Materiały źródłowe

• #1 Pathogenesis of hemangioma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC208951/

  Hemangioma is the most common tumor of any kind seen in infancy. […] Nonetheless, the pathogenesis of hemangioma is still not understood. […] Although growth factors and hormonal and mechanical influences have been postulated to affect the abnormal proliferation of endothelial cells in hemangioma, the primary, causative defect in hemangiogenesis remains unknown and no genetic alteration has been implicated. […] The data of Boye et al. (13) support the hypothesis that the primary defect is intrinsic to endothelial cells, rather than other cell types constituting the hemangioma. […] A competing hypothesis, holding that proliferation of endothelial cells is primarily a response to factors secreted by neighboring cells, can therefore be ruled out. […] One possible explanation, favored by the authors, is that a precursor endothelial cell had undergone a mutation in a gene regulating angiogenesis, resulting in clonal expansion.

• #2

  https://www.jci.org/articles/view/12470

  Hemangioma is the most common tumor of any kind seen in infancy. […] Nonetheless, the pathogenesis of hemangioma is still not understood. […] The data of Boye et al. (13) support the hypothesis that the primary defect is intrinsic to endothelial cells, rather than other cell types constituting the hemangioma. […] One possible explanation, favored by the authors, is that a precursor endothelial cell had undergone a mutation in a gene regulating angiogenesis, resulting in clonal expansion. […] Evidence for somatic mutations in hemangioma comes from Berg and colleagues, who showed that loss of heterozygosity (LOH) in hemangioma tissue is prevalent on chromosome 5q (17), suggesting that loss-of-function mutations contributes to hemangioma development. […] An equally likely possibility is a somatic mutation leading to constitutive activation of an angiogenesis-promoting gene.

• #3 Infantile Hemangiomas: An Update on Pathogenesis and Treatment

  https://www.mdpi.com/2077-0383/10/20/4631

  Infantile hemangiomas are the most common benign vascular tumors in infancy. This review includes an update on the current knowledge on pathogenesis […] Over the years, scientists have postulated what seemed to be different theories of the pathogenesis of IH. It now appears that most of them are somehow connected. In recent studies, authors have suggested that IHs are a result of dysregulated vasculogenesis (i.e., the formation of new blood vessels from stem cells) and angiogenesis (i.e., the formation of new blood vessels from existing vessels). Hypoxia, which seems to be the trigger for this dysregulation, causes the overexpression of angiogenic factors such as vascular endothelial growth factor (VEGF) by inducing the transcription of the VEGF gene. […] Understanding the pathogenesis of IH is crucial for identifying patients at the highest risk of complications caused by the size or location of IH, and for developing a therapy with the most beneficial ratio of efficacy to adverse effects.

• #4

  https://journals.lww.com/plasreconsurg/fulltext/2006/02000/the_pathogenesis_of_hemangiomas__a_review.45.aspx

  Hemangiomas of infancy are common endothelial tumors. […] To date, there is no universally accepted theory that explains the pathogenesis and pathophysiology of hemangiomas. […] The most authoritative theories focus on angioblast origins, trophoblast origins, mutations in cytokine regulatory pathways, and field defects as the cause of the deranged angiogenesis of hemangiomas. […] To date, no single theory can easily explain all the characteristics of hemangiomas, such as predilection for the female sex, usual occurrence after birth, spontaneous involution, abnormal tissue architecture, and distribution within a developmental field. Hemangiomas are probably the final common expression of several pathophysiological mechanisms taking effect alone or in combination.

• #5 Signaling pathways in the development of infantile hemangioma | Journal of Hematology & Oncology | Full Text

  https://jhoonline.biomedcentral.com/articles/10.1186/1756-8722-7-13

  Infantile hemangioma (IH), which is the most common tumor in infants, is a benign vascular neoplasm resulting from the abnormal proliferation of endothelial cells and pericytes. […] Recent studies have provided some insight into the pathogenesis of these vascular tumors, leading to a better understanding of the biological features of IH and, in particular, indicating that during hemangioma neovascularization, two main pathogenic mechanisms prevail, angiogenesis and vasculogenesis. Both mechanisms have been linked to alterations in several important cellular signaling pathways. […] We now recognize that IH may be not only a disorder of angiogenesis (i.e., the sprouting of new vessels from existing ones) but also at least in part a disorder of vasculogenesis (i.e., the de novo formation of new blood vessels from stem cells).

