Brain tumors in children: A Report from our friend Dr. Antonio Iavarone of Columbia University's Brain Cancer Research Lab
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Pediatric brain tumors have surpassed leukemia as the leading cause of cancer death in children. Over 3,000 new cases of childhood primary brain tumors are diagnosed each year, with over 70% occurring in children less than 15 years of age.
Research has helped decrease the brain cancer death rate by more or less 20% over the past 30 years. Despite this double-digit decline, in comparison, research for cures of other pediatric cancers has led to successful death rate decreases by 40-70% over the same time period. Improvements in prognosis and quality of life for many children with CNS tumors have been much less dramatic than that seen for other childhood malignancies. On the largest scale, the overriding challenge for research into pediatric brain tumors is to improve outcome for children with a host of different types of brain tumors.
The predominant barrier is the lack of interest in, focus on, and funding for research on these primitive tumors.
Tumors in childhood differ significantly from adult lesions in their sites of origin, histological features, clinical presentations, and proclivity to disseminate throughout the nervous system early in the course of illness.
Whereas 90% of adult tumors arise in the cerebral cortex, 50% of childhood brain tumors originate in the cerebellum, brain stem, or fourth ventricular region. A large proportion of brain tumors in adults are the result of metastatic lesions from non-primary brain sites, and the primary tumors are for the most part glial tumors and meningiomas. In contrast, childhood brain tumors mainly represent primary CNS lesions and, although gliomas make up the majority of childhood neoplasms, other tumor types such as medulloblastomas, primitive neuroectodermal tumors, pineoblastomas, atypical teratoid tumors, and other embryonal neoplasms, contribute a significant proportion.
The pattern of tumor dissemination is extremely important for childhood brain tumors. Control of local disease remains problematic for many forms of childhood brain tumors; however, specific types of tumors, especially embryonal tumors, have a high proclivity for early dissemination within the nervous system and treatment approaches must take into account this tendency for early tumor spread. The neurobiological bases of these differences are largely unknown: the relationship between tumor type and location is poorly understood and the reasons why particular tumors have propensity to specific areas of brain are unclear. Even within the tumor types commonly found in both children and adults, studies focusing on tumors occurring in adults do not result in new insights for pediatric tumors. For progress to be made in this subset of tumors, research must be focused directly on pediatric low-grade gliomas. Aspects of brain tumors in Infants and very young children are unique to the early childhood. Some of these tumors, such as atypical teratoid tumors, are apparently true congenital tumors, and studies of the mechanism of their development may also lead to important insights into general brain development. Similarly, studies of brain development may lead to insights into the neurobiological aspects of these and other embryonal tumors.
Specific challenges associated with improving outcomes are:
• Improved understanding of the cell of origin of different types of pediatric brain tumors
• Greater insight into the relationship between normal brain development and the biologic bases of childhood brain tumors
• Determination of factors responsible for the propensity of some childhood brain tumors to disseminate within the nervous system early in the course of illness
• Enhanced understanding of the biologic differences between childhood and adult gliomas and the development of treatment approaches that take advantage of such differences
• Development of better animal models that mimic human pediatric brain tumors
• Definition of relevant molecular markers for the prognosis of the diverse forms of childhood brain tumors
The impediments to achieve these goals are of several types. There is insufficient appreciation of the important distinction between research required for childhood brain tumors and research required for adult tumors and there is a lack of emphasis on defining biologic differences between histologically identical tumors occurring in children and adults, especially gliomas. Furthermore, the few studies that focus on the molecular, genetic, and biologic aspects of childhood brain tumors seldom address the relationship between normal brain development and aberrations of such development in the etiology of childhood brain tumors. In conclusion, there is a need for understanding the uniqueness of childhood brain tumors and their overall importance, together with the urgency to learn more about these tumors to identify targeted and effective therapeutic strategies.
Research in our lab
Dr. Iavarone and Dr. Lasorella’ s laboratory at Columbia University Medical Center in New York is recognized internationally for his contributions to the biology of cell cycle regulation and cellular differentiation and the alteration of these processes in neural cancer of children and adults.
A striking feature of cancer is the phenotypic resemblance in growth and differentiation properties between tumor cells and embryonic cells. Indeed, cancer is a disease of differentiation, which translates in aberrant cell proliferation and survival signals and restoring differentiation mechanisms is a strategy to treat human cancer. This is not a new concept among cancer researchers especially in the pediatric field. Histopathologists have long noted that loss of differentiated features (anaplasia) and resemblance of tumor cells to the embryonic counterpart coincides with the most aggressive behavior of human neoplasm. However, it was unclear which molecules dictate such aberrant effect.
Many of the new capabilities acquired by malignant cells recapitulate normal characteristics of embryonic cells. This is especially true for the brain tumors arising in children. These tumors are thought to originate from aberration of the normal processes that control proliferation and differentiation during development. Among the many interesting projects related to pediatric brain tumors that are currently being conducted in our laboratory, we have discovered the family of proteins known as Id (Inhibitor of differentiation) that now is known to maintain the undifferentiated state of normal stem cells. However, this same family of proteins must be eliminated from the normal brain after development is completed. If Id protein levels remain high, cells in the brain undergo cancerous transformation. In particular, our work has found that the protein Id2 blocks cell maturation during malignant transformation and boosts the most important hallmarks of brain tumor aggressiveness such as the capacity of tumor cells to invade the normal brain and stimulate the formation of new blood vessels (neo-angiogenesis).
