Abstract
Highlighted Article
Human vascular malformations cause disease as a result of changes in blood flow and vascular hemodynamic forces. Although the genetic mutations that underlie the formation of many human vascular malformations are known, the extent to which abnormal blood flow can subsequently influence the vascular genetic program and natural history is not. Loss of the SH2 domain-containing leukocyte protein of 76 kDa (SLP76) resulted in a vascular malformation that directed blood flow through mesenteric lymphatic vessels after birth in mice. Mesenteric vessels in the position of the congenital lymphatic in mature Slp76-null mice lacked lymphatic identity and expressed a marker of blood vessel identity. Genetic lineage tracing demonstrated that this change in vessel identity was the result of lymphatic endothelial cell reprogramming rather than replacement by blood endothelial cells. Exposure of lymphatic vessels to blood in the absence of significant flow did not alter vessel identity in vivo, but lymphatic endothelial cells exposed to similar levels of shear stress ex vivo rapidly lost expression of PROX1, a lymphatic fate-specifying transcription factor. These findings reveal that blood flow can convert lymphatic vessels to blood vessels, demonstrating that hemodynamic forces may reprogram endothelial and vessel identity in cardiovascular diseases associated with abnormal flow.
In this article, Chen and colleagues postulate that hemodynamics can affect vessel type. They study mice having abnormal blood-lymphatic networks, due to absence of the SH2 domain–containing leukocyte protein of 76 kDa (SLP76). While the majority of SLP76-deficient mice develop ascites and succumb, those animals which survive into adulthood develop “post-natal vascular remodeling”, with large intestinal arterio-venous malformations, presumably due to vascular remodeling from blood flow changes. They analyzed the influence of blood flow hemodynamics in this process by studying the lymphatic vessels in the efferent portion of vascular malformations, and established that 1) “changes in hemodynamic forces can completely reprogram vessel identity in postnatal life” and 2) ”lymphatic endothelial and vessel identity are negatively regulated by blood flow”. They studied dermal and intestinal vessels (blood and lymphatic) during development and after birth, in wild-type and SLP76-deficient mice, demonstrating that there is blood lymphatic mixing in knock-out neonates, and in the adult animals, the mesenteric lymphatics become arterio-venous shunts with shunt vessels (having blood vessels markers) and mesenteric lymphatics carrying the efferent flow. Lineage tracing experiments showed that lymphatic endothelial cells in SLP76-deficient mice converted to venous endothelial cells. Further studies demonstrated that lymphatic vessels lost their identity in the presence of flowing (but not static) blood, via downregulation PROX1 expression by fluid shear stress. As the authors state, “The key finding in this study is the demonstration that lymphatic vessels exposed to blood flow in vivo after birth are reprogrammed to acquire blood vessel identity”. The findings in this provocative study add to our understanding of these disease will hopefully lead to further research and therapies.
Basic Science
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Hypoxia inducible factor (HIF) 1a, EPAS1 and NEPAS are expressed in the embryonic mouse lung and each isoform exhibits distinct spatiotemporal expression patterns throughout morphogenesis. To further assess the role of the HIF1a isoform in lung epithelial cell differentiation and homeostasis, we created transgenic mice that express a constitutively active isoform of human HIF-1a (HIF-1a three point mutant (TPM)), in a doxycycline-dependent manner. Expression of HIF1a TPM in the developing pulmonary epithelium resulted in lung hypoplasia characterized by defective branching morphogenesis, altered cellular energetics and impaired epithelial maturation, culminating in neonatal lethality at birth from severe respiratory distress. Histological and biochemical analyses revealed expanded glycogen pools in the pulmonary epithelial cells at E18.5, concomitant with decreased pulmonary surfactant, suggesting a delay or an arrest in maturation. Importantly, these defects occurred in the absence of apoptosis or necrosis. In addition, sub-pleural hemorrhaging was evident as early as E14.5 in HIF1a TPM lungs, despite normal patterning of the blood vasculature, consistent with defects in endothelial barrier function. Epithelial expression of HIF1a TPM also resulted in increased VEGFA and VEGFC production, an increase in the number of lymphatic vessels and indirect activation of the multiple Notch pathway components in endothelial precursor cells. Collectively, these data indicate that HIF-1a protein levels in the pulmonary epithelium must be tightly controlled for proper development of the epithelial and mesenchymal compartments.
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HSV-1 is the leading cause of infectious corneal blindness in the industrialized world. CD4(+) T cells are thought to be the major leukocyte population mediating immunity to HSV-1 in the cornea as well as the likely source of immunopathology that reduces visual acuity. However, the role of CD8(+) T cells in immune surveillance of the cornea is unclear. Thus, we sought to evaluate the role of CD8(+) T cells in ocular immunity using transgenic mice in which >98% of CD8(+) T cells are specific for the immunodominant HSV-1 epitope (gBT-I.1). We found a significant reduction in virus, elevation in HSV-specific CD8(+) T cell influx, and more CD8(+) T cells expressing CXCR3 in the cornea of transgenic mice compared with those in the cornea of wild-type controls yet similar acute corneal pathology. However, by day 30 postinfection, wild-type mice had drastically more blood and lymphatic vessel projections into the cornea compared with gBT-I.1 mice, in which only lymphatic vessel growth in response to VEGF-C could be appreciated. Taken together, these results show that CD8(+) T cells are required to eliminate virus more efficiently from the cornea but play a minimal role in immunopathology as a source of VEGF-C.
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Etv2 is a master gene for the commitment of hematopoietic/endothelial cells and is a potent inducer of endothelial/hematopoietic cells from embryonic stem cells. Etv2 is highly expressed in endothelial/hematopoietic precursors but downregulated when they are differentiated, indicating that Etv2 should have transient but not constitutive function. However, relatively little attention has been paid to the importance of transient Etv2 expression. To determine whether transient Etv2 expression is essential to normal development and cell differentiation, we generated mice that constitutively express Etv2 from a Cre-activatable ROSA26 locus in endothelial/hematopoietic, somite, or neuronal lineages. Constitutive Etv2 expression caused profound phenotypes in hematopoietic/endothelial cells, with little effect on somite or neuronal lineages. In hematopoietic/endothelial lineages, constitutive Etv2 expression induced by Tie-2 Cre transgene caused abnormal yolk sac vasculature. Prolonged VE-cadherin expression and decreased B lymphopoiesis were observed in Etv2 expressing VE-cadherin(+)/CD45(+) cells, indicating that Etv2 forces endothelial program on hematopoietic cells. Etv2 expression in adult hematopoietic cells by Vav-iCre transgene also conferred an endothelial phenotype on hematopoietic stem cells and suppressed hematopoiesis, with erythropoiesis severely affected. We conclude that constitutive Etv2 expression perturbs vascular development and hematopoiesis. While promoting hematopoiesis/vasculogenesis, Etv2 expression should be tightly regulated to achieve normal vascular development and hematopoiesis.
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CRSBP-l/LYVE-1 ligands (PDGF-BB, VEGF-A(165) and hyaluronic acid) have been shown to induce opening of lymphatic intercellular junctions in vitro and in vivo by stimulating contraction of lymphatic endothelial cells (LECs). The mechanism by which CRSBP-1 ligands stimulate contraction of LECs is not understood. Here we demonstrate that CRSBP-1 is localized to the plasma membrane as well as intracellular fibrillar structures in LECs, including primary human dermal LECs and SVEC4-10 cells. CRSBP-1-associated fibrillar structures are identical to the ER network as evidenced by the co-localization of CRSBP-1 and BiP in these cells. CRSBP-1 ligands stimulate contraction of the ER network in a CRSBP-1-dependent and paclitaxel (a microtubule-stabilizing agent)-sensitive manner. These results suggest that ligand-stimulated ER contraction is associated with ligand-stimulated contraction in LECs.