• #6 Infantile Hemangioma | IntechOpen

  https://www.intechopen.com/chapters/1175355

  The pathogenesis of IHs is complex and poorly understood. There are many researches that aim to have a better understanding of the pathogenesis of IHs in the literature and several hypotheses have been proposed. Scientists have suggested that IHs are a result of dysregulated vasculogenesis and angiogenesis. Angiogenesis and vasculogenesis are regulated by many important signaling pathways, such as vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) pathway, Notch pathway, -adrenergic signaling, hypoxia-inducible growth factor- (HIF-)-mediated pathway, etc. These pathways have been linked to each other by several interactions in the development of angiogenesis and vasculogenesis. […] The first hypothesis is the somatic mutation of hemangioma stem cells and upregulation of vascular endothelial growth factor receptor (VEGFR) signaling pathway. Hemangioma stem cells (HemSCs) and hemangioma endothelial cells (HemECs) are the two most important cells in the pathogenesis of IHs. Hemangioma stem cells have the ability to undergo self-renewal and can differentiate into HemECs, pericytes and adipocytes.

• #7 Infantile hemangioma-mechanism(s) of drug action on a vascular tumor

  https://bischofflab.hms.harvard.edu/publications/infantile-hemangioma-mechanisms-drug-action-vascular-tumor

  Infantile hemangioma (IH), a benign vascular tumor, is the most common tumor of infancy, with an incidence of 5%-10% at the end of the first year. […] Thus, IH represents a unique model of postnatal vasculogenesis, angiogenesis, and vessel regression. […] This article will focus on the mechanism of action of these two drugs, the old and the new treatments, in slowing the growth and accelerating involution of IH.

• #8 Pathogenesis of hemangioma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC208951/

  Evidence for somatic mutations in hemangioma comes from Berg and colleagues, who showed that loss of heterozygosity (LOH) in hemangioma tissue is prevalent on chromosome 5q (17), suggesting that loss-of-function mutations contributes to hemangioma development. […] An equally likely possibility is a somatic mutation leading to constitutive activation of an angiogenesis-promoting gene. […] The similarities in gene expression between hemangiomal and placental vessels might be explained by a somatic mutation in a regulatory gene that directs hemangiomal endothelial cells toward a placental phenotype, but North and colleagues also suggest an alternative theory (19). […] The otherwise puzzling observation that chorionic villus sampling increases the risk of hemangiomas (20, 21) further supports this model, since the local placental injury caused in this procedure might increase shedding of endothelial cells from chorionic villi into the fetal circulation.

• #9

  https://omim.org/entry/602089

  Breugem et al. (2002) tentatively suggested that congenital capillary malformation syndrome (CMC1) was separate and distinct from capillary infantile hemangioma, but admitted the possibility that vascular tumors (hemangiomas) and vascular malformations, which are classified into 2 separate categories (Mulliken and Young, 1988), may have similar etiologies. […] In hemangioma endothelial cells, Jinnin et al. (2008) found that expression of VEGFR1 (FLT1; 165070) was markedly reduced, and that VEGFR2 activity was increased, compared to controls. In normal endothelial cells, FLT1 transcription is dependent on NFAT (see, e.g., NFATC2; 600490) activation. Further studies indicated that low VEGFR1 expression in hemangioma cells was caused by reduced activity of a pathway involving ITGB1 (135630), TEM8, VEGFR2, and NFAT. Jinnin et al. (2008) identified germline mutations in the TEM8 gene (606410.0001) and in the VEGFR2 gene (191306.0002) in patients with infantile hemangioma. These mutations disrupted the normal association of this molecular complex. Jinnin et al. (2008) postulated that these mutations conferred increased susceptibility to the formation of hemangiomas, but were probably associated with a secondary somatic event to trigger the expansion of endothelial cells within the lesions.

