Pathogenesis of infantile haemangioma: new molecular and cellular insights

Infantile haemangioma is the most common tumour of infancy, yet the origin of these lesions remains controversial and the predictable life cycle is poorly understood. Much new information on infantile haemangiomas has emerged over the past decade, but experts continue to debate fundamental features, including cell of origin, nonrandom distribution, and mechanisms regulating the sometimes explosive growth and slow involution. The development of useful laboratory models has been difficult, in turn restricting the development of treatment options available to the clinician. Despite this, new research and creative thinking has spawned several hypotheses on the origin of these tumours and their interesting clinical behaviour, including suggestions of an intrinsic defect in local endothelial cells, a contribution of circulating endothelial progenitors or haemangioblasts, embolisation of shed placental cells and developmental field defects. While no single hypothesis seems to describe all features of infantile haemangioma, continued research seeks to integrate these ideas, create a better understanding of these important tumours and bring new treatments to the clinic.

[1]  J. Bischoff Monoclonal expansion of endothelial cells in hemangioma: an intrinsic defect with extrinsic consequences? , 2002, Trends in cardiovascular medicine.

[2]  Richard P. Davis,et al.  A Novel In Vitro Human Model of Hemangioma , 2000, Modern Pathology.

[3]  Michael I Dorrell,et al.  Identifying potential regulators of infantile hemangioma progression through large-scale expression analysis: a possible role for the immune system and indoleamine 2,3 dioxygenase (IDO) during involution. , 2003, Lymphatic research and biology.

[4]  N. Sepp,et al.  Infantile hemangioma is a proliferation of beta 4-negative endothelial cells adjacent to HLA-DR-positive cells with dendritic cell morphology. , 2004, Human pathology.

[5]  Napoleone Ferrara,et al.  Angiogenesis as a therapeutic target , 2005, Nature.

[6]  S. Ogawa,et al.  Hypoxia induces glucose transporter expression in endothelial cells. , 1992, The American journal of physiology.

[7]  J. Mulliken,et al.  Differential expression of CD146 in tissues and endothelial cells derived from infantile haemangioma and normal human skin , 2003, The Journal of pathology.

[8]  M. Friedlander,et al.  Recent progress in our understanding of the pathogenesis of infantile hemangiomas. , 2005, Lymphatic research and biology.

[9]  M. Mihm,et al.  Congenital nonprogressive hemangioma: a distinct clinicopathologic entity unlike infantile hemangioma. , 2001, Archives of dermatology.

[10]  D. Siegel,et al.  Infantile Hemangiomas: Current Knowledge, Future Directions. Proceedings of a Research Workshop on Infantile Hemangiomas , 2005, Pediatric dermatology.

[11]  G. Nahass,et al.  Infantile hemangiomas: speculation on placental trophoblastic origin. , 2001, Archives of dermatology.

[12]  M. Mihm,et al.  Vascular tumors of infancy and childhood: beyond capillary hemangioma. , 2006, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.

[13]  I. Frieden,et al.  PHACE Syndrome: The Association of Posterior Fossa Brain Malformations, Hemangiomas, Arterial Anomalies, Coarctation of the Aorta and Cardiac Defects, and Eye Abnormalities , 1996 .

[14]  D. Jackson,et al.  A view through the clouds of imprinting. , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  P. Davis,et al.  Cellular and Extracellular Markers of Hemangioma , 2000, Plastic and reconstructive surgery.

[16]  M. Mihm,et al.  The nonrandom distribution of facial hemangiomas. , 2003, Archives of dermatology.

[17]  A. Tzankov,et al.  Infantile hemangioma is a proliferation of LYVE-1-negative blood endothelial cells without lymphatic competence , 2006, Modern Pathology.

[18]  G. Gurtner,et al.  Circulating endothelial progenitor cells and vascular anomalies. , 2005, Lymphatic research and biology.

[19]  M. Brodsky,et al.  Are infantile hemangiomas of placental origin?1 , 2002 .

[20]  G. Gurtner,et al.  Increased circulating AC133+ CD34+ endothelial progenitor cells in children with hemangioma. , 2003, Lymphatic research and biology.

[21]  G. Semenza,et al.  Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. , 1999, Annual review of cell and developmental biology.

[22]  I. Frieden,et al.  Prospective Study of Infantile Hemangiomas: Clinical Characteristics Predicting Complications and Treatment , 2006, Pediatrics.