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Rationale: Lymphatic vasculature plays important roles in tissue fluid homeostasis maintenance and in the pathology of human diseases. Yet, the molecular mechanisms that control lymphatic vessel maturation remain largely unknown. Objective: We analyzed the gene expression profiles of ex vivo isolated lymphatic endothelial cells to identify novel lymphatic vessel expressed genes and we investigated the role of Sema3A and neuropilin-1 (Nrp-1) in lymphatic vessel maturation and function. Methods and Results: Lymphatic and blood vascular endothelial cells from mouse intestine were isolated using fluorescence-activated cell sorting and transcriptional profiling was performed. We found that the axonal guidance molecules Sema3A and Sema3D were highly expressed by lymphatic vessels. Importantly, we found that the semaphorin receptor Nrp-1 is expressed on the perivascular cells of the collecting lymphatic vessels. Treatment of mice in utero (E12.5-E16.5) with an antibody that blocks Sema3A binding to Nrp-1, but not with an antibody that blocks VEGF-A binding to Nrp-1, resulted in a complex phenotype of impaired lymphatic vessel function, enhanced perivascular cell coverage and abnormal lymphatic vessel and valve morphology. Conclusions: Together, these results reveal an unanticipated role of Sema3A/Nrp-1 signaling in the maturation of the lymphatic vascular network likely via regulating the perivascular cell coverage of the vessels thus affecting lymphatic vessel function and lymphatic valve development.
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Active lymph transport relies on smooth muscle cell (SMC) contractions around collecting lymphatic vessels, yet regulation of lymphatic vessel wall assembly and lymphatic pumping are poorly understood. Here, we identify Reelin, an extracellular matrix glycoprotein previously implicated in central nervous system development, as an important regulator of lymphatic vascular development. Reelin-deficient mice showed abnormal collecting lymphatic vessels, characterized by a reduced number of SMCs, abnormal expression of lymphatic capillary marker lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), and impaired function. Furthermore, we show that SMC recruitment to lymphatic vessels stimulated release and proteolytic processing of endothelium-derived Reelin. Lymphatic endothelial cells in turn responded to Reelin by up-regulating monocyte chemotactic protein 1 (MCP1) expression, which suggests an autocrine mechanism for Reelin-mediated control of endothelial factor expression upstream of SMC recruitment. These results uncover a mechanism by which Reelin signaling is activated by communication between the two cell types of the collecting lymphatic vessels-smooth muscle and endothelial cells-and highlight a hitherto unrecognized and important function for SMCs in lymphatic vessel morphogenesis and function.
Matsumoto-Okazaki, Y., M. Furuse, et al. (2012). “Claudin-5 haploinsufficiency exacerbates UVB-induced oedema formation by inducing lymphatic vessel leakage.” Exp Dermatol 21(7): 557–559.
Acute exposure of skin to ultraviolet (UV) B irradiation (290–320 nm) leads to epidermal hyperplasia, erythema and oedema formation. We have elucidated that UV irradiation induced the leakiness of cutaneous lymphatic vessels. Although these studies indicated a crucial role of the lymphatic integrity in skin inflammation, the mechanisms underlying its disruption by UVB exposure remain unknown. Here we demonstrated that a vascular-specific tight junction molecule, claudin-5 has an important role in lymphatics and skin inflammation. Claudin-5(+/-) mice, whose claudin-5 expression was greatly downregulated in skin, exacerbates oedema formation and inflammation by a low dose of UVB irradiation. Lymphatic vessels of claudin-5(+/-) mice were markedly enlarged and leaky after low-dose UVB exposure, compared with those of wild-type mice, while the morphology of blood vessels were not different between groups. These results suggest that claudin-5 in the lymphatic tight junction maintains lymphatic integrity and plays a protective role in skin inflammation.
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Dendritic cell (DC) migration via lymphatic vessels to draining lymph nodes (dLNs) is crucial for the initiation of adaptive immunity. We imaged this process by intravital microscopy (IVM) in the ear skin of transgenic mice bearing red-fluorescent vasculature and yellow-fluorescent DCs. DCs within lymphatic capillaries were rarely transported by flow, but actively migrated within lymphatics and were significantly faster than in the interstitium. Pharmacologic blockade of the Rho-associated protein kinase (ROCK), which mediates nuclear contraction and de-adhesion from integrin ligands, significantly reduced DC migration from skin to dLNs in steady-state. IVM revealed that ROCK blockade strongly reduced the velocity of interstitial DC migration, but only marginally affected intralymphatic DC migration. By contrast, during tissue inflammation, ROCK blockade profoundly decreased both interstitial and intralymphatic DC migration. Inhibition of intralymphatic migration was paralleled by a strong upregulation of ICAM-1 in lymphatic endothelium, suggesting that during inflammation ROCK mediates de-adhesion of DC-expressed integrins from lymphatic-expressed ICAM-1. Flow chamber assays confirmed an involvement of lymphatic-expressed ICAM-1 and DC-expressed ROCK in DC crawling on lymphatic endothelium. Overall, our findings further define the role of ROCK in DC migration to dLNs and reveal a differential requirement for ROCK in intralymphatic DC crawling during steady-state and inflammation.
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We have generated novel transgenic lines that brightly mark the lymphatic system of zebrafish using the lyve1 promoter. Facilitated by these new transgenic lines, we generated a map of zebrafish lymphatic development up to 15 days post-fertilisation and discovered three previously uncharacterised lymphatic vessel networks: the facial lymphatics, the lateral lymphatics and the intestinal lymphatics. We show that a facial lymphatic vessel, termed the lateral facial lymphatic, develops through a novel developmental mechanism, which initially involves vessel growth through a single vascular sprout followed by the recruitment of lymphangioblasts to the vascular tip. Unlike the lymphangioblasts that form the thoracic duct, the lymphangioblasts that contribute to the lateral facial lymphatic vessel originate from a number of different blood vessels. Our work highlights the additional complexity of lymphatic vessel development in the zebrafish that may increase its versatility as a model of lymphangiogenesis.
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Sabine, A., Y. Agalarov, et al. (2012). “Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation.” Dev Cell 22(2): 430–445.
Lymphatic valves are essential for efficient lymphatic transport, but the mechanisms of early lymphatic-valve morphogenesis and the role of biomechanical forces are not well understood. We found that the transcription factors PROX1 and FOXC2, highly expressed from the onset of valve formation, mediate segregation of lymphatic-valve-forming cells and cell mechanosensory responses to shear stress in vitro. Mechanistically, PROX1, FOXC2, and flow coordinately control expression of the gap junction protein connexin37 and activation of calcineurin/NFAT signaling. Connexin37 and calcineurin are required for the assembly and delimitation of lymphatic valve territory during development and for its postnatal maintenance. We propose a model in which regionally increased levels/activation states of transcription factors cooperate with mechanotransduction to induce a discrete cell-signaling pattern and morphogenetic event, such as formation of lymphatic valves. Our results also provide molecular insights into the role of endothelial cell identity in the regulation of vascular mechanotransduction.
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Shi, V. Y., L. Bao, et al. (2012). “Inflammation-driven Dermal Lymphangiogenesis in Atopic Dermatitis is Associated with CD11b+ Macrophage Recruitment and VEGF-C Up-regulation in the IL-4-Transgenic Mouse Model.” Microcirculation. [Epub ahead of print]
Objective: To investigate the presence and extent of inflammatory lymphangiogenesis in atopic dermatitis (AD) and determine the role of IL-4 in lymphatic proliferation in both Keratin14-IL-4 Transgenic (Tg) mouse model of AD. Methods: Skin tissue from Tg mice were collected for immunostaining against PDPN, LYVE-1, CD11b and VEGF-C. The regulation of specific lymphatic biomarkers and growth factors were determined using qPCR and Western Blot analyses. Dermal lymphatic uptake and drainage were assessed using intradermal Evans Blue (EB) dye micro-injections. Total RNA from IL-4 stimulated HaCaT cells were analyzed in a PCR array to evaluate the regulation of lymphangiogenic-related genes. Results: Prominent dermal microvascular lymphangiogenesis occurs in the Tg mice, characterized by a significant increase in number and caliber of the vasculature. The extent of both lymphatic proliferation and drainage parallel the progression of lesion severity, as do the up-regulation of pro-lymphangiogenic factors VEGF-C, VEGFR-3, ANG-1, and ANG-2. IL-4-stimulated HaCaT cells express high levels of MCP-1, a strong macrophage chemo-attractant. Additionally, Tg mice show significantly increased number of dermal CD11b+ macrophages expressing VEGF-C in the skin. Conclusion: Our results provide the first demonstration of inflammation-mediated lymphangiogenesis in AD and that IL-4 triggered macrophage recruitment may be closely linked to this phenomenon. (c) 2012 John Wiley & Sons Ltd.