• #10

  https://omim.org/entry/602089

  In 1 of 15 infantile hemangioma specimens, Walter et al. (2002) identified a mutation in the FLT4 gene (136352.0007). This result, and the finding of a somatic missense mutation in the VEGFR2 gene (191306.0001) in another of the 15 specimens, suggested that alteration of the FLT4 signaling pathway in endothelial and/or pericytic cells may be a mechanism involved in hemangioma formation. […] Pramanik et al. (2009) identified an apparently somatic ser147-to-pro (S147P) mutation in the DUSP5 gene (603069) in 1 of 3 infantile hemangioma samples and in 12 of 17 lymphatic, arteriovenous, and venous malformation samples. The mutation was not found in normal human placenta, control human umbilical vein endothelial cells, or tonsillar tissue from unrelated individuals. In zebrafish, the authors demonstrated that Dusp5 was expressed in angioblasts and played a role in vascular development, suggesting that variation in this gene may provide susceptibility to the development of vascular anomalies in humans.

• #11

  https://www.jci.org/articles/view/12470

  The similarities in gene expression between hemangiomal and placental vessels might be explained by a somatic mutation in a regulatory gene that directs hemangiomal endothelial cells toward a placental phenotype, but North and colleagues also suggest an alternative theory (19). […] The otherwise puzzling observation that chorionic villus sampling increases the risk of hemangiomas (20, 21) further supports this model, since the local placental injury caused in this procedure might increase shedding of endothelial cells from chorionic villi into the fetal circulation. […] The intriguing data of Boye and colleagues (13) suggest one mechanism for hemangioma formation and bring the field a step closer to understanding the molecular etiology of this common tumor.

• #12 Infantile Hemangioma | IntechOpen

  https://www.intechopen.com/chapters/1175355

  Boscolo and Bischoff recognize that IHs may not only be a disorder of angiogenesis (i.e., the formation of new blood vessels from existing vessels) but alsoat least in parta disorder of vasculogenesis (i.e., the de novo formation of new blood vessels from cells. […] The second hypothesis is the placental theory which proposes that a fetal placental progenitor cell is the cell type of origin for IHs. North et al. published an article that identified the marker GLUT-1 as a specific feature of IHs during all phases of these lesions. The GLUT-1 is highly expressed in human brain and placenta but not in normal skin or subcutaneous tissue. GLUT-1 immunoreactivity, which is a highly selective and diagnostically useful maker for IHs, was not found in any of the vascular malformations in this research.

• #13 Infantile haemangioma: Definition and pathogenesis

  https://dermnetnz.org/topics/infantile-haemangioma-definition-and-pathogenesis

  A placental origin for infantile haemangioma is suggested due to GLUT1 protein expression. Fetal vascular origins are proposed due to the presence of primitive marker CD133 from the fetal cardinal vein. […] Defective vascular stem cell regulation involving endothelial progenitor cells (EPC), or extrinsic factors such as hypoxia and developmental vascular field disturbances can influence the development of vascular anomalies.

• #14 Hemangiomas Linked to Placental Abnormalities | MDedge

  https://www.mdedge.com/content/hemangiomas-linked-placental-abnormalities

  Hypoxia is extremely important as a precursor lesion, and placental anomalies provoke a low-oxygen atmosphere, which is one—and probably the most important—of the suggested factors for hemangioma development, Dr. Lopez said. […] Prior research suggests that abnormal placentas increase the likelihood of infantile hemangiomas through shearing and embolization of placental tissue. […] Thus, the hypoxic environment created by placental insufficiency could be the trigger that turns on a vasculogenic response in any endothelial cells that have escaped into a fetus’s circulation, they wrote. […] Dr. Paula North, chief of pediatric pathology at the Medical College of Wisconsin, Milwaukee, pioneered the embolization theory of hemangioma pathogenesis and said that Dr. Lopez’s study raises some valid issues.

• #15 Hemangioma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Hemangioma_pathophysiology

  Development of hemangioma is the result of genetic mutations, overexpression of angiogenic factors and downregulation of inhibitors of angiogenesis. […] The pathogenesis of hemangiomas has not been elucidated, but there are two competing theories; […] The first theory supports the notion that there is overexpression of angiogenic factors such as: Vascular endothelial growth factor, Basic fibroblast growth factor, Matrix metalloproteinases. […] And there is downregulation of some inhibitors of angiogenesis such as: Tissue inhibitor of metalloproteinase-I. […] The second theory is that the presence of liver hemangiomas involves a genetic background of mutations. […] Genetic errors in growth factor receptors have also been shown to affect development of hemangiomas. […] Metalloproteinases can accumulate in the endoplasmic reticulum of the tumor cells causing: Self-digestion, Vacuole formation.

