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Pharmacologic Therapies for Infantile Hemangioma

Is There a Rational Basis?

Itinteang, Tinte M.B.B.S.; Withers, Aaron H. J. M.B.Ch.B.; Leadbitter, Philip F.R.A.C.P.; Day, Darren J. Ph.D.; Tan, Swee T. F.R.A.C.S., Ph.D.

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Plastic and Reconstructive Surgery: April 2012 - Volume 129 - Issue 4 - p 725e-727e
doi: 10.1097/PRS.0b013e318245e7cd
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Sir:

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Figure

We thank you for the opportunity to respond to Dr. Arneja's letter regarding our article, “Pharmacologic Therapies in Infantile Hemangioma: Is There a Rational Basis?”1 We are also grateful for Dr. Arneja's generous and insightful comments.

There have been emerging data showing the involvement of stem cells in the biology of infantile hemangioma,1,2 giving both insight into the cause and an understanding of the currently available but largely empirical pharmacologic therapies, and glimpses of potential novel treatment in the future. Dr. Arneja raises some pertinent questions that can only be answered by an ongoing better understanding of the biological processes that govern the programmed biological behavior of infantile hemangioma. Our recent data suggest a placental chorionic villus mesenchymal core cell origin of infantile hemangioma.3 These aberrantly displaced and presumably embolized primitive cells undergo differentiation within the fetus proper. The rich milieu of cytokines in the newborn, including components of the renin-angiotensin system, provides the critical environment for aberrant proliferation and differentiation of the hemogenic endothelium phenotype.4,5

We hypothesized that the high levels of renin at birth (approximately 14 times those of adult life) result in elevated levels of the peptide angiotensin II that drives infantile hemangioma growth during the proliferative phase.4 Reduced levels of renin, and thus presumably angiotensin II, at the end of the first year provide a break in this initial proliferation stage and potential release on the inhibition of mesenchymal differentiation, which promotes en masse terminal mesenchymal differentiation, resulting in the fatty deposition in involuted lesions.6 There is also strong evidence that apoptosis of the primitive cells within infantile hemangioma is governed by the tumor necrosis factor–related apoptosis-inducing ligand/osteoprotegerin pathway.7 Our model for infantile hemangioma (Fig. 1)312 also explains the observed accelerated involution of infantile hemangioma induced by β-blockers,1,8,9 and predicted a role for other modulators of the renin-angiotensin system in the treatment of this condition.8,9 We have recently submitted an article reporting the preliminary results of the efficacy of captopril, an angiotensin-converting enzyme inhibitor, on infantile hemangioma in our clinical trial.10 The ability of captopril to ameliorate proliferation and induce accelerated involution supports our hypothesis for a key role of the renin-angiotensin system in the progression of infantile hemangioma.

Fig. 1
Fig. 1:
Our proposed model of infantile hemangioma accounting for the observed programmed biological behavior and accelerated involution induced by modulators of the renin-angiotensin system: β-blockers or angiotensin-converting enzyme inhibitors (ACEi). Infantile hemangioma is caused by aberrantly displaced/embolized placental chorionic villus mesenchymal core cells into the fetus proper,3 which gives rise to a primitive mesoderm-derived hemogenic endothelium with a neural crest phenotype5 , 11 regulated by the renin-angiotensin system.4 This hemogenic endothelium differentiates into stem cells of neuroglial, mesenchymal, endothelial, and hematopoietic lineages with downstream mesenchymal6 and erythropoietic12 and potentially myeloid differentiation capabilities. During the proliferative phase of infantile hemangioma, high levels of renin indirectly lead to high levels of angiotensin II, resulting in aberrant proliferation of the hemogenic endothelium and secretion of vascular endothelial growth factor (VEGF) from the accumulating mesenchymal stem cells, leading to both proliferation of the endothelial progenitor cells and downstream endothelial cells.4 High levels of angiotensin II also lead to overexpression of the tumor necrosis factor–related apoptosis-inducing ligand decoy receptor osteoprotegerin (OPG), preventing apoptosis of the hemogenic endothelium, mesenchymal stem cells, and endothelial progenitor cells, with further proliferation and accumulation of these cellular elements and endothelial cells.7 High levels of angiotensin II also prevent terminal differentiation of mesenchymal stem cells to downstream adipocytes, further increasing the accumulation of mesenchymal stem cells.6 During the involuting phase of infantile hemangioma, reduced levels of angiotensin II, indirectly caused by decreasing levels of renin, ease accumulation of endothelial progenitor cells and endothelial cells. Reduced levels of angiotensin II also allow termination differentiation of mesenchymal stem cells into adipocytes, resulting in a fibrofatty residuum.6 Inhibition of renin by β-blockers1 , 8 , 9 or angiotensin-converting enzyme inhibitor10 leads to reduced levels of angiotensin II, resulting in accelerated involution of infantile hemangioma.