[23]  G. Creatsas,et al.  Changes in Serum Levels of Vascular Endothelial Growth Factor in Males and Females Throughout Life , 2000, The Journal of the Society for Gynecologic Investigation: JSGI.

[24]  W. Bloch,et al.  Opposite effects of endostatin on different endothelial cells , 2004, Cancer biology & therapy.

[25]  M. Wong,et al.  Myeloid lineage progenitors give rise to vascular endothelium , 2006, Proceedings of the National Academy of Sciences.

[26]  B. Burton,et al.  An increased incidence of haemangiomas in infants born following chorionic villus sampling (CVS) , 1995, Prenatal diagnosis.

[27]  J. Mulliken,et al.  Endothelial progenitor cells in infantile hemangioma. , 2004, Blood.

[28]  J. Mulliken,et al.  Increased Apoptosis Coincides with Onset of Involution in Infantile Hemangioma , 1998, Microcirculation.

[29]  R. Auerbach,et al.  A hemangioendothelioma-derived cell line: its use as a model for the study of endothelial cell biology. , 1990, Laboratory investigation; a journal of technical methods and pathology.

[30]  J. Mulliken,et al.  Increased Tie2 expression, enhanced response to angiopoietin-1, and dysregulated angiopoietin-2 expression in hemangioma-derived endothelial cells. , 2001, The American journal of pathology.

[31]  Michael I Dorrell,et al.  Insulin-like growth factor 2 and potential regulators of hemangioma growth and involution identified by large-scale expression analysis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[32]  O. Hayaishi,et al.  Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase. , 1986, The Journal of biological chemistry.

[33]  J. Mulliken,et al.  Mesenchymal Stem Cells and Adipogenesis in Hemangioma Involution , 2006, Stem cells.

[34]  H. Zoghbi,et al.  Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. , 1992, American journal of human genetics.

[35]  M. Garzón,et al.  A prospective study of PHACE syndrome in infantile hemangiomas: Demographic features, clinical findings, and complications , 2006, American journal of medical genetics. Part A.

[36]  S. Toda,et al.  Mast cells and angiogenesis , 2003, Microscopy research and technique.

[37]  R. Cooke,et al.  Epidemiology of strawberry haemangioma in low birthweight infants , 1987, The British journal of dermatology.

[38]  Takayuki Asahara,et al.  Isolation of Putative Progenitor Endothelial Cells for Angiogenesis , 1997, Science.

[39]  J. Prchal,et al.  Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. , 2007, Blood.

[40]  G. Burton,et al.  Increased incidence of placental chorioangioma in high-altitude pregnancies: hypobaric hypoxia as a possible etiologic factor. , 1996, American journal of obstetrics and gynecology.

[41]  J. Mulliken,et al.  Complications of systemic corticosteroid therapy for problematic hemangioma. , 1999, Plastic and reconstructive surgery.

[42]  P. Davis,et al.  Altered Mitochondrial Cytochrome b Gene Expression during the Regression of Hemangioma , 2001, Plastic and reconstructive surgery.

[43]  M. Brodsky,et al.  Are infantile hemangiomas of placental origin? , 2002, Ophthalmology.

[44]  W. Reik,et al.  Placental-specific IGF-II is a major modulator of placental and fetal growth , 2002, Nature.

[45]  Gabriel S. Eichler,et al.  Evidence by molecular profiling for a placental origin of infantile hemangioma. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[46]  K. Havemann,et al.  In vitro transformation of monocytes and dendritic cells into endothelial like cells. , 2003, Advances in experimental medicine and biology.

[47]  J. Folkman,et al.  Successful treatment of infantile hemangiomas with interferon-α-2b , 1997 .

[48]  G. Parmaksiz,et al.  Case of Large Placental Chorioangioma Associated with Diffuse Neonatal Hemangiomatosis , 2004, Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society.

[49]  M. Mihm,et al.  Infantile hemangiomas are arrested in an early developmental vascular differentiation state , 2004, Modern Pathology.

[50]  J. Glowacki,et al.  Hemangiomas and Vascular Malformations in Infants and Children: A Classification Based on Endothelial Characteristics , 1982, Plastic and reconstructive surgery.

[51]  C. Drake,et al.  Vasculogenesis in the day 6.5 to 9.5 mouse embryo. , 2000, Blood.