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CLEC-2 was first identified by sequence similarity to C-type lectin-like molecules with immune functions and has been reported as a receptor for the platelet-aggregating snake venom toxin rhodocytin and the endogenous sialoglycoprotein podoplanin. Recent researches indicate that CLEC-2-deficient mice were lethal at the embryonic stage associated with disorganized and blood-filled lymphatic vessels and severe edema. In view of a necessary role of CLEC-2 in the individual development, it is of interest to investigate its phylogenetic homology and highly conserved functional regions. In this work, we reported that CLEC-2 from different species holds with an extraordinary conservation by sequence alignment and phylogenetic tree analysis. The functional structures including N-linked oligosaccharide sites and ligand-binding domain implement a structural and functional conservation in a variety of species. The glycosylation sites (N120 and N134) are necessary for the surface expression CLEC-2. CLEC-2 from different species possesses the binding activity of mouse podoplanin. Nevertheless, the expression of CLEC-2 is regulated with a species-specific manner. The alternative splicing of pre-mRNA, a regulatory mechanism of gene expression, and the binding sites on promoter for several key transcription factors vary between different species. Therefore, CLEC-2 shares high sequence homology and functional identity. However the transcript expression might be tightly regulated by different mechanisms in evolution.
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Yang, J. D., K. Ishikawa, et al. (2012). “Morphology of the ligament of Treitz likely depends on its fetal topographical relationship with the left adrenal gland and liver caudate lobe as well as the developing lymphatic tissues: a histological study using human fetuses.” Surg Radiol Anat. [Epub ahead of print]
To investigate the factors affecting the development of the ligament of Treitz, we examined sagittal and frontal histological sections of 35 human fetuses with a crown-rump length of 100–300 mm (approximately 16–38 weeks of gestation). The retropancreatic fascia consistently extended in a layer behind the pancreatic body and the splenic artery and vein, and also in front of the left renal vein and left adrenal. In 18 specimens, a connective tissue band was seen originating from the diaphragmatic crus around the esophageal opening and ending at the retropancreatic fascia to the left of the origin of the celiac artery. In 10 of these 18 specimens, these putative upper parts of the ligament contained striated muscles, or so-called Hilfsmuskel. Although most of other 17 specimens were larger fetuses, the left adrenal, the liver caudate lobe and the celiac ganglion made space for the ligament very limited. In 22 specimens including the above 18, the retropancreatic fascia extended inferiorly to approach the fourth portion of the duodenum (D4) or the duodenojejunal junction (DJJ). However, in 11 of the 22 examples of the putative lower part of the ligament, the connection between the duodenal muscle coat and the fascia was interrupted by developing lymphatic tissues. Consequently, the ligament of Treitz seemed to develop from both pleuroperitoneal membrane-derived cells and the retropancreatic fusion fascia, although the morphology was markedly modified by adjacent structures such as the adrenal gland. The ligament may “recover” after the adrenal becomes reduced in size after birth.
Yoo, J., H. N. Lee, et al. (2012). “Opposing Regulation of PROX1 by Interleukin-3 Receptor and NOTCH Directs Differential Host Cell Fate Reprogramming by Kaposi Sarcoma Herpes Virus.” PLoS Pathog 8(6): e1002770.
Lymphatic endothelial cells (LECs) are differentiated from blood vascular endothelial cells (BECs) during embryogenesis and this physiological cell fate specification is controlled by PROX1, the master regulator for lymphatic development. When Kaposi sarcoma herpes virus (KSHV) infects host cells, it activates the otherwise silenced embryonic endothelial differentiation program and reprograms their cell fates. Interestingly, previous studies demonstrated that KSHV drives BECs to acquire a partial lymphatic phenotype by upregulating PROX1 (forward reprogramming), but stimulates LECs to regain some BEC-signature genes by downregulating PROX1 (reverse reprogramming). Despite the significance of this KSHV-induced bidirectional cell fate reprogramming in KS pathogenesis, its underlying molecular mechanism remains undefined. Here, we report that IL3 receptor alpha (IL3Ralpha) and NOTCH play integral roles in the host cell type-specific regulation of PROX1 by KSHV. In BECs, KSHV upregulates IL3Ralpha and phosphorylates STAT5, which binds and activates the PROX1 promoter. In LECs, however, PROX1 was rather downregulated by KSHV-induced NOTCH signal via HEY1, which binds and represses the PROX1 promoter. Moreover, PROX1 was found to be required to maintain HEY1 expression in LECs, establishing a reciprocal regulation between PROX1 and HEY1. Upon co-activation of IL3Ralpha and NOTCH, PROX1 was upregulated in BECs, but downregulated in LECs. Together, our study provides the molecular mechanism underlying the cell type-specific endothelial fate reprogramming by KSHV.
Zhi, Z., Y. Jung, et al. (2012). “Label-free 3D imaging of microstructure, blood, and lymphatic vessels within tissue beds in vivo.” Opt Lett 37(5): 812–814.
Zhou, J., X. Zhu, et al. (2012). “Water-stable NaLuF(4)-based upconversion nanophosphors with long-term validity for multimodal lymphatic imaging.” Biomaterials. 33: 6201–6210.
Zignego, A. L., C. Giannini, et al. (2012). “HCV and lymphoproliferation.” Clin Dev Immunol 2012: 980942.
Hepatitis C virus (HCV) infection is a serious public health problem because of its worldwide diffusion and sequelae. It is not only a hepatotropic but also a lymphotropic agent and is responsible not only for liver injury-potentially evolving to cirrhosis and hepatocellular carcinoma-but also for a series of sometimes severely disabling extrahepatic diseases and, in particular, B-cell lymphoproliferative disorders. These latter range from benign, but prelymphomatous conditions, like mixed cryoglobulinemia, to frank lymphomas. Analogously with Helicobacter pylori related lymphomagenesis, the study of the effects of viral eradication confirmed the etiopathogenetic role of HCV and showed it is an ideal model for better understanding of the molecular mechanisms involved. Concerning these latter, several hypotheses have been proposed over the past two decades which are not mutually exclusive. These hypotheses have variously emphasized the important role played by sustained stimulation of the immune system by HCV, infection of the lymphatic cells, viral proteins, chromosomal aberrations, cytokines, or microRNA molecules. In this paper we describe the main hypotheses that have been proposed with the corresponding principal supporting data.
Zumsteg, A. and G. Christofori (2012). “Myeloid cells and lymphangiogenesis.” Cold Spring Harb Perspect Med 2(6): a006494.
The lymphatic vascular system and the hematopoietic system are intimately connected in ontogeny and in physiology. During embryonic development, mammalian species derive a first lymphatic vascular plexus from the previously formed anterior cardinal vein, whereas birds and amphibians have a lymphatic vascular system of dual origin, composed of lymphatic endothelial cells (LECs) of venous origin combined with LECs derived from mesenchymal lymphangioblasts. The contribution of hematopoietic cells as building blocks of nascent lymphatic structures in mammals is still under debate. In contrast, the importance of myeloid cells to direct lymphatic vessel growth and function postnatally has been experimentally shown. For example, myeloid cells communicate with LECs via paracrine factors or cell-cell contacts, and they also can acquire lymphatic endothelial morphology and marker gene expression, a process reminiscent of developmental vasculogenesis. Here, we present an overview of the current understanding of how lymphatic vessels and the hematopoietic system, in particular myeloid cells, interact during embryonic development, in normal organ physiology, and in disease.
Oncology
Alam, A., I. Blanc, et al. (2012). “SAR131675, a potent and selective VEGFR-3-TK inhibitor with antilymphangiogenic, anti-tumoral and anti-metastatic activities.” Mol Cancer Ther. 11: 1637–1649.
Beck, M., A. Wanchai, et al. (2012). “Palliative Care for Cancer-Related Lymphedema: A Systematic Review.” J Palliat Med. 15:821–827.
Becker, J., J. Frohlich, et al. (2012). “The lymphangiogenesis inhibitor esVEGFR-2 in human embryos: expression in sympatho-adrenal tissues and differentiation-induced up-regulation in neuroblastoma.” Histol Histopathol 27(6): 721–733.
