Epigenetic alterations include CpG dinucleotide methylation in which the CpG dinucleotides are present in islands near the gene promoter region of a tumor suppressor gene. Their methylation suppresses the expression of a tumor suppressor gene that leads to the formation of a tumor . Genetic alterations in cancer stem cells include the presence of surface antigen markers on the cells that are present at the time of tumor diagnosis and increase in frequency number during relapse such as the CD34 and CD38 markers, along with various other cancer stem cell markers .
Researchers are creating new studies and experiments for the detection and deletion of cancer stem cells. Cancer stem cells that are present in Acute Myelogenous Leukemia proliferate into the transitamplifying progenitor cells of the disease that can be targeted and destroyed with chemotherapy and various radiation therapy cancer treatments that serve to minimize the tumor. However, the leukemic stem cells pose a greater challenge for destruction. Therefore, the use of novel nanotechnology methods to target and destroy cancer stem cells is an effective method that minimizes harm and damage to the patient and is also minimally invasive. Further research is still required in order to achieve optimal results of cancer stem cell targeting in cancer treatment methods.
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