[52]  A. Metzker,et al.  Strawberry Hemangioma in Preterm Infants , 1986, Pediatric dermatology.

[53]  S. Ogino,et al.  Villous capillary lesions of the placenta: distinctions between chorangioma, chorangiomatosis, and chorangiosis. , 2000, Human pathology.

[54]  Geoffrey C Gurtner,et al.  Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1 , 2004, Nature Medicine.

[55]  S. Orlow,et al.  Genetic mapping of a novel familial form of infantile hemangioma. , 1999, American journal of medical genetics.

[56]  A. Butte,et al.  Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. , 2000, The New England journal of medicine.

[57]  S. Rafii,et al.  Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. , 2000, Blood.

[58]  P. Baker,et al.  Apoptosis is a rare event in first-trimester placental tissue. , 2000, American journal of obstetrics and gynecology.

[59]  M. Brodsky,et al.  Are infantile hemangioma of placental origin? , 2002, Ophthalmology.

[60]  D. Metry,et al.  Response of ulcerated perineal hemangiomas of infancy to becaplermin gel, a recombinant human platelet-derived growth factor. , 2004, Archives of dermatology.

[61]  N. Dupin,et al.  Endothelial cells in infantile haemangiomas originate from the child and not from the mother (a fluorescence in situ hybridization‐based study) , 2007, The British journal of dermatology.

[62]  E. Boscolo,et al.  Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin. , 2006, Blood.

[63]  D. Hanahan,et al.  Endothelial cell tumors develop in transgenic mice carrying polyoma virus middle T oncogene , 1987, Cell.

[64]  J. Mulliken,et al.  E-selectin is present in proliferating endothelial cells in human hemangiomas. , 1996, The American journal of pathology.

[65]  J. Glowacki,et al.  Mast cells in hemangiomas and vascular malformations. , 1982, Pediatrics.

[66]  M. Eccles,et al.  Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour , 1993, Nature.

[67]  J. Hand,et al.  Vascular birthmarks of infancy: resolving nosologic confusion. , 2002, American journal of medical genetics.

[68]  J. Mulliken,et al.  Interferon alfa‐2a therapy for life‐threatening hemangiomas of infancy , 1992, The New England journal of medicine.

[69]  P. Steijlen,et al.  The Pathogenesis of Hemangiomas: A Review , 2006, Plastic and reconstructive surgery.

[70]  J. Mulliken,et al.  Clonality and altered behavior of endothelial cells from hemangiomas. , 2001, The Journal of clinical investigation.

[71]  I. Bukovsky,et al.  Placental Apoptosis in Normal and Abnormal Pregnancies , 2000, Gynecologic and Obstetric Investigation.

[72]  P. Cejudo-Martı́n,et al.  A new notch in the HIF belt: how hypoxia impacts differentiation. , 2005, Developmental cell.

[73]  M. Longaker,et al.  Proliferative hemangiomas: analysis of cytokine gene expression and angiogenesis. , 1999, Plastic and reconstructive surgery.

[74]  J. Mulliken,et al.  Spastic Diplegia as a Complication of Interferon Alfa‐2a Treatment of Hemangiomas of Infancy , 1998, The Journal of pediatrics.

[75]  S. Orlow,et al.  Increased risk of symptomatic hemangiomas of the airway in association with cutaneous hemangiomas in a "beard" distribution. , 1997, The Journal of pediatrics.

[76]  M. Mihm,et al.  Infantile hemangioma: clinical resolution with 5% imiquimod cream. , 2002, Archives of dermatology.

[77]  J. Wittliff,et al.  Pathogenesis and Treatment of Infant Skin Strawberry Hemangiomas: Clinical and in Vitro Studies of Hormonal Effects , 1984, Plastic and reconstructive surgery.

[78]  M. Adn,et al.  Pathophysiology of capillary haemangioma growth after birth. , 2005, Medical hypotheses.

[79]  Song Yu,et al.  The establishment of the hemangioma model in nude mouse. , 2005, Journal of pediatric surgery.

[80]  B. Smoller,et al.  Proliferation and apoptosis within juvenile capillary hemangiomas. , 1996, The American Journal of dermatopathology.

[81]  G. Semenza,et al.  Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. , 2005, Blood.

[82]  M. Mihm,et al.  A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. , 2001, Archives of dermatology.