Tumour-induced hem- and lymph-angiogenesis are frequently associated with tumour progression. Vascular endothelial growth factor-C (VEGF-C) is a potent inducer of lymphangiogenesis, while the endogenous soluble splice-variant of VEGF receptor-2, esVEGFR-2, acts as a natural inhibitor. Previously we have shown down-regulation of esVEGFR-2 mRNA in progressed stages of neuro-blastoma (NB), a tumour derived from sympatho-adrenal precursor cells. Here we studied the immunolocalization of esVEGFR-2 in human embryos, infantile adrenal gland and primary NB. We also quantified esVEGFR-2 mRNA in NB cell lines after differentiation-induction by all-trans retinoic acid (ATRA). By immunoperoxidase staining we observed expression of esVEGFR-2 in both the sympathetic trunk and the adrenal medulla. Additionally, esVEGFR-2 was found in spinal ganglia, floor plate of the neural tube, choroid plexus, notochord, arterial endothelium, skeletal muscle, epidermis and gut epithelium. Developing and circulating leukocytes showed the strongest signal. In NB, esVEGFR-2 was considerably stronger in differentiating low grade tumours with neuronal phenotype than in undifferentiated lesions. Differentiation-induction of the NB cell line SMS-Kan with 5–10 microM ATRA resulted in a significant increase of esVEGFR-2 mRNA after 6, 9 and 12 days. We show that esVEGFR-2 is widely expressed in embryonic tissues. Especially, the adrenal medulla and circulating leukocytes seem to be potent inhibitors of lymphangiogenesis. We provide additional evidence for a role of esVEGFR-2 in NB. Thereby, high levels of esVEGFR-2 correlate with a more differentiated phenotype, and may inhibit tumour progression by inhibition of lymphangiogenesis.
Cai, X., S. Ma, et al. (2012). “Survivin regulates the expression of VEGF-C in lymphatic metastasis of breast cancer.” Diagn Pathol 7(1): 52.
Christiansen, A. and M. Detmar (2011). “Lymphangiogenesis and cancer.” Genes Cancer 2(12): 1146–1158.
Duong, T., S. T. Proulx, et al. (2012). “Genetic ablation of SOX18 function suppresses tumor lymphangiogenesis and metastasis of melanoma in mice.” Cancer Res. 72: 3105–3114.
The lymphatic vasculature provides a major route for tumor metastasis and inhibiting neo-lymphangiogenesis induced by tumors can reduce metastasis in animal models. Developmental biology studies have identified the transcription factor SOX18 as a critical switch for lymphangiogenesis in the mouse embryo. Here, we show that SOX18 is also critical for tumor-induced lymphangiogenesis and we demonstrate that suppressing SOX18 function is sufficient to impede tumor metastasis. Immunofluorescence analysis of murine tumor xenografts showed that SOX18 is re-expressed during tumor-induced neo-lymphangiogenesis. Tumors generated by implantation of firefly luciferase-expressing B16-F10 melanoma cells exhibited a reduced rate of metastasis to the regional draining lymph node in Sox18-deficient mice, as assessed by live bioluminescence imaging. Lower metastatic rates correlated with reduced tumoral lymphatic vessel density and diameter, and with impaired drainage of peri-tumoral injected liposomes specific for lymph vessels from the sentinel lymph nodes. Overall, our findings suggested that SOX18 induction is a key step in mediating tumor lymphangiogenesis and metastasis, and they identify SOX18 as a potential therapeutic target for metastatic blockade.
Ferris, R. L., M. T. Lotze, et al. (2012). “Lymphatics, lymph nodes and the immune system: barriers and gateways for cancer spread.” Clin Exp Metastasis. [Epub ahead of print]
Hadj-Hamou, N. S., M. Lae, et al. (2012). “A transcriptome signature of endothelial lymphatic cells coexists with the chronic oxidative stress signature in radiation-induced post-radiotherapy breast angiosarcomas.” Carcinogenesis. [Epub ahead of print]
Radiation-induced breast angiosarcomas are rare but recognised complication of breast cancer radiotherapy and are of poor prognosis. Little is known about the genetic abnormalities present in these secondary tumors. Herein, we investigated the differences in the genome and in the transcriptome that discriminate these tumors as a function of their etiology. Seven primary breast angiosarcomas and 18 secondary breast angiosarcomas arising in the irradiation field of a radiotherapy were analysed. Copy number alterations and gene expression were analysed using Affymetrix SNP 6.0 Array and Affymetrix Exon Arrays, respectively. We showed that two transcriptome signatures of the radiation tumorigenesis coexisted in these tumors. One was histology specific and correctly discriminated 100% of the primary tumors from the radiation-induced tumors. The deregulation of marker genes, including podoplanin (PDPN), prospero homeobox 1 (PROX-1), vascular endothelial growth factor 3 (VEGFR3) and endothelin receptor A (EDNRA), suggests that the radiation-induced breast angiosarcomas developed from radiation-stimulated lymphatic endothelial cells. None of the genes of the histology-specific signature were present in our previously published signature of the radiation tumorigenesis which showns the presence of a chronic oxidative stress in radiation-induced sarcomas of various histologies. Nevertheless, this oxidative stress signature classified correctly 88% of the breast angiosarcomas as a function of the etiology. In contrast, MYC amplification, which is observed in all radiation-induced tumors but also at a low rate in primary tumors, was not a marker of the radiation tumorigenesis.
Holopainen, T., V. Lopez-Alpuche, et al. (2012). “Deletion of the endothelial Bmx tyrosine kinase decreases tumor angiogenesis and growth.” Cancer Res. 72: 3512–3521.
Hoye, A. M., J. R. Couchman, et al. (2012). “The newcomer in the integrin family: Integrin alpha9 in biology and cancer.” Adv Biol Regul 52(2): 326–339.
Hu, Y. Y., M. H. Zheng, et al. (2012). “Notch signaling pathway and cancer metastasis.” Adv Exp Med Biol 727: 186–198.
Karnezis, T., R. Shayan, et al. (2012). “VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium.” Cancer Cell 21(2): 181–195.
Lymphatic metastasis is facilitated by lymphangiogenic growth factors VEGF-C and VEGF-D that are secreted by some primary tumors. We identified regulation of PGDH, the key enzyme in prostaglandin catabolism, in endothelial cells of collecting lymphatics, as a key molecular change during VEGF-D-driven tumor spread. The VEGF-D-dependent regulation of the prostaglandin pathway was supported by the finding that collecting lymphatic vessel dilation and subsequent metastasis were affected by nonsteroidal anti-inflammatory drugs (NSAIDs), known inhibitors of prostaglandin synthesis. Our data suggest a control point for cancer metastasis within the collecting lymphatic endothelium, which links VEGF-D/VEGFR-2/VEGFR-3 and the prostaglandin pathways. Collecting lymphatics therefore play an active and important role in metastasis and may provide a therapeutic target to restrict tumor spread.
Larrieu-Lahargue, F., A. L. Welm, et al. (2012). “Blocking fibroblast growth factor receptor signaling inhibits tumor growth, lymphangiogenesis, and metastasis.” PLoS One 7(6): e39540.
Levine, P. H., C. C. Portera, et al. (2012). “Evaluation of lymphangiogenic factors, vascular endothelial growth factor d and e-cadherin in distinguishing inflammatory from locally advanced breast cancer.” Clin Breast Cancer 12(4): 232–239.
Li, T., J. Yang, et al. (2012). “Molecular Regulation of Lymphangiogenesis in Development and Tumor Microenvironment.” Cancer Microenviron. [Epub ahead of print]
Li, X., X. Dang, et al. (2012). “Expression of survivin and VEGF-C in breast cancer tissue and its relation to lymphatic metastasis.” Eur J Gynaecol Oncol 33(2): 178–182.
Majumder, M., E. Tutunea-Fatan, et al. (2012). “Co-Expression of alpha9beta1 Integrin and VEGF-D Confers Lymphatic Metastatic Ability to a Human Breast Cancer Cell Line MDA-MB-468LN.” PLoS One 7(4): e35094.
Morita, Y., K. Hata, et al. (2012). “Cyclooxygenase-2 promotes tumor lymphangiogenesis and lymph node metastasis in oral squamous cell carcinoma.” Int J Oncol. 41: 885–892.