• #16 Pathogenesis of infantile haemangioma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3707963/

  The endothelium is plump and appears metabolically active, suggesting an immature phenotype. […] The contribution of HemEC to the total non-hematopoietic (CD45-) cell population in proliferating phase hemangioma ranges from 24% when VEGFR-2/KDR is used to quantify endothelial cells and up to 30% when a cocktail of antibodies against endothelial markers are used to quantify the endothelial compartment. […] The pericytes are abundant in the proliferating phase and appear to undergo a maturation process concurrently with the endothelial cells. […] The high expression of VEGF might be related to hypoxia, as increased hypoxia inducible factor-1 (HIF-1) stabilization was reported in patients with proliferating IH. […] In summary, several lines of research point to a critical role for VEGF and its receptors in the pathological vasculogenesis and angiogenesis in IH.

• #17 Capillary Hemangioma – EyeWiki

  https://eyewiki.org/Capillary_Hemangioma

  Capillary hemangiomas are classified as hamartomas, or abnormal proliferation of normal tissue in a normal location, namely endothelial cells. Histologically, the appearance of these lesions depends on the stage of the evolution. Early lesions may be very cellular, with solid nests of plump endothelial cells and little vascular lumen. Established lesions comprise of well-developed, flattened, endothelium-lined capillary channels of varying sizes in a lobular configuration. Involuting lesions show increased fibrosis and hyalinization of capillary walls with luminal occlusion. […] The mechanism of action is not completely understood, it includes vasoconstriction, decreased expression of bFGF and VEGF which are present during the growth phase of the capillary hemangioma, as well as the triggering of apoptosis.

• #18 Infantile Hemangioma Originates From A Dysregulated But Not Fully Transformed Multipotent Stem Cell | Scientific Reports

  https://www.nature.com/articles/srep35811

  Infantile hemangioma (IH) is the most common tumor of infancy. Its cellular origin and biological signals for uncontrolled growth are poorly understood, and specific pharmacological treatment is unavailable. […] We found that IH is characterized by high expression of genes involved in vasculogenesis, angiogenesis, tumorigenesis and associated signaling pathways. These results show that IH derives from a dysregulated stem cell that remains in an immature, arrested stage of development. […] We hypothesized that the HemSC is a vascular stem/progenitor cell whose proliferation is dysregulated, but not a fully transformed cell, which orchestrates IH pathophysiology through multiple signaling and regulatory networks. Therefore, to understand the process of hemangioma-genesis we characterized the progenitor hemangioma-derived stem cell (HemSC) and its lineage and non-lineage specific derivatives. The results of our comprehensive phenotypic and gene expression analysis and the characterization of the tumorigenic potential of HemSCs in vitro show that IH derives from a dysregulated stem cell that remains in an immature, arrested stage of development.

• #19

  https://omim.org/entry/602089

  Hemangiomas progress through distinct phases, thus providing an opportunity for studying endothelial cell biology and angiogenesis. […] Using DNA microarrays representing approximately 10,000 human genes, Ritter et al. (2002) identified insulin-like growth factor-2 (IGF2; 147470) as a potentially important regulator of hemangioma growth. IGF2 was highly expressed during the proliferative phase and substantially decreased during involution. This finding was confirmed at the level of mRNA by quantitative reverse transcription-PCR and at the protein level by immunohistochemistry. IGF2 protein was localized primarily to tumor vessels or vascular channels. Using a human hemangioma explant model, the authors showed that IGF2 promotes sprouting from intact hemangioma tissue. In addition, several angiogenesis-related factors, including integrins ITGAV (193210)/ITGB3 (173470) and ITGA5 (135620)/ITGB1 (135630), are present in proliferating hemangiomas. During the involuting phase, an increase in several interferon-induced genes was observed. These studies identified potential regulators of hemangioma growth and involution and provided a foundation on which to build further mechanistic investigations into angiogenesis, using hemangiomas as a model.