Thus, a tumor is a tumor because normal cells have lost their specialized identities as skin or brain cells and have gone back to primitive immature cells. Therefore, if we can find ways to turn on specialization, we can use these ways to reconstitute a normal cell from a cancer cell. The recent analysis of Id2 in tumors showed that the accumulation of Id2 in pediatric tumors from the nervous system correlates with unfavorable clinical stages and its presence is associated with the worse clinical outcome.
The main attribute that determines the malignancy of pediatric brain tumors is the rate of tumor growth. Relentless tumor expansion depends on two crucial tumor capabilities, the intrinsic alterations of cell cycle regulatory pathways and the dramatic induction of tumor angiogenesis - the formation of new blood vessels. There is large consensus that any useful, targeted therapy for malignant pediatric brain tumors should be aimed at these biological features of the tumor. We have identified Id proteins as key molecules providing essential signals to promote cellular proliferation and angiogenesis in the developing nervous system and in pediatric neoplasm. We will continue to determine the molecular mechanisms used by Id to sustain cell proliferation and angiogenesis. We will also develop a high-throughput screening assay for the search of new drugs that inhibit Id activity in glioma cells. This is a systematic search for small-molecule drugs and/or anti-sense compounds directed against Id2 expression and function. These drugs might become an effective therapeutic approach for new clinical trials aimed at treatment of children with cancer. Among a constellation of potential tumor targets for intervention, few other molecules offer the attractive targeting mechanisms against multiple essential traits of cancer that might be associated with the ablation of Id function in malignant pediatric pediatric brain tumors.
Our most recent research interest is to tackle the problem of the link between stem/progenitor cells with cancer stem cells in the nervous system. We have used bioinformatics tools to identify transcriptional networks that act as functional modules committed to maintain cancer stem cell properties and generate defined tumor phenotypes. Our findings indicate that transcription factors in the network are interdependent and cooperate to maintain a defined tumor phenotype. We are inducing reprogramming of cancer cells into normal cells and vice versa in order to demonstrate that activation of the master transcription factors in the network not only is sufficient to perturb differentiation of neural stem cells but can also confer malignant properties. Manipulation of the master transcriptional inducers of malignant gliomas would provide an impressive example of how molecular pathways can be reprogrammed in tumor cells by a small set of transcriptional regulators. The ultimate goal here is to understand the signaling systems involved in initiating and maintaining pediatric gliomas and use this understanding to identify new targets for pediatric brain tumor therapy.
Selected publications
1. Iavarone, A., Garg, P., Lasorella, A., Hsu, J. & Israel, M. A. The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein. Genes Dev 8, 1270-1284 (1994).
2. Lasorella, A., Noseda, M., Beyna, M., Yokota, Y. & Iavarone, A. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 407, 592-598. (2000).
3. Lasorella A, Boldrini R, Dominici C, Donfrancesco A, Yokota Y, Inserra A, Iavarone A. Id2 is critical for cellular proliferation and is the oncogenic effector of N-myc in human neuroblastoma. Cancer Res 62, 301-306. (2002).
4. Lasorella, A., Uo, T. & Iavarone, A. Id proteins at the cross-road of development and cancer. Oncogene 20, 8326-8333. (2001).
5. Iavarone, A. et al. Retinoblastoma promotes definitive erythropoiesis by repressing Id2 in fetal liver macrophages. Nature 432, 1040-1045 (2004).
6. Perk, J., Iavarone, A. & Benezra, R. Id family of helix-loop-helix proteins in cancer. Nat Rev Cancer 5, 603-614 (2005).
7. Lasorella, A., Rothschild, G., Yokota, Y., Russell, R. G. & Iavarone, A. Id2 mediates tumor initiation, proliferation, and angiogenesis in Rb mutant mice. Mol Cell Biol 25, 3563-3574 (2005).
8. Lasorella A., Stegmüller J., Guardavaccaro D., Liu G., Carro M.S., Rothschild G., de la Torre-Ubieta L., Pagano M., Bonni A., Iavarone A. Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature 442, 471-474 (2006). (see also News & Views, Jackson P. Nature, 442:365-366, 2006; Research Highlights, Degrading Id. Nature Reviews Neuroscience, 7:592, 2006; Making the Paper. Nature 442(7101)xiii, 2006)
9. Iavarone, A. & Lasorella, A. ID proteins as targets in cancer and tools in neurobiology. Trends Mol Med 12, 588-594 (2006).
10. X. Zhao, J. Ik-Tsen Heng, D, Guardavaccaro, R. Jiang, M. Pagano, F. Guillemot, A. Iavarone & A. Lasorella The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein Nature Cell Biology Published online: 18 May 2008 | doi:10.1038/ncb1727
