Neuroblastoma Stem Cell

Lay Review

Human neuroblastoma is an embryonic.  Neural crest stem cells arise from the neural folds during embryonic development. These stem cells are the precursors to the sympathetic nervous system and failure of the neural crest stem cells to differentiate (or to give rise to other types of cells) leads to neuroblastoma [3] [Figure 1.]

Four clinical stages of Neuroblastoma have been described. [4]  Stage I neuroblastoma is the least developed and Stage IV is indicative of possible metastasis and is the most developed and aggresive neuroblastoma stage.  Stage IV is termed “neuroblastoma proper” due to the severe damage accrued in the sympathetic nervous system and the usual finding of a tumor in the adrenal gland. [4]

Studies have revealed that cancer stem cells are located within neuroblastoma.  These cancer stem cells are disrupted or deregulated which allows them to self-renew uncontrollably.  Self renewal of a cancer stem cell is a process where stem cells not only give rise to daughter cells which can differentiate among various lineages, but also creates an exact copy of itself for self preservation. [2] This process also allows the progenitor cell to be immortalized, thus dividing uncontrollably while giving rise to other tumor cells.  The outcome is a mixture of cells that differentiate and are non-cancerous, while the cancer stem cells have the ability to proliferate uncontrollably and are difficult to destroy since they are not targeted by chemotherapy.[Figure 2.]

One of the most important findings in neuroblastoma that raises the possibility of cancer stem cells within the tumor, is cell heterogeneity within the tumor population. Three different cell types are commonly present in many primary human neuroblastoma cell lines: a neuroblastic (N-type) cell which is an embryonic neuronal precursor cell, a substrate-adherent (S-type) non-neuronal cell representing the glial/melanoblastic precursor cell, and an intermediate (I-type) stem cell from which the first two may arise[2].  All three cell types have been demonstrated to occur in human neuroblastoma tumors but N cells demonstrate malignant properties and uncontrolled growth, whereas S cells are non tumorigenic.

The human neuroblastoma (I-type) cancer stem cells exhibit the greatest malignant potential of all three neuroblastoma phenotypes [2]. They express stem cell markers CD133 and c-kit which allows for differentiability along different lineages when treated with the necessitated factors.[5]   N or S cells don’t express these markers or retain this capability to differentiate along different lineages, thus it has been suggested that I cells may represent the cancer stem cells in a neuroblastoma tumor. [5] [Figure 3]

The presence of side population cells and the ability of the neuroblastoma tumor to remain immortal and be multipotent are other indicators that cancer stem cells are present within the tumor.  These side population cells test positive for some of the markers which are indicative to stem cells thus ascertaining that cancer stem cells possibly are within the neuroblastoma.[4]

The ability for the cancer stem cell to be over-expanded can be attributed to the regulation factor MYCN, a probable transcription factor.  This regulation factor is important in development and growth and is augmented in neuroblastoma tumors.  High amplification of this gene is seen in severe cases of neuroblastoma, revealing an important target for possibly eradicating the tumor.[6] 

During the last two decades, improvements in the treatment plan in patients with high-risk neuroblastoma have not translated into significant increases in survival rates. Efforts to improve outcome have used high-dose chemotherapy with bone marrow stem cell rescue and more recently, differentiating (retinoids) and antiangiogenic agents.[3] 

The aggressive from of neuroblastoma has demonstrated low success with chemotherapeutic agents in eradicating tumors from children thus further strengthening the theory that cancer stem cells may be present and are able to survive the lethal chemotherapy.  In parallel, immunotherapy has become an increasingly important part of the treatment of high-risk neuroblastoma.  Acquiring the knowledge as to how cancer stem cells become cancerous and form tumors is and ultimately will be one of the most important components in finally being able to eradicate neuroblastoma.

Figure 1

Figure 2

Figure 3

References:

1. 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.
2. Reya T, Morrison SJ. (2001). Stem cells, caner and cancer stem cells. Nature  414:105-111
3. Ross RA, Spengler BA. (2006) Human neuroblastoma stem cells. Sem Cancer Biol (In press).
4. Sven P, Marie-Thérése S, Erik F, Håkan A. (2004) Notch signaling in neuroblastoma; Sem Cancer Biol 14:365-373
5. Walton JD, Kattan DR, Thomas SK, Spengler BA, Guo HF, Biedler JL, Cheung NK, Ross RA (2004) Characteristics of stem cells from human neuroblastoma cell lines and tumors.  Neoplasia. 6:838-45.
6. Westermann F, Manfred S. (2002) Genetic parameters of neuroblastomas, Cancer Lett 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