Oral squamous cell carcinoma (OSCC) is the sixth most common cancer and frequently metastasizes to the cervical lymph nodes, leading to poor survival of patients with OSCC. However, the mechanism of lymph node metastasis is not fully understood. To clarify the molecular mechanism underlying OSCC metastasis to regional lymph nodes, the highly metastatic fluorescent labeled OSCC cell line SAS-LM3 was successfully established allowing us to monitor the progression of lymph node metastases in a non-invasive manner. SAS-LM3 tumors showed increased lymphangiogenesis and elevated expression of VEGF-C, a potent stimulator of lymphangiogenesis, compared to parental SAS tumors. SAS-LM3 showed high expression of cyclooxygenase-2 (COX-2) compared to parental SAS cells and immunohistochemical analysis demonstrated intense COX-2 expression at the primary site. Inactivation of COX-2 by knockdown or the COX-2 inhibitor NS-398 decreased VEGF-C expression. Administration of COX-2 inhibitor NS-398 in SAS-LM3 tumor-bearing mice suppressed tumor lymphangiogenesis and lymphatic metastases. Collectively, our results indicate that COX-2 promotes tumor lymphangiogenesis and lymph node metastasis of OSCC. COX-2 ablation holds promise as a potential therapeutic approach for lymph node metastasis in OSCC.
Niederleithner, H., M. Heinz, et al. (2012). “Wnt1 Is Anti-Lymphangiogenic in a Melanoma Mouse Model.” J Invest Dermatol. 132: 2235–2244.
Ozardili, I., M. E. Guldur, et al. (2012). “Correlation between lymphangiogenesis and clinicopathological parameters in renal cell carcinoma.” Singapore Med J 53(5): 332–335.
Ramani, P., M. S. Somerville, et al. (2012). “Podoplanin lymphatic density and invasion correlate with adverse clinicopathologic and biological factors and survival in neuroblastomas.” Am J Surg Pathol 36(6): 908–915.
Neuroblastoma (NB) is a challenging problem in oncology, as the majority of patients have lymphatic and/or hematogenous metastases at diagnosis. We investigated the prognostic significance of lymphatic density (LD) and invasion (LI) in NBs using the lymphatic endothelial marker podoplanin (PDPN). A total of 77 neuroblastic tumors and 9 ganglioneuromas (GNs) were immunostained for PDPN using D2-40 antibody. Intratumoral lymphatics were identified in 87% (67/77) of NBs and 7/9 GNs. The LD counts were significantly higher (P<0.01) in NBs (median=19.6, range=0.00 to 89.3) than in GNs (median=10.2, range=0 to 18.7). LI, assessed in D2-40-stained lymphatics, was present in 52/67 (78%) NBs. LDs were significantly higher in NBs from patients with adverse clinical factors (advanced-stage, high-risk group, primary abdominal compared with extra-abdominal sites), biological factors (MYCN amplification, 1p deletion, 17q gain), and distant lymph node metastases. LDs and LI were also significantly higher in NBs belonging to an unfavorable pathology prognostic group and in those with a high mitosis-karyorrhexis index. High LD and the presence of LI correlated with a shorter event-free survival in univariable analyses. High LD and the presence of LI were also associated with worse overall survival, although the association was less strong. In conclusion, increased LDs and the presence of LI correlated with adverse clinicopathologic and biological factors and survival. These findings suggest that PDPN has the potential to provide valuable prognostic information to clinicians for risk assessment in NBs.
Sleeman, J. P., B. Cady, et al. (2012). “The connectivity of lymphogenous and hematogenous tumor cell dissemination: biological insights and clinical implications.” Clin Exp Metastasis. [Epub ahead of print]
Swoboda, A., O. Schanab, et al. (2012). “MET expression in melanoma correlates with a lymphangiogenic phenotype.” Hum Mol Genet. 21: 3387–3396.
Wang, Z., Y. Yu, et al. (2012). “LyP-1 Modification to Enhance Delivery of Artemisinin or Fluorescent Probe Loaded Polymeric Micelles to Highly Metastatic Tumor and Its Lymphatics.” Mol Pharm. [Epub ahead of print]
Wiig, H. and M. A. Swartz (2012). “Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer.” Physiol Rev 92(3): 1005–1060.
Witte, M. H., M. T. Dellinger, et al. (2012). “Overlapping biomarkers, pathways, processes and syndromes in lymphatic development, growth and neoplasia.” Clin Exp Metastasis. [Epub ahead of print]
Wu, S., J. Lian, et al. (2011). “Correlation of macrophage migration inhibitory factor gene polymorphism with the risk of early-stage cervical cancer and lymphatic metastasis.” Oncol Lett 2(6): 1261–1267.
Xin, X., M. Majumder, et al. (2012). “Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model.” Lab Invest 92(8): 1115–1128.
We reported that cyclo-oxygenase (COX)-2 expression in human breast cancer stimulated cancer cell migration and invasiveness, production of vascular endothelial growth factor (VEGF)-C and lymphangiogenesis in situ, largely from endogenous PGE2-mediated stimulation of prostaglandin E (EP)1 and EP4 receptors, presenting them as candidate therapeutic targets against lymphatic metastasis. As human breast cancer xenografts in immuno-compromised mice have limitations for preclinical testing, we developed a syngeneic murine breast cancer model of spontaneous lymphatic metastasis mimicking human and applied it for mechanistic and therapeutic studies. We tested the roles of COX-2 and EP receptors in VEGF-C and -D production by a highly metastatic COX-2 expressing murine breast cancer cell line C3L5. These cells expressed all EP receptors and produced VEGF-C and -D, both inhibited with COX-2 inhibitors or EP4 (but not EP1, EP2 or EP3) antagonists. C3H/HeJ mice, when implanted SC in both inguinal regions with C3L5 cells suspended in growth factor-reduced Matrigel, exhibited rapid tumor growth, tumor-associated angiogenesis and lymphangiogenesis (respectively measured with CD31 and LYVE-1 immunostaining), metastasis to the inguinal and axillary lymph nodes and the lungs. Chronic oral administration of COX-1/COX-2 inhibitor indomethacin, COX-2 inhibitor celecoxib and an EP4 antagonist ONO-AE3-208, but not an EP1 antagonist ONO-8713 at nontoxic doses markedly reduced tumor growth, lymphangiogenesis, angiogenesis, and metastasis to lymph nodes and lungs. Residual tumors in responding mice revealed reduced VEGF-C and -D proteins, AkT phosphorylation and increased apoptotic/proliferative cell ratios consistent with blockade of EP4 signaling. We suggest that EP4 antagonists deserve clinical testing for chemo-intervention of lymphatic metastasis in human breast cancer.
Zhao, Y. C., X. J. Ni, et al. (2012). “Tumor-derived VEGF-C, but not VEGF-D, promotes sentinel lymph node lymphangiogenesis prior to metastasis in breast cancer patients.” Med Oncol. [Epub ahead of print]
Clinical
Anand, S. B., V. Rajagopal, et al. (2012). “Brugia malayi Thioredoxin Peroxidase as a Potential Vaccine Candidate Antigen for Lymphatic Filariasis.” Appl Biochem Biotechnol. 167: 1351–1364.
Chen, E. and M. Itkin (2011). “Thoracic duct embolization for chylous leaks.” Semin Intervent Radiol 28(1): 63–74.
Choudhury, B. K., U. K. Saiki, et al. (2011). “Intestinal lymphangiectasia in a patient with autoimmune polyglandular syndrome type III.” J Assoc Physicians India 59: 729–731.
Feldman, J. L., N. L. Stout, et al. (2012). “Intermittent pneumatic compression therapy: a systematic review.” Lymphology 45(1): 13–25.
Hajo-Maghsoudi, O., A. Talebpour, et al. (2012). “Segmentation of Crohn, Lymphangiectasia, Xanthoma, Lymphoid Hyperplasia and Stenosis diseases in WCE.” Stud Health Technol Inform 180: 143–147.
Hara, H., M. Mihara, et al. (2012). “Presence of thoracic duct abnormalities in patients with primary lymphoedema of the extremities.” J Plast Reconstr Aesthet Surg. [Epub ahead of print]
OBJECTIVES: Primary lymphoedema is said to be caused by lymph duct malformations, lymphatic hypoplasia or lymphatic agenesis, but no definite treatment has been established. In this study, we used magnetic resonance thoracic ductography (MRTD) to assess the morphology of the thoracic duct in patients with primary lymphoedema. METHODS: The study was conducted on nine patients with primary lymphoedema who were hospitalised at the Department of Plastic and Reconstructive Surgery (University of Tokyo Hospital) from September 2007 through April 2011. RESULTS: The patients consisted of five men and four women, aged 20–54 years (mean age: 31.1 years). Five of them were in early-onset group and the rest were in late-onset group. In the 6 months prior to the onset of oedema, three of the four patients in the late-onset group had episodes of trauma near the areas which would later be affected by lymphoedema. MRTD showed no clear image of the thoracic duct in four of five patients in the early-onset group. CONCLUSIONS: MRTD assessment of patients diagnosed as ‘primary lymphoedema’ indicates that the pathogenetic mechanisms seen in late-onset patients are completely different from those found in early-onset patients, and may be classified as ‘traumatic lymphoedema.’