[83]  P. Hazen,et al.  Proliferating Hemangioma of Infancy: Successful Treatment with Topical 5% Imiquimod Cream , 2005, Pediatric dermatology.

[84]  H. Losken,et al.  No evidence for maternal-fetal microchimerism in infantile hemangioma: a molecular genetic investigation. , 2006, The Journal of investigative dermatology.

[85]  Golder N Wilson,et al.  Malformations and minor anomalies in children whose mothers had prenatal diagnosis: comparison between CVS and amniocentesis. , 1990, American journal of medical genetics.

[86]  G. Damonte,et al.  Tryptophan-derived Catabolites Are Responsible for Inhibition of T and Natural Killer Cell Proliferation Induced by Indoleamine 2,3-Dioxygenase , 2002, The Journal of experimental medicine.

[87]  M. Waner,et al.  Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma , 2002, Genes, chromosomes & cancer.

[88]  D. Metry,et al.  Benign cutaneous vascular tumors of infancy: when to worry, what to do. , 2000, Archives of dermatology.

[89]  F. C. Lucibello,et al.  Endothelial-like cells derived from human CD14 positive monocytes. , 2000, Differentiation; research in biological diversity.

[90]  M. Waner,et al.  Hemangiomas and vascular malformations of the head and neck , 1999 .

[91]  M. Kennedy,et al.  A common precursor for hematopoietic and endothelial cells. , 1998, Development.

[92]  D. Munn,et al.  Prevention of T cell–driven complement activation and inflammation by tryptophan catabolism during pregnancy , 2001, Nature Immunology.

[93]  I. Frieden,et al.  Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics. , 2007, The Journal of pediatrics.

[94]  S. Orlow,et al.  Familial segregation of hemangiomas and vascular malformations as an autosomal dominant trait. , 1998, Archives of dermatology.

[95]  M. Furihata,et al.  HIGH FREQUENCY OF APOPTOSIS IN INFANTILE CAPILLARY HAEMANGIOMA , 1996, The Journal of pathology.

[96]  G. Semenza,et al.  Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. , 1999, Cancer research.

[97]  E. Boscolo,et al.  Genomic Imprinting of IGF2 Is Maintained in Infantile Hemangioma despite its High Level of Expression , 2004, Molecular medicine.

[98]  B. Berman,et al.  Treatment of infantile hemangiomas with short-term application of imiquimod 5% cream. , 2004, Journal of the American Academy of Dermatology.

[99]  A. Kurzyna,et al.  [Hemangiomas and vascular malformations of the head and neck]. , 2006, Otolaryngologia polska = The Polish otolaryngology.

[100]  R. Smith,et al.  An update on the treatment of hemangiomas in children with interferon alfa-2a. , 1999, Archives of otolaryngology--head & neck surgery.

[101]  R. Marcucio,et al.  Patterns of Infantile Hemangiomas: New Clues to Hemangioma Pathogenesis and Embryonic Facial Development , 2006, Pediatrics.

[102]  J. Folkman,et al.  Successful treatment of infantile hemangiomas with interferon-alpha-2b. , 1997, Journal of pediatric hematology/oncology.

[103]  P. Davis,et al.  Mast Cells and Hemangioma , 2004, Plastic and reconstructive surgery.

[104]  Peter Carmeliet,et al.  Angiogenesis in life, disease and medicine , 2005, Nature.

[105]  C. Bucana,et al.  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. , 1999, International journal of oncology.

[106]  P. Davis,et al.  Clusterin/apoJ expression during the development of hemangioma. , 2000, Human pathology.

[107]  J. Glowacki,et al.  Congenital vascular lesions: clinical application of a new classification. , 1983, Journal of pediatric surgery.

[108]  J. Mulliken,et al.  Cellular markers that distinguish the phases of hemangioma during infancy and childhood. , 1994, The Journal of clinical investigation.

[109]  A. Fleischer,et al.  Oral corticosteroid use is effective for cutaneous hemangiomas: an evidence-based evaluation. , 2001, Archives of dermatology.

[110]  M. Friedlander,et al.  Myeloid cells in infantile hemangioma. , 2006, The American journal of pathology.

[111]  D. Passaro,et al.  Hemangiomas of infancy: clinical characteristics, morphologic subtypes, and their relationship to race, ethnicity, and sex. , 2002, Archives of dermatology.