• #20 Infantile Hemangioma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1083849-overview

  As the endothelial cells differentiate, an influx of mast cells, various myeloid cells, and tissue inhibitors of metalloproteinases (TIMPs) occurs. […] TIMPs, along with interferon and transforming growth factor produced by the mast cells, terminate the endothelial cell proliferation and passively induce involution by senescence of endothelial cells. […] Several VEGF receptors (VEGFRs) may play a role in the development of hemangiomas. […] Hemangioma endothelial cells exhibit low levels of VEGFR1, with marked constitutive activation of VEGFR2. […] Missense mutations in genes encoding for VEGFR2 and TEM8 have been identified in a subset of infantile hemangiomas. […] It is believed that infantile hemangiomas may be derived from endothelial progenitor cells (EPCs). […] Two possibly interrelated theories exist regarding the pathogenesis of hemangiomas with regard to the EPCs, intrinsic and extrinsic. […] Mesenchymal stem cells may also play a role in the formation of infantile hemangiomas. […] Evidence to support a hereditary/genetic component in the development of most infantile hemangiomas is minimal; most appear to be sporadic.

• #21 Signaling pathways in the development of infantile hemangioma | Journal of Hematology & Oncology | Full Text

  https://jhoonline.biomedcentral.com/articles/10.1186/1756-8722-7-13

  Improved knowledge of the signaling pathways that regulate angiogenesis and vasculogenesis has led to the identification of several possible therapeutic targets that have driven the development of molecularly targeted therapies. […] The expression level of VEGF is also increased in HemECs, although this increase is not dramatic. […] The abnormal activation of VEGFR-2 on the cell surface may also be beneficial to the survival of HemECs as VEGF-A plays a critical role in protecting ECs against apoptotic cell death. […] These findings suggest that HemECs may be able to adapt to the abnormal physical environment of the tumor by undergoing a form of reprogramming that involves an increase in apoptosis resistance and by up-regulating a VEGF autocrine survival feedback loop to sustain these effects and stabilize the aberrant phenotype.

• #22 Update on infantile hemangioma

  https://www.e-cep.org/journal/view.php?number=20125555443

  The third hypothesis is the tissue hypoxia-induced vascular proliferation theory, which suggests that the induction and proliferation of EPCs are stimulated by hypoxic conditions (preterm, low birth weight, increased maternal age, placental anomalies) mediated by HIF-1. Tissue hypoxia induces neovascularization and angiogenesis by stimulating the expression of angiogenic factors such as VEGF and basic fibroblast growth factor (bFGF), on EPCs. VEGF may be the most potent angiogenic factor involved in the pathogenesis of IH, stimulating endothelial cell proliferation and mobilization through matrix metalloproteinases. […] The fourth hypothesis is the renin-angiotensin system theory, which suggests that the proliferation of IH-derived blast cells is induced by angiotensin (AT) II stimulated indirectly by high renin levels. Renin converts angiotensinogen to AT I, which leads to high levels of AT II. High renin levels in infants and high-risk groups of IH patients and the expression of angiotensin-converting enzyme and AT II receptor 2 on the endothelium of proliferating IHs support this theory. The mechanism of -adrenergic blockers inducing the accelerated involution of IHs may be associated with the blocking of 1-adrenergic receptors in the kidney, leading to the inhibition of renin release.

• #23 Infantile Hemangioma Originates From A Dysregulated But Not Fully Transformed Multipotent Stem Cell | Scientific Reports

  https://www.nature.com/articles/srep35811

  The data presented show that IH originates from a dysregulated but not fully transformed multipotent stem cell. IH is characterized by high expression of genes involved in vasculogenesis, angiogenesis, tumorigenesis, and associated signaling pathways. […] The identification of transcriptional regulator genes and analysis of gene expression at the single-cell level suggests the existence of intermediate phenotypes, unique subsets, and stem cell heterogeneity. […] Our data also show that HemSC have the potential to regenerate GLUT1+ tumorspheres from which differentiated derivatives originate. The de novo formation of pericyte-like derivatives reflects the heterogeneity of a hemangioma-derived multipotential stem cell arrested at an early stage of development (incompletely differentiated) with the ability to differentiate into several cellular lineages (lineage- and non-lineage specific differentiation).

• #24 Intrinsic regulation of hemangioma involution by platelet-derived growth factor | Cell Death & Disease

  https://www.nature.com/articles/cddis201258

  Infantile hemangioma is a vascular tumor that exhibits a unique natural cycle of rapid growth followed by involution. […] In the present study, we have elucidated the intrinsic mechanisms of adipocyte differentiation using hemangioma-derived stem cells (hemSCs). We found that platelet-derived growth factor (PDGF) is elevated during the proliferating phase and may inhibit adipocyte differentiation. […] In summary, this study identifies PDGF signaling as an intrinsic negative regulator of hemangioma involution and highlights the therapeutic potential of disrupting PDGF signaling for the treatment of hemangiomas. […] Until recently, the molecular mechanisms underlying hemangioma growth and involution have been poorly understood. […] Although the levels of PDGFRs are lower than placenta (a commonly used tissue for comparisons), the findings do point to a possible role for PDGF signaling in hemangioma pathogenesis.