Liu, N. F., Z. X. Yan, et al. (2012). “Classification of Lymphatic-system Malformations in Primary Lymphoedema based on MR Lymphangiography.” Eur J Vasc Endovasc Surg.
OBJECTIVES: The study aims to investigate lymphatic-system malformations and proposes a classification of primary lymphoedema based on comprehensive imaging data of both lymph vessel- and lymph-node abnormalities. MATERIALS AND METHODS: A total of 378 patients with primary lymphoedema of the lower extremity were examined with magnetic resonance lymphangiography (MRL) using gadobenate dimeglumine as contrast agent. Lymph vessels and drainage lymph nodes were evaluated, leading to the proposal of the classification of primary lymphoedema and the relative proportions. RESULTS: A total of 63 (17%) patients exhibited defects of the inguinal lymph nodes with mild or moderate dilatation of afferent lymph vessels. A total of 123 (32%) patients exhibited lymphatic anomalies as lymphatic aplasia, hypoplasia or hyperplasia with no obvious defect of the drainage lymph nodes. The involvement of both lymph vessel- and lymph-node abnormalities in the affected limb was found in 192 (51%) patients. The primary lymphoedema was classified as three major types as: (1) lymph nodes affected only; (2) lymph vessel affected only with three subtypes and (3) both lymph vessel and lymph node affected with subgroups. CONCLUSIONS: A comprehensive classification of lymphatic-system malformation in primary lymphoedema is proposed, which clearly defines the location and pathologic characteristics of both lymphatics and lymph node and may lead to further study of the aetiology as well as rational treatment of the disease.
Michelini, S., D. Degiorgio, et al. (2012). “Clinical and genetic study of 46 Italian patients with primary lymphedema.” Lymphology 45(1): 3–12.
Primary lymphedema is characterized by altered morphological development of lymphatic vessels causing fluid accumulation in interstitial spaces. In familial forms, it is primarily transmitted as a dominant Mendelian trait with heterozygous mutations in genes involved in lymphangiogenesis. We used PCR and direct sequencing to analyze the region of the fms-related tyrosine kinase 4 (FLT4) gene encoding the “tyrosine-kinase domain” and the single exon of the forkhead box C2 (FOXC2) gene in 46 Italian probands with primary lymphedema, 42 of whom had familial forms. We identified 12 mutations in 12 patients (12/46, 26%), six in the FLT4 gene and six in the FOXC2 gene. Most of the mutations (9/12, 75%) were new, and none were identified in 100 healthy subjects or listed in the NCBI dbSNP. A clear relation emerged between genotype and phenotype because 4/5 (80%) probands with onset at birth showed FLT4 mutations and 4/5 (80%) probands without distichiasis and with FOXC2 mutations had an amino-acid substitution outside the forkhead domain. Besides the allelic heterogeneity shown by unique mutations in each proband, the absence of mutations in almost 75% of familial cases of primary lymphedema also suggests genetic heterogeneity.
Mihara, M., H. Hara, et al. (2012). “Indocyanine Green (ICG) Lymphography Is Superior to Lymphoscintigraphy for Diagnostic Imaging of Early Lymphedema of the Upper Limbs.” PLoS One 7(6): e38182.
Molyneux, D. H. (2012). “Tropical lymphedemas–control and prevention.” N Engl J Med 366(13): 1169–1171.
Pastora, N., J. Peralta-Calvo, et al. (2012). “Conjunctival Lymphangiectasia Presenting as Pediatric Pseudopterygium.” Eye Contact Lens. [Epub ahead of print]
Pavlista, D. and O. Eliska (2012). “Relationship Between the Lymphatic Drainage of the Breast and the Upper Extremity: A Postmortem Study.” Ann Surg Oncol. [Epub ahead of print]
Reichelt, U., S. Keichel, et al. (2012). “High Lymph Vessel Density and Expression of Lymphatic Growth Factors in Peritoneal Endometriosis.” Reprod Sci. 19: 876–882.
Reitsma, W., M. J. Wiegman, et al. (2012). “Penile and scrotal lymphedema as an unusual presentation of Crohn's disease: case report and review of the literature.” Lymphology 45(1): 37–41.
Seeger, H., M. Bonani, et al. (2012). “The role of lymphatics in renal inflammation.” Nephrol Dial Transplant 27(7): 2634–2641.
Vida, V. L., M. A. Padalino, et al. (2012). “Efficacy of Fibrinogen/Thrombin-Coated Equine Collagen Patch in Controlling Lymphatic Leaks.” J Card Surg. 27: 441–442.
Wessel, J. M., C. Hofmann-Rummelt, et al. (2012). “Invasion of Lymphatic Vessels into the Eye after Open Globe Injuries.” Invest Ophthalmol Vis Sci. 53: 3717–3725.
Yaginuma, T., I. Yamamoto, et al. (2012). “Increased Lymphatic Vessels in Patients with Encapsulatingperitoneal Sclerosis.” Perit Dial Int. [Epub ahead of print]
Yiannakopoulou, E. (2011). “Modulation of Lymphangiogenesis: A New Target for Aspirin and Other Nonsteroidal Anti-inflammatory Agents? A Systematic Review.” J Clin Pharmacol. [Epub ahead of print]
Zhang, J., S. K. Zhou, et al. (2012). “Automated analysis of investigational near-infrared fluorescence lymphatic imaging in humans.” Biomed Opt Express 3(7): 1713–1723.
Vascular Anomalies
Abate, M. V., R. Davanzo, et al. (2012). “RICH (Rapidly Involuting Congenital Hemangioma): Not Only a Definition of Wealth.” J Pediatr 161(2): 365–365 e361.
Adams, M. T., B. Saltzman, et al. (2012). “Head and Neck Lymphatic Malformation Treatment: A Systematic Review.” Otolaryngol Head Neck Surg.
Objective: To systematically review literature pertaining to head and neck lymphatic malformation treatment and to use individual-level data presented in qualifying case series to describe the reported efficacy, complications, and functional impact of surgery and sclerotherapy. The authors evaluated whether treatment modalities differ by lymphatic malformation stage. Data Sources: The terms lymphangioendothelioma, lymphangioma, cystic hygroma, and malformation were used to perform an Ovid literature search yielding 6292 references. The authors excluded references that did not involve head and neck lymphatic malformation treatment, include at least 5 patients, follow patients 1 year, define treatment modality, and state complications. Review Methods: The authors summarized data from 1205 patients reported in 41 articles. Individual-level data, in the 29 articles reporting these data, were pooled and tabulated. Results: The absence of within-study comparisons of treatment success, as well as the range of reporting methods, precluded a formal meta-analysis. Most reports were case series (37; 90%). The primary treatment modality was sclerotherapy in 17 (41%), surgery in 16 (39%), or surgery combined with other modalities in 9 (20%). Individual-level data were captured for 283 patients. No treatment modality clearly resulted in superior treatment outcome. Complications were more frequent in surgical series but were reported inconsistently in sclerotherapy studies. Conclusion: There is evidence that lymphatic malformation treatment can be done effectively with surgery or sclerotherapy, but further study is necessary to determine which is superior. Standardized guidelines for reporting lymphatic malformation case series do not currently exist, making comparison of treatment outcomes of differing treatment modalities difficult.
Akcay, A., Z. Karakas, et al. (2012). “Infantile Hemangiomas: Complications and Follow-Up.” Indian Pediatr.
OBJECTIVE: To study the risk factors for hemangioma-related complications, treatment indications and analyze the outcome of patients with infantile hemangioma. DESIGN: Retrospective. SETTING: University hospital. PATIENTS: Fifty-five patients (1–69 months; median: 12 months). with infantile hemangioma with mean follow-up 19 months. The eligibility was based on the criteria of the International Society for the Study of Vascular Anomalies (ISSVA). INTERVENTION: The surgical treatment included total excision whereas medical treatment was carried out by interferon and /or corticosteroids. MAIN OUTCOME MEASURES: Data was collected including sex, age, prematurity, age at onset, number, anatomic location and size of hemangioma, age at treatment, cause of treatment decision, family history, presence of extra malformations, involvement of internal organs, presence of life altering or life threatening complications, response to treatment, dose and duration of medications, complications associated with treatment, follow-up period, and final outcome. RESULTS: Thirty-four (62%) patients were followed-up without treatment, whereas 21 others underwent treatment including steroids, interferon, and surgery. The size of hemangioma was a major factor that predicted hemangioma-related complications (P=0.002). Patients with hemangioma related complications had bigger lesions (size >40cm2 or the longest size on a single plane >5 cm). Nineteen patients (34%) had complications, but only 8 (14.5%) out of them had life or function-threatening complications. CONCLUSION: Although dosing and treatment protocol is still datatable, steroids and interferon are good options for hemangioma treatment. The management strategy should be individualized for each case.
