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Neuroblastoma: Cancer Stem Cells

Scientific Summary

Introduction
Neuroblastoma is an embryonic/early childhood cancer that is caused by lack of differentiation of cells in the neural crest. [3] The development of neuroblastoma is thought to be derived from precursor cells of the sympathetic nervous system. [12] Neuroblastoma usually develops in the adrenal gland above the kidney however, it may also develop in other locations and may metastasize throughout the body. (Figure1.) Most occurrences of neuroblastoma are found in children under the age of 14. [6] Neuroblastoma has shown varied clinical behavior. There are four stages of neuroblastoma ranging from stage I being the least developed to stage IV being the most developed with possible metastasis. [6] The most developed aggressive form of neuroblastoma is called “neuroblastoma proper”. In this form of neuroblastoma there is severe damage to the sympathetic nervous system and a tumor can usually be found in the adrenal gland. [12] The second less aggressive form of neuroblastoma which comprises both tumor and non-tumor cells is called “ganglioneuroblastoma”. Finally there is a benign form or neuroblastoma termed ganglioneuroma. [11] Approximately half the population of children that have neuroblastoma have the more aggressive form with metastasis and the survival rate for these children is low. [1]

Evidence of Cancer Stem Cells in Neuroblastoma
Cancer stem cells are defined as cells that become biologically deregulated and gain the ability to proliferate uncontrollably through genetic or microenvironmental changes. [15] Like the typical stem cell, these cells have the ability to self renew, however cancer stem cells are not under proper regulatory control.  They are thought to compose only a small portion of the actual “cancer” or “tumor”. [15] It is still unclear whether cancer stem cells are actually derivatives of normal stem cells that have become mutated or if they are progenitors that have acquired mutations which give them the ability to act as stem cells. [16]


The ability of neurobalstoma to persist in young children had been studied for many years, however new findings suggest that this ability to relapse after chemotherapeutic treatment may be due to cancer stem cells. One of the most important aspects of neuroblastoma that indicates the presence of stem cells is the aspect of cellular heterogeneity within the tumor. [10] Studies on the different types of cells in neuroblastoma have revealed that there are three phenotypically distinct types of cells. These cells can be termed N cells, S cells and the most recently discovered I cells. N cells, neuroblastic cells, are embryonic neuronal precursors containing many of the same enzymatic and biosynthetic properties of a neuron, [14] are malignant and show uncontrollable growth. S cells, substrate adherent cells, can form melanocytes, Schwann cells, and smooth muscle cells, [13] but are not tumorgenic. [14] This leads to the third distinct cell type, I cells. These cells were termed I, intermediate, because they appear to be a cross of N and S cells. One important finding of I type cells is that only I cells not N or S cells express stem cell markers CD133 and c-kit. [10] This gives rise to the thought that I cells are the cancer stem cells and that N and S cells are the progenitor cells that come from I cells. When I cells are treated with factors that allow for differentiation among the N or S cell lines they show the ability to differentiate among both lineages. This ability is not present in N or S cells. It has also been observed in culture that I cells possess the greatest malignant ability as opposed to N cells or S cells. [10] This important finding indicates that I cells may be cancer stem cells and are important targets in a therapeutic approach to destroy neuroblastoma tumors. (Figure 2)


Another strong piece of evidence that neuroblastoma comprises cancer stem cells is the discovery of side population cells among the tumor. One study looked at cells from patients who had a relapse and whose tumor was undifferentiated. [10] Approximately 66% of the patients had side population cells within their tumor and these cells ranged in amount present among the tumor. [10] They further went on to look at cell markers of the side population cells to further prove these side population cells as cancer stem cells. Some of the markers that were used are c-kit/CD117, AC133/CD133, CD71 and CD56. Studies have also shown the ability of neuroblastoma cells to expand many times in culture. [7] This multipotent ability is a defining characteristic of stem cells further indicating the presence of stem cells among the neuroblastoma cell population.


As mentioned above, neuroblastoma can take on a very aggressive form in some children.  This aggressive form of neuroblastoma has been treated with multiple combined approaches such as chemotherapy, surgery and bone marrow stem cell transplants [5]. However, there is still a low rate of survival among patients with stage IV neuroblastoma. [1] While a small portion of patients do better after receiving chemotherapy, surgery and bone marrow transplants, many patients will succumb to aggressive neuroblastoma. One of the most important aspects of a stem cell is the ability to self renew. This ability of neuroblastoma to persist among patients even though therapeutic agents such as chemotherapy and bone marrow transplants have been used, suggests that some cells remain and have the ability to proliferate indefinitely. This supports the idea that neuroblastoma cells are primitive and are comprised of cancer stem cells. (Figure 3)


The regulation of stem cells is extremely important for them to function properly. When these cells are disrupted or disturbed they may be genetically altered and function improperly. This will result in a cancer stem cell. One important regulation factor in neuroblastoma is MYCN. MYCN, a probable transcription factor, is amplified in neuroblastoma tumors and is important for the growth and development of neuroblastoma cells. This has been found in a significant amount of neuroblastoma tumors and is considered a proto-oncogene. The amplification of MYCN is most prevalent in the more severe cases of neuroblastoma indicating its importance in the cancer. Individuals who have high amplification of MYCN have shown worse survival rates than those with less amplification. [18]

