Skip to main content
Top
Published in: Orphanet Journal of Rare Diseases 1/2018

Open Access 01-12-2018 | Research

Estrogen is involved in hemangioma regression associated with mast cells

Authors: Fang Hou, Yuemeng Dai, Chun-Yang Fan, James Y. Suen, Gresham T. Richter

Published in: Orphanet Journal of Rare Diseases | Issue 1/2018

Login to get access

Abstract

Background

Estrogen plays a role in infantile hemangioma (IH) development, but the underlying mechanism remains unclear. This study aimed to assess estrogen and estrogen receptor (ER) localization and expression levels in IH. In addition, the unexpected relationship between mast cells (MCs) and estrogen in human IH was discussed.

Methods

IH (n = 29), vascular malformation (VMs, n = 33) and normal skin (n = 15) specimens were assessed. IH was classified into proliferative (n = 9; age, 3.56 ± 1.01 months), early involuting (n = 10; age, 8.90 ± 2.69 months) and late involuting (n = 10; age, 20.10 ± 4.93 months) groups. Estradiol (E2), ER-a, ER-β, and tryptase (MC marker) levels were determined immunohistochemically and/or by double immunofluorescence staining. Quantification and localization of tryptase, ER-a, and E2 were assessed for each specimen.

Results

ER-a, E2, and tryptase were expressed in the cytoplasm and nucleus of MCs in IH. The IH specimens showed significantly more tryptase, ER-a, and E2 positive MCs (30.6 ± 12.7, 9.7 ± 5.6, and 19.8 ± 8.7 cells/high-power field [HPF], respectively) compared with VM specimens (9.0 ± 9.8, 1.5 ± 2.4, and 2.5 ± 4.1 cells/HPF, respectively) and normal skin (6.1 ± 8.5, 0.5 ± 1.2, and 1.9 ± 3.4 cells/HPF, respectively). Proliferating IH displayed fewer E2 positive MCs (14.0 6.3 cells/HPF) compared with early (22.3 ± 10.2 cells/HPF, P = 0.023) and late (22.4 ± 6.8 cells/HPF, P = 0.006) involuting specimens. In addition, proliferating IH showed fewer tryptase positive MCs (24.7 ± 10.8 cells/HPF) compared with early involuting specimens (35.7 ± 15.3 cells/HPF, P = 0.043). All IH specimens were ER-a positive and ER-β negative.