Albinana, V., L. Recio-Poveda, et al. (2012). “Propranolol as antiangiogenic candidate for the therapy of hereditary haemorrhagic telangiectasia.” Thromb Haemost 108(1).
The beta-blocker propranolol, originally designed for cardiological indications (angina, cardiac arrhythmias and high blood pressure), is nowadays, considered the most efficient drug for the treatment in infantile haemangiomas (IH), a vascular tumour that affects 5–10% of all infants. However, its potential therapeutic benefits in other vascular anomalies remain to be explored. In the present work we have assessed the impact of propranolol in endothelial cell cultures to test if this drug could be used in the vascular disease hereditary haemorrhagic telangiectasia (HHT). This rare disease is the result of abnormal angiogenesis with epistaxis, mucocutaneous and gastrointestinal telangiectases, as well as arteriovenous malformations in several organs, as clinical manifestations. Mutations in Endoglin (ENG) and ACVLR1 (ALK1) genes, lead to HHT1 and HHT2, respectively. Endoglin and ALK1 are involved in the TGF-beta1 signalling pathway and play a critical role for the proper development of the blood vessels. As HHT is due to a deregulation of key angiogenic factors, inhibitors of angiogenesis have been used to normalise the nasal vasculature eliminating epistaxis derived from telangiectases. Thus, the antiangiogenic properties of propranolol were tested in endothelial cells. The drug was able to decrease cellular migration and tube formation, concomitantly with reduced RNA and protein levels of ENG and ALK1. Moreover, the drug showed apoptotic effects which could explain cell death in IH. Interestingly, propranolol showed some profibrinolytic activity, decreasing PAI-1 levels. These results suggest that local administration of propranolol in the nose mucosa to control epistaxis might be a potential therapeutic approach in HHT.
Alghonaim, Y., R. Varshney, et al. (2012). “Coblation technique as an alternative treatment modality for oral lymphangioma.” Int J Pediatr Otorhinolaryngol. [Epub ahead of print]
Balakrishnan, K., T. C. Edwards, et al. (2012). “Functional and Symptom Impacts of Pediatric Head and Neck Lymphatic Malformations: Developing a Patient-Derived Instrument.” Otolaryngol Head Neck Surg. [Epub ahead of print]
Bertrand, J., R. Sammour, et al. (2012). “Propranolol in the treatment of problematic infantile hemangioma: review of 35 consecutive patients from a vascular anomalies clinic.” J Cutan Med Surg 16(2): 115–121.
Bingham, M. M., B. Saltzman, et al. (2012). “Propranolol reduces infantile hemangioma volume and vessel density.” Otolaryngol Head Neck Surg 147(2): 338–344.
Celik, A., S. Tiryaki, et al. (2012). “Propranolol as the first-line therapy for infantile hemangiomas: preliminary results of two centers.” J Drugs Dermatol 11(7): 808–811.
Chisholm, K. M., K. W. Chang, et al. (2012). “beta-Adrenergic receptor expression in vascular tumors.” Mod Pathol. [Epub ahead of print]
Propranolol has recently emerged as an effective therapy for infantile hemangiomas causing regression. The beta-adrenergic receptor (AR) antagonist is thought to cause vasoconstriction by its effect on nitric oxide, block angiogenesis by its effect on vascular endothelial growth factor (VEGF), and induce apoptosis. In a prior report, we identified expression of beta2-AR (B2-AR) and its phosphorylated form (B2-ARP) in a case of infantile hemangioma that responded to propranolol treatment. We now explore the expression of betaARs on a variety of vascular lesions utilizing a tissue microarray containing 141 lesions, including infantile hemangiomas, angiosarcomas, hemangiomas, hemangioendotheliomas, and various vascular malformations. The array was immunostained for B2-AR, B2-ARP, and beta3-AR (B3-AR), and the results scored for the intensity of endothelial cell expression as negative, weak positive, or strong positive. All phases of infantile hemangiomas had strong expression of all three receptors, with the exception of only weak expression of B2-ARP in the proliferative phase infantile hemangioma. Strong expression of all three receptors was present in many hemangiomas, hemangioendotheliomas, and vascular malformations. Absent to weak expression of all three receptors was seen in glomus tumor, hobnail hemangioendothelioma, pyogenic granuloma, and reactive vascular proliferations. This is the first study to report beta-AR expression in a variety of vascular lesions. Although immunohistochemical expression of the receptors does not necessarily indicate that similar pathways of responsiveness to beta-blockade are present, it does raises the possibility that beta-blockade could potentially affect apoptosis and decrease responsiveness to VEGF. Additional study is warranted, as therapeutic options are limited for some patients with these lesions. Modern Pathology advance online publication, 29 June 2012; doi: 10.1038/modpathol.2012.108.
Chiu, Y. E., B. A. Drolet, et al. (2012). “Variable response to propranolol treatment of kaposiform hemangioendothelioma, tufted angioma, and Kasabach-Merritt phenomenon.” Pediatr Blood Cancer. [Epub ahead of print]
Christou, E. M. and O. Wargon (2012). “Effect of captopril on infantile haemangiomas: A retrospective case series.” Australas J Dermatol. 53: 216–218.
Chung, S. H., D. H. Park, et al. (2012). “Successful and safe treatment of hemangioma with oral propranolol in a single institution.” Korean J Pediatr 55(5): 164–170.
Collettini, F., G. Diederichs, et al. (2011). “Sturge-Weber syndrome.” Pediatr Neurosurg 47(1): 80.
Conway, M. and S. L. Hosking (2012). “Investigation of ocular hemodynamics in Sturge-Weber syndrome.” Optom Vis Sci 89(6): 922–928.
Couto, R. A., A. H. Hassanein, et al. (2012). “Infantile Hemangioma in Four Siblings.” Pediatr Dermatol. [Epub ahead of print]
Croteau, S. E., M. G. Liang, et al. (2012). “Kaposiform Hemangioendothelioma: Atypical Features and Risks of Kasabach-Merritt Phenomenon in 107 Referrals.” J Pediatr. [Epub ahead of print]
Denzer, F., C. Denzer, et al. (2012). “A case of PHACE syndrome and acquired hypopituitarism?” Int J Pediatr Endocrinol 2012(1): 20.
Dupuis-Girod, S., I. Ginon, et al. (2012). “Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output.” JAMA 307(9): 948–955.
Durr, M. L., A. K. Meyer, et al. (2012). “Airway hemangiomas in PHACE syndrome.” Laryngoscope. [Epub ahead of print]
Esposito, C., I. Giurin, et al. (2012). “Blue rubber bleb nevus: an uncommon cause of intestinal intussusception.” Eur J Pediatr. 171: 1139–1140.
Georgountzou, A., E. Karavitakis, et al. (2012). “Propranolol treatment for severe infantile hemangiomas: a single-centre 3-year experience.” Acta Paediatr. 10: e469–e474.
Hartzell, L. D. and L. M. Buckmiller (2012). “Current management of infantile hemangiomas and their common associated conditions.” Otolaryngol Clin North Am 45(3): 545–556, vii.
Hill, R. H., 3rd, W. E. Shiels, 2nd, et al. (2012). “Percutaneous drainage and ablation as first line therapy for macrocystic and microcystic orbital lymphatic malformations.” Ophthal Plast Reconstr Surg 28(2): 119–125.
Jagtap, S., G. Srinivas, et al. (2012). “Sturge-Weber Syndrome: Clinical Spectrum, Disease Course, and Outcome of 30 Patients.” J Child Neurol. [Epub ahead of print]
Jamal, N., S. Ahmed, et al. (2012). “Doxycycline sclerotherapy for pediatric head and neck macrocystic lymphatic malformations: A case series and review of the literature.” Int J Pediatr Otorhinolaryngol. 76: 1127–1131.