Importance of Future Research of Therapeutic agents for Neuroblastoma
Neuroblastoma is one of the leading causes of cancer in young children today. It affects 1 out of 100,000 children each year with 50% of the children who are diagnosed die from the cancer. [11] and [18] As mentioned earlier this form of cancer primarily affects children and 90% of the cases diagnosed are in children under the age of 5. [18] This form of cancer accounts for approximately 10% of all cancers seen in children. [11] A large portion, 40%, of children who have neuroblastoma have the more severe and malignant form of neuroblastoma. [18] While neuroblastoma has the highest incidence of regression of all childhood cancers in some forms of the disease it is still of major clinical importance for those that succumb to the disease. The extreme variability in clinical behavior has puzzled many clinicians and scientists thus challenging efficacious therapy. Recent evidence has shown that stem cells play a significant role in cancer, especially in neuroblastoma. A suitable treatment to eradicate the tumor may indeed need to be to target these cancer stem cells. The first step towards this is to identify the cancer stem cells from the entire population of tumor cells. Once this can be successfully carried out then we can begin to understand the cancer stem cells and why they become oncogenic. Interpreting what factors cause these stem cells to become deregulated can allow us to target this specific population of cells. With this knowledge in combination with already mentioned techniques such as chemotherapy there is the possibility of eradicating the cancer entirely.

 

Figure 1

Figure 2

Figure 3

References

  1. Stanton AE, Robert S; Robert GB. London WB, Matthay KK, Haase GM. (2004) Efficacy of complete resection for high-risk neuroblastoma: a children’s cancer group study. J Ped Surg 39:931-936
  2. von Allmen D, Grupp S, Diller L, Marcus K, Ecklund K, Meyer J, Shamberger RC. (2005) Aggressive surgical therapy and radiotherapy for patients with high-risk neuroblastoma treated with rapid sequence tandem transplant. J Ped Surg 40:936-941.
  3. Bapat S.A. Evolution of cancer stem cells (2006) Sem Cancer Biol(In Press)
  4. Cantos MF, Gerstle JT, Irwin MS, Pappo A, Farley S, Timothy C, Kim PCW. (2006) Surgical challenges associated with intensive treatment protocols for high-risk neuroblastoma. J Ped Surg  41:960-965
  5. Cui1 H, Ma1 J, Ding J, Li T, Alam G, Ding H-F. (2006) Bmi-1 Regulates the Differentiation and Clonogenic Self-renewal of I-type Neuroblastoma Cells in a Concentration-dependent Manner. J Biol Chem 281:34696–34704
  6. Anders E, Linda H, Sven P. (2006) Neuroblastoma as an experimental model for neuronal differentiation and hypoxia-induced tumor cell dedifferentiation. Sem Cancer Biol (In Press)
  7. Escobar MA, Grosfeld JL, Powell RL, West KW, Scherer III LR, Fallon RJ, Rescorla FJ.  (2006) Long-termnext term outcomes in patients with stage IV previous termneuroblastoma. J Ped Surg 41:377-381
  8. Johnsen JI, Lindskog JI, Ponthan F, Pettersen I, Elfman L, Orrego A, Sveinbjörnsson B, Kogner P. (2005) NSAIDs in neuroblastoma therapy. Cancer Letters 228:195-201
  9. Kang J-H, Rychahou PG, Ishola TA, Qiao JB, Evers M, Chung DH. (2006) MYCN silencing induces differentiation and apoptosis. Biochem Biophys Res Comm 351:192-197
  10. Ross RA, Spengler BA. Human neuroblastoma stem cells; Sem Cancer Biol  (In Press)
  11. Lu, Xiaohong; Pearson, Andrew and Lunec, John (2003) The MYCN oncoprotein as a drug development target. Cancer Letters  197:125-130
  12. McConville CM, Forsyth J. (2003) Neuroblastoma – a developmental perspective Cancer Lett  197:3-9
  13. Muller J-M; Philippe M, Chevrier L, Héraud C, Alleaume C, Chadéneau C. (2006) The VIP-receptor system in neuroblastoma cells Regulatory Peptides.  Cancer Lett 184:34-41
  14. Påhlman, Sven; Stockhausen, Marie-Thérése; Fredlund, Erik; and Axelson, Håkan; (2004) Notch signaling in neuroblastoma.Sem Cancer Biol 14:365-373
  15. Ross RA, Spengler BA. (2006) Human neuroblastoma stem cells. Sem Cancer Biol (In Press)
  16. Ross RA, Spengler BA, Domenech C, Porubcin M, Rettig WJ, Biedler JL (1995) Human neuroblastoma I-type cells are malignant neural crest stem cells. Cell Growth and Differentiation 6:449-56.
  17. Schwab, Manfred; Westermann, Frank; Hero, Barbara; and Berthold, Frank (2003) Neuroblastoma: biology and molecular and chromosomal pathology; The Lancet Oncol 4: 472-480
  18. Westermann F, Schwab M. (2002) Genetic parameters of neuroblastomas.Cancer Letters 184:127-147

 

Acknowledgements

This review was prepared by the following graduate students in the Stem Cell Biology Class, Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey:

Babak Baseri, Jennifer Brady, Nadia Senmartin (in alphabetical order)

Teaching Assistant: Kathy Trzaska