Summary

The pathogenesis of hemangioma—its life cycle of growth and involution—is still a mystery. The studies described here support the hypothesis that sporadic heman-

Tunel Assay Clinical Uses

Figure 3 Increased Apoptosis Coincides with the Onset of the Involuting Phase. Apoptotic cells were quantitated using the TUNEL assay on 16 hemangioma specimens from children ranging from two months to nine years of age. Normal skin from infants and young children (n = 8) was analyzed for comparison. On average, apoptotic nuclei in eight fields, viewed at 630X magnification, were counted. Hemangiomas from children 13 to 48 months of age had a higher mean count of apoptotic nuclei compared to hemangiomas from younger children (0 to 12 months) (p < 0.001) and compared to hemangiomas from older children (> 48 months of age) (p = 0.002). There was no significant difference between younger (0 to 12 months) versus older (> 48 months) patients (p = 0.68). This figure is a graphical summary of data from Razon et al. (1998). Microcirculation 5, 189-195.

Figure 3 Increased Apoptosis Coincides with the Onset of the Involuting Phase. Apoptotic cells were quantitated using the TUNEL assay on 16 hemangioma specimens from children ranging from two months to nine years of age. Normal skin from infants and young children (n = 8) was analyzed for comparison. On average, apoptotic nuclei in eight fields, viewed at 630X magnification, were counted. Hemangiomas from children 13 to 48 months of age had a higher mean count of apoptotic nuclei compared to hemangiomas from younger children (0 to 12 months) (p < 0.001) and compared to hemangiomas from older children (> 48 months of age) (p = 0.002). There was no significant difference between younger (0 to 12 months) versus older (> 48 months) patients (p = 0.68). This figure is a graphical summary of data from Razon et al. (1998). Microcirculation 5, 189-195.

giomas are caused by a somatic mutation in a single endothelial cell, possibly an immature endothelial cell or endothelial progenitor, that leads to clonal expansion of abnormal endothelial cells. It is likely that several somatic mutations, in one or more genes, will be discovered in individual hemangiomas, and that the assortment of mutations will reflect the differences in severity and life span of the individual tumors. Much progress has been made toward distinguishing hemangioma from the many other types of human vascular anomalies using cellular and biochemical markers. The goals now are (1) to identify the genetic defects that cause hemangiomas, so alterations in cellular signaling and function can be studied at the molecular level; (2) to develop animal models that recapitulate hemangio-genesis, so that growth and regression can be studied in vivo; and (3) to use the animal models to evaluate anti-angiogenic therapies that will either prevent growth or accelerate involution, so that better, fast-acting therapies can be provided to children with endangering hemangiomas.

Glossary

Apoptosis: A mechanism by which cell death can occur. It is characterized by morphologic changes in the nucleus and cytoplasm and chromatin cleavage at regularly spaced sites resulting in DNA fragmentation. This mode of cell death is contributes to the regulation of the size of animal tissues and in mediating pathologic processes associated with tumor growth.

Clonal expansion: A single cell undergoes multiple cell divisions to give rise to a population of descendent cells.

Endothelial progenitor cells: immature endothelial cells that co-express stem cell markers and endothelial lineage specific markers.

Immunohistochemistry: An indirect means of determining the expression and localization of a protein or antigenic determinant within a tissue. Histological tissue sections are incubated with an antibody directed against the protein of interest, followed by detection of bound antibody using a secondary antibody conjugated to a reporter.

Somatic mutations: Alterations in DNA sequence that cause defective gene products in any cell in the body except germ cells.

References

1. Huang, S. A., Tu, H. M., Harney, J. W., Venihaki, M., Butte, A. J., Kozakewich, H. P., Fishman, S. J., and Larsen, P.R. (2000). Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N. Engl. J. Med. 343, 185-189.

2. Cheung, D. S., Warman, M. L. & Mulliken, J. B. (1997). Hemangioma in twins. Ann. Plast. Surg. 38, 269-274.

3. Walter, J. W., Blei, F., Anderson, J. L., Orlow, S. J., Speer, M. C., and Marchuk, D. A. (1999). Genetic mapping of a novel familial form of infantile hemangioma. Am. J. Med. Genet. 82, 77-83.

4. North, P. E., Waner, M., Mizeracki, A., and Mihm, M. C., Jr. (2000). GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum. Pathol. 31, 11-22.