Conclusions

E2 and ER-a are expressed on MCs and not on IH endothelial cells. Furthermore, activated MCs may be involved in IH regression.
Literature
1.
go back to reference Léauté-Labrèze C, Harper JI, Hoeger PH. Infantile haemangioma. Lancet. 2017;1:85–94.CrossRef Léauté-Labrèze C, Harper JI, Hoeger PH. Infantile haemangioma. Lancet. 2017;1:85–94.CrossRef
2.
go back to reference Munden A, Butschek R, Tom WL, Marshall JS, Poeltler DM, Krohne SE, Alió AB, Ritter M, Friedlander DF, Catanzarite V, Mendoza A, Smith L, Friedlander M, Friedlander SF. Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies. Br J Dermatol. 2014;170:907–13.CrossRef Munden A, Butschek R, Tom WL, Marshall JS, Poeltler DM, Krohne SE, Alió AB, Ritter M, Friedlander DF, Catanzarite V, Mendoza A, Smith L, Friedlander M, Friedlander SF. Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies. Br J Dermatol. 2014;170:907–13.CrossRef
3.
go back to reference Mulliken JB, Bischoff J. Pathogenesis of infantile hemangioma. In: Mulliken JB, Burrows PE, Fishman SJ, editors. Vascular anomalies: hemangiomas and malformations. 2nd ed. New York: Oxford University Press; 2013. p. 43–67.CrossRef Mulliken JB, Bischoff J. Pathogenesis of infantile hemangioma. In: Mulliken JB, Burrows PE, Fishman SJ, editors. Vascular anomalies: hemangiomas and malformations. 2nd ed. New York: Oxford University Press; 2013. p. 43–67.CrossRef
4.
go back to reference Tan ST, Hasan Q, Velickovic M, Ruger BM, Davis RP, Davis PF. A novel in vitro human model of hemangioma. Mod Pathol. 2000;13:92–9.CrossRef Tan ST, Hasan Q, Velickovic M, Ruger BM, Davis RP, Davis PF. A novel in vitro human model of hemangioma. Mod Pathol. 2000;13:92–9.CrossRef
5.
go back to reference Darrow DH, Greene AK, Mancini AJ, Nopper AJ, Section On Dermatology, Section On Otolaryngology–Head And Neck Surgery, And Section On Plastic Surgery. Diagnosis and Management of Infantile Hemangioma. Pediatrics. 2015;136:e1060–104.CrossRef Darrow DH, Greene AK, Mancini AJ, Nopper AJ, Section On Dermatology, Section On Otolaryngology–Head And Neck Surgery, And Section On Plastic Surgery. Diagnosis and Management of Infantile Hemangioma. Pediatrics. 2015;136:e1060–104.CrossRef
6.
go back to reference Chiller KG, Passaro D, Frieden IJ. Hemangiomas of infancy: clinical characteristics, morphologic subtypes, and their relationship to race, ethnicity, and sex. Arch Dermatol. 2002;138:1567–76.CrossRef Chiller KG, Passaro D, Frieden IJ. Hemangiomas of infancy: clinical characteristics, morphologic subtypes, and their relationship to race, ethnicity, and sex. Arch Dermatol. 2002;138:1567–76.CrossRef
7.
go back to reference Sasaki GH, Pang CY, Wittliff JL. Pathogenesis and treatment of infant skin strawberry hemangiomas: clinical and in vitro studies of hormonal effects. Plast Reconstr Surg. 1984;73:359–70.CrossRef Sasaki GH, Pang CY, Wittliff JL. Pathogenesis and treatment of infant skin strawberry hemangiomas: clinical and in vitro studies of hormonal effects. Plast Reconstr Surg. 1984;73:359–70.CrossRef
8.
go back to reference Sun ZY, Yang L, Yi CG, Zhao H, Han DL, Yang T, Wang L, Nie CL, Zhang GY, Yin GQ, Wang G, Teng XP, Fei DM, Wang J, Zhou WK, Li Y, Liu B, Liu Y, Zhang MJ, Wu SM, Zhang X, Pan H, Xiao B, Zhao KF, Liu D, Guo SZ. Possibilities and potential roles of estrogen in the pathogenesis of proliferation hemangiomas formation. Med Hypotheses. 2008;71:286–92.CrossRef Sun ZY, Yang L, Yi CG, Zhao H, Han DL, Yang T, Wang L, Nie CL, Zhang GY, Yin GQ, Wang G, Teng XP, Fei DM, Wang J, Zhou WK, Li Y, Liu B, Liu Y, Zhang MJ, Wu SM, Zhang X, Pan H, Xiao B, Zhao KF, Liu D, Guo SZ. Possibilities and potential roles of estrogen in the pathogenesis of proliferation hemangiomas formation. Med Hypotheses. 2008;71:286–92.CrossRef
9.