• #25 Intrinsic regulation of hemangioma involution by platelet-derived growth factor | Cell Death & Disease

  https://www.nature.com/articles/cddis201258

  The purpose of this study was to investigate the role of PDGF signaling in the involution of infantile hemangioma. […] Our results show significantly elevated PDGFR-α and PDGFR-β in proliferating hemangiomas as compared with normal skin. […] We next assessed whether hemangioma-derived CD133+ stem cells express PDGF ligands and receptors in culture. […] These findings suggest that the main ligand for PDGFRs in hemangioma stem cells is PDGF-BB and that an autocrine signaling loop exists. […] We investigated the role of PDGF on the final fate of the hemSCs: terminal differentiation into adipocytes. […] These findings demonstrate that PDGF signaling actively inhibits the induction of adipogenic transcription factors. […] This study was based on the hypothesis that specific isoforms of PDGF are involved in the involution phase of hemangioma, and that the regulation of adipogenesis is via specific receptor-mediated signaling mechanisms. […] Overall, our data point to an inhibitory role for receptor-mediated PDGF signaling in hemangioma involution.

• #26

  https://step2.medbullets.com/dermatology/120082/infantile-hemangioma

  capillary hemangiomas are benign endothelial neoplasms with two phases […] the proliferative phase is characterized by rapid growth and increase in the number of endothelial and mast cells […] a stimulus for blood vessel proliferation […] the involutional phase is characterized by regression of the lesion and decrease in the number of mast cells […] hypoxia may be the initiating factor in the development of hemangiomas.

• #27 Infantile Hemangioma | IntechOpen

  https://www.intechopen.com/chapters/1175355

  The third hypothesis is the tissue hypoxia-induced vascular proliferation theory. Hypoxia is one of the most powerful inducers of angiogenesis and vasculogenesis by stimulating the expression of angiogenic factors, such as VEGF-A and basic fibroblast growth factor (bFGF), on endothelial progenitor cells. Many of the conditions such as preterm birth, low birth weight, preeclampsia and placental anomalies, which predispose an infant to development of IHs, are associated with hypoxia. It is believed that hypoxia stimulates the release of hypoxia-inducible factor-1 (HIF-1) which promotes the production of VEGF. […] Hypoxia-inducible factor-1 (HIF-1) is expressed significantly high in HemECs than normal in endothelial cells (ECs). It is also a significant contributor to the elevated VEGF levels produced in HemECs when it is upregulated. The decreased expression of HIF-1 reduces the proliferation of these cells.

• #28 Progress in the treatment of infantile hemangioma

  https://atm.amegroups.org/article/view/30918/26804

  Hypoxia is an inducing factor of revascularization and angiogenesis. In hypoxic conditions, pro-angiogenesis is stronger than anti-angiogenesis, so the balance moves towards pro-angiogenesis. This angiogenic switch stimulates tumor cells and stroma cells to express angiogenic factors including VEGF, bFGF, GLUT1, stromal cell-derived factor-1 (SDF-1), hypoxia-inducible factor-1 (HIF-1), platelet-derived growth factors (PDGFs), lysophosphatidic acid (LPA), and angiotensin to promote angiogenesis. […] Studies have shown that follicle-stimulating hormone (FSH) is expressed in IH tissues, and the FSH receptor is enriched in IH-adjacent cells, suggesting that this cell type may be involved in tumor pathogenesis. […] Studies have also shown that FSH promotes the expression of VEGF and HIF-1.

• #29 Infantile Hemangioma | IntechOpen

  https://www.intechopen.com/chapters/1175355

  The fourth hypothesis is the renin-angiotensin system theory. Itinteang et al. reported that IH endothelial cells in the proliferative phase express angiotensin-converting enzyme (ACE) and angiotensin II-receptor-2 (ATII-receptor-2), both integral components of the renin-angiotensin system. According to their hypothesis, the high serum levels of renin lead to a high concentration of angiotensin II. Both angiotensin II and angiotensin II-receptor-2 upregulate VEGF that activates the proliferation of IHs-derived blast cells. The expression of ACE and ATII-receptor-2 on the endothelium of proliferating IH supports this theory.