5. Yu, Y., Flint, A. F., Mulliken, J. B., Wu, J. K., and Bischoff, J. (2004). Endothelial progenitor cells in infantile hemangioma. Blood 103, 1373-1375.

6. Boye, E., Yu, Y., Paranya, G., Mulliken, J. B., Olsen, B. R., and Bischoff, J. (2001). Clonality and altered behavior of endothelial cells from hemangiomas. J. Clin. Invest. 107, 745-752.

7. Walter, J. W., North, P. E., Waner, M., Mizeracki, A., Blei, F., Walker, J. W., Reinisch, J. F., and Marchuk, D. A. (2002). Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosomes Cancer 33, 295-303.

8. Bielenberg, D. R., Bucana, C. D., Sanchez, R., Mulliken, J. B., Folkman, J., and Fidler, I. J. (1999). Progressive growth of infantile cutaneous hemangiomas is directly correlated with hyperplasia and angiogenesis of adjacent epidermis and inversely correlated with expression of the endogenous angiogenesis inhibitor, IFN-beta. Int. J. Oncol. 14, 401-408.

9. Yu, Y., and Bischoff, J., unpublished observations.

10. Razon, M. J., Kraling, B. M., Mulliken, J. B., and Bischoff, J. (1998). Increased apoptosis coincides with onset of involution in infantile hemangioma. Microcirculation 5, 189-195.

Further Reading

Cohen, M. M., Jr. (2002). Vasculogenesis, angiogenesis, hemangiomas, and vascular malformations. Am. J. Med. Genet. 108, 265-274. This excellent review article integrates clinical information on hemangiomas and vascular anomalies with the cellular and molecular regulation of vascular development.

Ezekowitz, R. A., Mulliken, J. B., and Folkman, J. (1992). Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N. Engl. J. Med. 326, 1456-1463.

Ferrara, N., Gerber, H. P., and LeCouter, J. (2003). The biology of VEGF and its receptors. Nat. Med. 9, 669-676.

Holmdahl, K. (1955). Cutaneous hemangiomas in premature infants. Acta Pediatrics 44, 370-379.

Mulliken, J. B., Fishman, S. J., and Burrows, P. E. (2000). Vascular anomalies. Curr. Prob. Surg. 37, 517-584. This comprehensive overviewpro-vides a clinical and pathophysiological overview of hemangiomas and other related vascular anomalies by internationally recognized leaders in the clinical diagnosis and treatment of vascular anomalies.

North, P. E., Waner, M., James, C. A., Mizeracki, A., Frieden, I. J., and Mihm, M. C., Jr. (2001). Congenital nonprogressive hemangioma: A distinct clinicopathologic entity unlike infantile hemangioma. Arch. Dermatol. 137, 1607-1620.

Rafii, S., and Lyden, D. (2003). Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat. Med. 9, 702-712. This article provides a comprehensive review of endothelial progenitor cells (EPCs). EPCs play important roles in normal vascu-larization and repair, but they can also contribute to tumor angiogenesis. The role of EPCs in disease, as well as potential applications for revascularization, is an exciting new area in vascular biology.

Smoller, B. R., and Apfelberg, D. B. (1993). Infantile (juvenile) capillary hemangioma: A tumor of heterogeneous cellular elements. J. Cutan. Pathol. 20, 330-336. Although not the first to propose that hemangioma contains primitive angioblastic-like cells, these authors were the first to show expression of an endothelial marker (CD34) on interstitial cells not associated with vascular channels in proliferating phase hemangiomas.

Takahashi, K., Mulliken, J. B., Kozakewich, H. P., Rogers, R. A., Folkman, J., and Ezekowitz, R. A. (1994). Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J. Clin. Invest. 93, 2357-2364. This study was one of the first to perform a comprehensive analysis of the expression patterns of angiogenic factors in proliferating, involuting, and involuted hemangiomas.

Capsule Biography

Dr. Bischoff is an Associate Professor in the Vascular Biology Program/Department of Surgery at Children's Hospital Boston and Harvard Medical School. Her laboratory has been investigating cellular and molecular mechanisms that cause hemangioma since 1997. In addition, her laboratory studies growth and differentiation of endothelial progenitor cells and endothelial cells that line cardiac valves.

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