Angiotensin II causes cellular proliferation in infantile haemangioma via angiotensin II receptor 2 activation.

AIMS: To investigate the effect of the angiotensin peptides and their agonists and antagonists on cellular proliferation in proliferating infantile haemangioma (IH) in vitro explants. METHODS: Proliferating IH samples from six patients were cultured in vitro in the presence of angiotensin I (ATI) alone, or AT1 and the ACE inhibitor, ramipril, or ATII alone, or ATII with the ATII receptor 1 (ATIIR1) blocker, losartan, or ATII with the ATIIR2 blocker, PD123319, or the ATIIR2 agonist, CGP42112. After 6 days in culture, the IH tissue pieces were harvested, formalin-fixed and paraffin-embedded. The effect of each treatment type on cellular proliferation was evaluated by immunohistochemical staining of these tissue pieces using the proliferation marker, Ki67. RESULTS: There was a significant increase in cellular proliferation in the ATI and ATII treated IH tissues compared with control samples. Their effect on cellular proliferation was reduced by adding ramipril and PD123319, respectively. CGP42112, but not losartan, significantly increased cellular proliferation. CONCLUSIONS: Our findings suggest a key regulatory role of ATI and ATII in promoting cellular proliferation in IH, and establish a role for ACE and ATIIR2 in the proliferation of this tumour.

Pharmacologic therapies for infantile hemangioma: is there a rational basis?

BACKGROUND: Infantile hemangioma is the most common tumor of infancy. The majority of cases are managed conservatively, but intervention is necessary in approximately 10 percent of cases because of the threat to life or function or because of tissue distortion or destruction. The mainstay treatment for these problematic proliferating infantile hemangiomas is pharmacologic therapy, mostly discovered serendipitously. METHODS: This review examines the rational basis of the hitherto empirical pharmacologic therapies for the enigmatic infantile hemangioma, in light of new knowledge regarding its biology, including the critical roles of stem cells and the renin-angiotensin system. RESULTS: Steroids have remained the first-line therapy for problematic infantile hemangioma for over 40 years despite their known side effects and failure rates. Vincristine has emerged as an alternative to interferon for steroid-resistant cases because of interferon's adverse effects, especially neurotoxicity. ß-Blockers are now the preferred first-line therapy for problematic cases. There is increasing evidence that infantile hemangioma is a disorder of aberrant proliferation and differentiation of primitive mesoderm-derived neural crest phenotypic cells. This primitive phenotype that gives rise to a hemogenic endothelium intermediate has the ability to undergo primitive erythropoiesis and terminal mesenchymal differentiation. CONCLUSIONS: The recent discovery of the crucial role of stem cells and the inferred role of the renin-angiotensin system in the biology of infantile hemangioma underscores the possibility of even more targeted therapies, by using modulators of the renin-angiotensin system, on infantile hemangioma. The observation of the potential role of these traditional antihypertensive agents in stem cell biology may lead to better understanding of developmental biology and tumor stem cell growth.

Low-dose propranolol for multiple hepatic and cutaneous hemangiomas with deranged liver function.

We report here the case of an infant with multiple hepatic and cutaneous infantile hemangiomas (IHs) associated with deranged liver function who was treated successfully with low-dose propranolol. We also discuss our recent data that show that IH is a developmental anomaly of hemogenic endothelium derived from primitive mesoderm with a neural crest-cell phenotype. We previously presented evidence that this hemogenic endothelium is governed by the renin-angiotensin system, which we propose can account for both the action of propranolol and the process of spontaneous involution of IH. We further speculate on the possibility of using inhibitors of angiotensin-converting enzyme and that of angiotensin II receptor 2 as potential alternative therapies.

Genetics, cellular biology and tumor microenvironment of melanoma.

Melanoma is an aggressive disease for which there is no effective curative treatment beyond surgical excision of the primary lesion and regional disease. Epidemiological, clinical, in vitro and in vivo studies have provided insight into the biology of the disease. This review focuses on current understanding of key molecular pathways, cellular interaction and tumor microenvironment, and the respective aberrations identified in melanoma. Common mutations and/or deregulated expressions of B-raf, N-ras, PTEN, protein kinase B (aka Akt), CDKN2A, CDK4 and MDM2 were presented. In addition to genetic abnormalities, important aspects of cellular biology including, (i) the loss of cell-cell adhesion resulting in an altered state in the relative expression of cadherins, catenins and integrins, (ii) the interaction between melanoma cells and surrounding keratinocytes, fibroblasts, and immune cells, and (iii) tumor angiogenesis and vascular mimicry, are discussed. Many ongoing clinical trials of targeted biological therapies are based on current knowledge, the outcomes are eagerly awaited.