• #30 Pathogenesis of hemangioma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC208951/

  The strong gender predilection of hemangioma toward female over male infants (3:1 or more) suggests hormonal effects in hemangiogenesis. […] This distinguishing characteristic has been shown to be due in part to apoptosis of the endothelial cells (22), but the trigger for this process remains unknown. […] The intriguing data of Boye and colleagues (13) suggest one mechanism for hemangioma formation and bring the field a step closer to understanding the molecular etiology of this common tumor.

• #31 Progress in the treatment of infantile hemangioma

  https://atm.amegroups.org/article/view/30918/26804

  The specific etiology and pathogenesis of IHs have not been fully understood, but some recent studies have supplied some in-depth understanding of the pathogenesis of IHs. Angiogenesis and vasculogenesis are considered the main pathogenic mechanisms during new vessel formation in IH. […] Studies have shown that basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), glucose transporter isoform 1 (GLUT1), matrix metalloproteinase-9 (MMP-9), proliferating cell nuclear antigen, type IV collagenase, and angiotensin are highly expressed in IHs in the proliferative phase inducing blood vessel proliferation. […] The number of mast cells and the level of tissue inhibitors of metalloproteinases (TIMPs) increases while the content of bFGF decreases in regressive hemangioma, causing neovascularization due to the imbalance of positive and negative angiogenic regulator expression in this hemangioma and adjacent normal tissues.

• #32 About Hemangeol | Discovery of Propranolol

  https://hemangeol.com/physician/about-hemangeol/

  The mechanism of action of HEMANGEOL (propranolol hydrochloride) in infantile hemangioma is not well understood. […] The hypothesis is that the drugs effect on proliferating infantile hemangioma can be attributed to 3 molecular mechanisms, leading to: A local hemodynamic effect (reduction in blood flow), An anti-angiogenic effect (reduction of growth factors), An apoptosis triggering effect on capillary endothelial cells (increase rate of infantile hemangioma cell death).

• #33 Is Infantile Hemangioma a Neuroendocrine Tumor?

  https://www.mdpi.com/1422-0067/23/9/5140

  Given the expression of catecholamine biosynthesis enzymes by IH tissues and the critical role of NA levels in creating an in vitro angiogenesis model with sensitivity to propranolol treatment, we wondered whether IHs possess adequate transporters for the paracrine secretion of catecholamine, as neural tissues do. […] Altogether, these results suggest that proliferative IH tissues present some of the features of neuroendocrine tumors. […] We therefore suggest that the high local production of NA is a specific feature of IHs and the major driver of its development.

• #34 Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells

  https://bischofflab.hms.harvard.edu/publications/corticosteroid-suppression-vegf-infantile-hemangioma-derived-stem-cells

  Corticosteroids are commonly used to treat infantile hemangioma, but the mechanism of action of this therapy is unknown. […] We investigated the effect of corticosteroids in a previously described in vivo model of infantile hemangioma and in cultured hemangioma-derived cells. […] Systemic treatment with dexamethasone led to dose-dependent inhibition of tumor vasculogenesis in the murine model. […] Dexamethasone suppressed VEGF-A production by hemangioma-derived stem cells in vitro but not by hemangioma-derived endothelial cells or human umbilical-vein endothelial cells. […] Corticosteroid treatment suppressed other proangiogenic factors in hemangioma-derived stem cells, including urokinase plasminogen activator receptor, interleukin-6, monocyte chemoattractant protein 1, and matrix metalloproteinase 1.

• #35 Infantile hemangiomas: from pathogenesis to clinical features | RRN

  https://www.dovepress.com/infantile-hemangiomas-from-pathogenesis-to-clinical-features-peer-reviewed-fulltext-article-RRN

  Infantile hemangiomas (IH) are benign vascular tumors consisting of a collection of immature cells, including progenitor stem cells and disorganized blood vessels. […] Recently, there have been significant, exciting advancements in the understanding of the pathogenesis and treatment of infantile hemangiomas, which are discussed in this review. […] Ongoing multi-institutional clinical trials will provide further important data on the efficacy and safety of hemangioma treatments.

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