Dr. Arneja raises the question of using combined therapies targeting various regulators of the renin-angiotensin system, potentially offering more efficacious treatment regimens for infantile hemangioma. This is highly relevant, and we also feel that combined targeting is likely to be more efficacious, although this remains to be investigated. The role of angiotensinogen-derived peptides other than angiotensin II that are likely to accumulate with blockade of enzymes involved in angiotensinogen cleavage and processing, in the progression of infantile hemangioma, is unclear. This complex interplay of the various processes regulating the proliferation and differentiation of the hemogenic endothelium of infantile hemangioma may account for the variations in the clinical responses of these tumors as stated in our article.1 An appreciation of the biology of infantile hemangioma may also account for the differences and subtleties between infantile hemangioma and rapidly involuting congenital hemangiomas and noninvoluting congenital hemangioma. Although it is now clear that infantile hemangioma has an origin downstream of embryonic stem cells3,12,13 and is best considered a developmental anomaly, our preliminary data suggest that rapidly involuting congenital hemangiomas and noninvoluting congenital hemangiomas have a different origin, which may account for their poor response to pharmacologic intervention.

The concept underpinning a tumor, such as infantile hemangioma, resulting from aberrantly derived/embolized placental chorionic villus mesenchymal core cells3 with a neural crest stem cell phenotype,11 and proliferation and differentiation of the resultant hemogenic endothelium,5 represents a paradigm shift in the understanding of this enigmatic condition and of tumor biology. The mesenchymal6 and erythropoietic12 differentiation capability of the hemogenic endothelium in infantile hemangioma is intriguing and offers immense potential applications in regenerative medicine. This prospect places plastic surgery as the vanguard in both the management of infantile hemangioma, and affords the opportunity to access sources of these primitive cells for research in stem cell biology.

Tinte Itinteang, M.B.B.S.

Centre for the Study & Treatment of Vascular Birthmarks, Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, Gillies McIndoe Research Institute, School of Biological Sciences, Victoria University of Wellington

Aaron H. J. Withers, M.B.Ch.B.

Centre for the Study & Treatment of Vascular Birthmarks, Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital

Philip Leadbitter, F.R.A.C.P.

Centre for the Study & Treatment of Vascular Birthmarks, Wellington Regional Plastic, Maxillofacial & Burns Unit, and, Department of Paediatrics, Hutt Hospital

Darren J. Day, Ph.D.

Centre for the Study & Treatment of Vascular Birthmarks, Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, Gillies McIndoe Research Institute, School of Biological Sciences, Victoria University of Wellington

Swee T. Tan, F.R.A.C.S., Ph.D.

Centre for the Study & Treatment of Vascular Birthmarks, Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, Gillies McIndoe Research Institute, University of Otago, School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand

REFERENCES

1. Itinteang T, Withers AH, Leadbitter P, Day DJ, Tan ST. Pharmacologic therapies for infantile hemangioma: Is there a rational basis? Plast Reconstr Surg. 2011;128:499–507.
2. Bischoff J. Progenitor cells in infantile hemangioma. J Craniofac Surg. 2009;20(Suppl 1):695–697.
3. Itinteang T, Tan ST, Guthrie S, et al.. A placental chorionic villous mesenchymal core cellular origin for infantile haemangioma. J Clin Pathol. 2011;64:870–874.
4. Itinteang T, Brasch HD, Tan ST, Day DJ. Expression of components of the renin-angiotensin system in proliferating infantile haemangioma may account for the propranolol-induced accelerated involution. J Plast Reconstr Aesthet Surg. 2011;64:759–765.
5. Itinteang T, Tan ST, Brasch HD, Day DJ. Haemogenic endothelium in infantile haemangioma. J Clin Pathol. 2010;63:982–986.
6. Itinteang T, Vishvanath A, Day DJ, Tan ST. Mesenchymal stem cells in infantile haemangioma. J Clin Pathol. 2011;64:232–236.
7. Vishvanath A, Itinteang T, Tan ST, Day DJ. Infantile haemangioma expresses tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), TRAIL receptors, osteoprotegerin and receptor activator for nuclear factor κB ligand (RANKL). Histopathology 2011;59:397–406.
8. Tan ST, Itinteang T, Leadbitter P. Low-dose propranolol for infantile haemangioma. J Plast Reconstr Aesthet Surg. 2011;64:292–299.
9. Tan ST, Itinteang T, Leadbitter P. Low-dose propranolol for multiple hepatic and cutaneous hemangiomas with deranged liver function. Pediatrics 2011;127:e772–e776.
10. Tan ST, Itinteang T, Day DJ, O'Donnell C, et al.. Treatment of infantile haemangioma with low dose captopril. Submitted for publication.
11. Itinteang T, Tan ST, Brasch HD, Day DJ. Primitive mesodermal cells with a neural crest stem cell phenotype predominate proliferating infantile haemangioma. J Clin Pathol. 2010;63:771–776.
12. Itinteang T, Tan ST, Brasch HD, Vishvanath A, Day DJ. Primitive erythropoiesis in infantile haemangioma. Br J Dermatol. 2011;164:1097–1100.
13. Itinteang T, Tan ST, Brasch HD, et al.. Infantile haemangioma expresses embryonic stem cell markers. Submitted for publication.

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