go back to reference Zaitsu M, Narita S, Lambert KC, Grady JJ, Estes DM, Curran EM, Brooks EG, Watson CS, Goldblum RM, Midoro-Horiuti T. Estradiol activates mast cells via a non-genomic estrogen receptor-alpha and calcium influx. Mol Immunol. 2007;44:1977–85.CrossRef Zaitsu M, Narita S, Lambert KC, Grady JJ, Estes DM, Curran EM, Brooks EG, Watson CS, Goldblum RM, Midoro-Horiuti T. Estradiol activates mast cells via a non-genomic estrogen receptor-alpha and calcium influx. Mol Immunol. 2007;44:1977–85.CrossRef
10.
go back to reference Jensen F, Woudwyk M, Teles A, Woidacki K, Taran F, Costa S, Malfertheiner SF, Zenclussen AC. Estradiol and progesterone regulate the migration of mast cells from the periphery to the uterus and induce their maturation and degranulation. PLoS One. 2010;5:e14409.CrossRef Jensen F, Woudwyk M, Teles A, Woidacki K, Taran F, Costa S, Malfertheiner SF, Zenclussen AC. Estradiol and progesterone regulate the migration of mast cells from the periphery to the uterus and induce their maturation and degranulation. PLoS One. 2010;5:e14409.CrossRef
11.
go back to reference Harnish DC, Albert LM, Leathurby Y, Eckert AM, Ciarletta A, Kasaian M, Keith JJ. Beneficial effects of estrogen treatment in the HLA-B27 transgenic rat model of inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol. 2004;286:118–25.CrossRef Harnish DC, Albert LM, Leathurby Y, Eckert AM, Ciarletta A, Kasaian M, Keith JJ. Beneficial effects of estrogen treatment in the HLA-B27 transgenic rat model of inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol. 2004;286:118–25.CrossRef
12.
go back to reference Tan ST, Wallis RA, He Y, Davis PF. Mast cells and hemangioma. Plast Reconstr Surg. 2004;113:999–1011.CrossRef Tan ST, Wallis RA, He Y, Davis PF. Mast cells and hemangioma. Plast Reconstr Surg. 2004;113:999–1011.CrossRef
13.
go back to reference Cui J, Shen Y, Li R. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med. 2013;19:197–209.CrossRef Cui J, Shen Y, Li R. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med. 2013;19:197–209.CrossRef
14.
go back to reference Reggiani BL, Boselli F, Lupi M, Bettelli S, Schirosi L, Bigiani N, Sartori G, Rivasi F. Expression of estrogen receptor in hemangioma of the uterine cervix: reports of three cases and review of the literature. Arch Gynecol Obstet. 2009;280:469–72.CrossRef Reggiani BL, Boselli F, Lupi M, Bettelli S, Schirosi L, Bigiani N, Sartori G, Rivasi F. Expression of estrogen receptor in hemangioma of the uterine cervix: reports of three cases and review of the literature. Arch Gynecol Obstet. 2009;280:469–72.CrossRef
15.
go back to reference Lui W, Zhang S, Hu T, Wei F, Gao Y, Cheng N. Sex hormone receptors of hemangiomas in children. Chin Med J. 1997;110:349–51.PubMed Lui W, Zhang S, Hu T, Wei F, Gao Y, Cheng N. Sex hormone receptors of hemangiomas in children. Chin Med J. 1997;110:349–51.PubMed
16.
go back to reference Itinteang T, Tan ST, Jia J, Steel R, Laing EL, Brasch HD, Day DJ. Mast cells in infantile haemangioma possess a primitive myeloid phenotype. J Clin Pathol. 2013;66:597–600.CrossRef Itinteang T, Tan ST, Jia J, Steel R, Laing EL, Brasch HD, Day DJ. Mast cells in infantile haemangioma possess a primitive myeloid phenotype. J Clin Pathol. 2013;66:597–600.CrossRef
17.
go back to reference Steel R, Day D. Increased apoptosis and secretion of tryptase by mast cells in infantile haemangioma treated with propranolol. Pathology. 2014;46:496–500.CrossRef Steel R, Day D. Increased apoptosis and secretion of tryptase by mast cells in infantile haemangioma treated with propranolol. Pathology. 2014;46:496–500.CrossRef
18.
go back to reference Tan ST, Velickovic M, Ruger BM, Davis PF. Cellular and extracellular markers of hemangioma. Plast Reconstr Surg. 2000;106:529–38.CrossRef Tan ST, Velickovic M, Ruger BM, Davis PF. Cellular and extracellular markers of hemangioma. Plast Reconstr Surg. 2000;106:529–38.CrossRef
19.
go back to reference Hasan Q, Ruger BM, Tan ST, Gush J, Davis PF. Clusterin/apoJ expression during the development of hemangioma. Hum Pathol. 2000;31:691–7.CrossRef Hasan Q, Ruger BM, Tan ST, Gush J, Davis PF. Clusterin/apoJ expression during the development of hemangioma. Hum Pathol. 2000;31:691–7.CrossRef
20.
go back to reference Caughey GH. Mast cell tryptases and chymases in inflammation and host defense. Immunol Rev. 2007;217:141–54.CrossRef Caughey GH. Mast cell tryptases and chymases in inflammation and host defense. Immunol Rev. 2007;217:141–54.CrossRef
21.
go back to reference Bosquiazzo VL, Ramos JG, Varayoud J, Munoz-de-Toro M, Luque EH. Mast cell degranulation in rat uterine cervix during pregnancy correlates with expression of vascular endothelial growth factor mRNA and angiogenesis. Reproduction. 2007;133:1045–55.CrossRef Bosquiazzo VL, Ramos JG, Varayoud J, Munoz-de-Toro M, Luque EH. Mast cell degranulation in rat uterine cervix during pregnancy correlates with expression of vascular endothelial growth factor mRNA and angiogenesis. Reproduction. 2007;133:1045–55.CrossRef
22.
23.
go back to reference Lee BS, Stewart EA, Sahakian M, Nowak RA. Interferon-alpha is a potent inhibitor of basic fibroblast growth factor-stimulated cell proliferation in human uterine cells. Am J Reprod Immunol. 1998;40:19–25.CrossRef Lee BS, Stewart EA, Sahakian M, Nowak RA. Interferon-alpha is a potent inhibitor of basic fibroblast growth factor-stimulated cell proliferation in human uterine cells. Am J Reprod Immunol. 1998;40:19–25.CrossRef
24.
go back to reference Akl MR, Nagpal P, Ayoub NM, Tai B, Prabhu SA, Capac CM, Gliksman M, Goy A, Suh KS. Molecular and clinical significance of fibroblast growth factor 2 (FGF2 /bFGF) in malignancies of solid and hematological cancers for personalized therapies. Oncotarget. 2016;7:44735–62.CrossRef Akl MR, Nagpal P, Ayoub NM, Tai B, Prabhu SA, Capac CM, Gliksman M, Goy A, Suh KS. Molecular and clinical significance of fibroblast growth factor 2 (FGF2 /bFGF) in malignancies of solid and hematological cancers for personalized therapies. Oncotarget. 2016;7:44735–62.CrossRef
26.
go back to reference Itinteang T, Withers AH, Davis PF, Tan ST. Biology of infantile hemangioma. Front Surg. 2014;1:38.CrossRef Itinteang T, Withers AH, Davis PF, Tan ST. Biology of infantile hemangioma. Front Surg. 2014;1:38.CrossRef
27.
go back to reference Jonker L. TGF-β & BMP receptors endoglin and ALK1: overview of their functional role and status as antiangiogenic targets. Microcirculation. 2014;21:93–103.CrossRef Jonker L. TGF-β & BMP receptors endoglin and ALK1: overview of their functional role and status as antiangiogenic targets. Microcirculation. 2014;21:93–103.CrossRef
28.
go back to reference Dethlefsen SM, Mulliken JB, Glowacki J. An ultrastructural study of mast cell interactions in hemangiomas. Ultrastruct Pathol. 1986;10:175–83.CrossRef Dethlefsen SM, Mulliken JB, Glowacki J. An ultrastructural study of mast cell interactions in hemangiomas. Ultrastruct Pathol. 1986;10:175–83.CrossRef
29.
go back to reference Hasan Q, Tan ST, Gush J, Peters SG, Davis PF. Steroid therapy of a proliferating hemangioma: histochemical and molecular changes. Pediatrics. 2000;105:117–20.CrossRef Hasan Q, Tan ST, Gush J, Peters SG, Davis PF. Steroid therapy of a proliferating hemangioma: histochemical and molecular changes. Pediatrics. 2000;105:117–20.CrossRef
30.
go back to reference Mulliken JB. Treatment of cutaneous hemangiomas. In: Mulliken JB, Burrows PE, Fishman SJ, editors. Vascular anomalies: hemangiomas and malformations. 2nd ed. New York: Oxford University Press; 2013. p. 182–259.CrossRef Mulliken JB. Treatment of cutaneous hemangiomas. In: Mulliken JB, Burrows PE, Fishman SJ, editors. Vascular anomalies: hemangiomas and malformations. 2nd ed. New York: Oxford University Press; 2013. p. 182–259.CrossRef
Metadata
Title
Estrogen is involved in hemangioma regression associated with mast cells
Authors
Fang Hou
Yuemeng Dai
Chun-Yang Fan
James Y. Suen
Gresham T. Richter
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2018
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-018-0928-x

Other articles of this Issue 1/2018

Orphanet Journal of Rare Diseases 1/2018 Go to the issue