Janmohamed, S. R., P. C. de Laat, et al. (2012). “Treating hemangioma of infancy with beta-blockers: Is there really a risk of hypotension?” J Am Acad Dermatol 67(2): 315–316.
Kadam, S. D., M. Gucek, et al. (2012). “Cell proliferation and oxidative stress pathways are modified in fibroblasts from Sturge-Weber syndrome patients.” Arch Dermatol Res 304(3): 229–235.
Sturge-Weber syndrome (SWS) is defined by vascular malformations of the face, eye and brain and an underlying somatic mutation has been hypothesized. We employed isobaric tags for relative and absolute quantification (iTRAQ-8plex)-based liquid chromatography interfaced with tandem mass spectrometry (LC-MS/MS) approach to identify differentially expressed proteins between port-wine-derived and normal skin-derived fibroblasts of four individuals with SWS. Proteins were identified that were significantly up- or down-regulated (i.e., ratios >1.2 or <0.8) in two or three pairs of samples (n=31/972 quantified proteins) and their associated p values reported. Ingenuity pathway analysis (IPA) tool showed that the up-regulated proteins were associated with pathways that enhance cell proliferation; down-regulated proteins were associated with suppression of cell proliferation. The significant toxicologic list pathway in all four observations was oxidative stress mediated by Nrf2. This proteomics study highlights oxidative stress also consistent with a possible mutation in the RASA1 gene or pathway in SWS.
Kanada, K. N., M. R. Merin, et al. (2012). “A prospective study of cutaneous findings in newborns in the United States: correlation with race, ethnicity, and gestational status using updated classification and nomenclature.” J Pediatr 161(2): 240–245.
OBJECTIVE: To provide incidence data based on ethnicity, prematurity, and body site for vascular, pigmented, and other common congenital cutaneous findings; to compare these results with previously published prospective studies; and to define updated nomenclature, classification, clinical course, and prognostic factors for the pediatric practitioner to promote a better understanding of benign versus more worrisome birthmarks. STUDY DESIGN: This prospective study enrolled 594 infants in San Diego, California. Cutaneous examination was performed by pediatric dermatologists in the first 48 hours of life, with subsequent longitudinal contact via telephone, and repeat evaluations if any new lesions were reported by parents. Incidence rates were calculated by ethnicity and prematurity status. RESULTS: The most common vascular lesion was nevus simplex (83%), followed by infantile hemangioma (4.5% by age 3 months), capillary malformation (0.3%), and rapidly involuting congenital hemangioma (0.3%). Pigmented lesions seen at birth included dermal melanocytosis (20%), congenital melanocytic nevi (2.4%), and cafe au lait macules (2%). Other common skin findings were erythema toxicum neonatorum (7%), milia (8%), and sebaceous gland hyperplasia (42.6%). CONCLUSION: This study of congenital cutaneous lesions, using current nomenclature and data acquired by pediatric cutaneous lesion experts, provides data regarding the role of race and ethnicity in the incidence of birthmarks, and provides valid data on the prevalence of infantile hemangioma.
Katz, M. S., C. M. Finck, et al. (2012). “Vacuum-assisted closure in the treatment of extensive lymphangiomas in children.” J Pediatr Surg 47(2): 367–370.
Meijer-Jorna, L. B., E. Aronica, et al. (2012). “Congenital vascular malformations - cerebral lesions differ from extracranial lesions by their immune expression of the glucose transporter protein GLUT1.” Clin Neuropathol 31(3): 135–141.
Background: Cerebral vascular malformations were investigated for the presence of the glucose transporter protein GLUT1, which is normally expressed in endothelial cells of the pre-existing microvasculature of the brain and absent in the vasculature of the choroid plexus and extracranial vasculature without a barrier function. Extracranial arteriovenous malformations (AVM) are known to show an absence of GLUT1 expression which distinguishes them from infantile hemangioma of skin and soft tissue. The expression of GLUT1 in cerebrovascular malformations is not systematically investigated. Methods: Paraffin-embedded sections of cerebral AVM (4), including one choroid plexus AVM, cerebral cavernous malformations (CCM, 3) and extracranial (facial) AVM (3) were immunostained with anti-CD31 and GLUT1 in doublestaining procedure which was further analyzed with the use of spectral analysis software. Results: All 7 cases of cerebral vascular malformations showed colocalization of GLUT1/CD31 of endothelial cells of the vessels within the malformation. Only in the extracranial AVM expression of GLUT1 was completely absent. Conclusion: Cerebral AVM differ from extracranial AVM by their endothelial immunoexpression of GLUT1, indicating that the vessels of these malformations retain the endothelial phenotype of the local vascular beds from which they are derived during embryogenesis.
Mitchell, S., D. H. Siegel, et al. (2012). “Candidate locus analysis for PHACE syndrome.” Am J Med Genet A. 158A: 1363–1367.
Moser, C. M. and C. Hamsch (2012). “Successful treatment of cutaneous venous malformations in a patient with blue rubber bleb naevus syndrome by Nd:YAG laser.” Br J Dermatol 166(5): 1143–1145.
Phillips, C. B., O. Pacha, et al. (2012). “A review of Beta antagonist treatment for infantile hemangioma.” J Drugs Dermatol 11(7): 826–829.
Prashanth, G. P. (2012). “How “unsafe” is propranolol when used in the treatment of infantile hemangioma?” J Am Acad Dermatol 66(5): 854–855; author reply 855–856.
Richter, G. T. and J. Y. Suen (2011). “Pediatric extracranial arteriovenous malformations.” Curr Opin Otolaryngol Head Neck Surg 19(6): 455–461.
Saha, K. and B. Leatherbarrow (2012). “Orbital lymphangiomas: a review of management strategies.” Curr Opin Ophthalmol. 23: 433–438.
Seca, M., P. Borges, et al. (2012). “Conjunctival lymphangioma: a case report and brief review of the literature.” Case Rep Ophthalmol Med 2012: 836573.
Shergill, A., P. John, et al. (2012). “Doxycycline sclerotherapy in children with lymphatic malformations: outcomes, complications and clinical efficacy.” Pediatr Radiol. 42: 1080–1088.
Siri, L., L. Giordano, et al. (2012). “Clinical features of Sturge-Weber syndrome without facial nevus: Five novel cases.” Eur J Paediatr Neurol. [Epub ahead of print]
Smit, D. P. and D. Meyer (2012). “Intralesional bleomycin for the treatment of periocular capillary hemangiomas.” Indian J Ophthalmol 60(4): 326–328.
Periocular infantile capillary hemangiomas do not always respond well to conventional treatment modalities such as systemic or intralesional corticosteroids, radiotherapy or debulking surgery. The authors describe the use of intralesional bleomycin injections (IBIs) to treat potentially amblyogenic lesions in two cases where other modalities have failed. In both cases monthly IBIs successfully cleared the visual axis of the affected eye before the age of 1 year thus preventing permanent sensory deprivation amblyopia. A total of five and nine injections, respectively, were used and no significant side effects were noted. IBI appears to be a useful alternative in the treatment of periocular capillary hemangiomas refractory to more conventional modalities.
Talaat, A. A., M. S. Elbasiouny, et al. (2012). “Propranolol treatment of infantile hemangioma: clinical and radiologic evaluations.” J Pediatr Surg 47(4): 707–714.
Tan, S. T., T. Itinteang, et al. (2012). “Treatment of infantile haemangioma with captopril.” Br J Dermatol. Saha, K. and B. Leatherbarrow (2012). “Orbital lymphangiomas: a review of management strategies.” Curr Opin Ophthalmol. [Epub ahead of print]
Background Infantile haemangioma (IH) has recently been reported as an aberrant proliferation and differentiation of a primitive mesoderm-derived haemogenic endothelium regulated by the renin-angiotensin system (RAS), leading us to propose angiotensin converting enzyme (ACE) as a potential
Thayal, P. K., P. S. Bhandari, et al. (2012). “Comparison of efficacy of intralesional bleomycin and oral propanolol in management of hemangiomas.” Plast Reconstr Surg 129(4): 733e-735e.
Tollefson, M. M. and I. J. Frieden (2012). “Early growth of infantile hemangiomas: what parents' photographs tell us.” Pediatrics 130(2): e314–320.
Verdegaal, S. H., J. V. Bovee, et al. (2011). “Incidence, predictive factors, and prognosis of chondrosarcoma in patients with Ollier disease and Maffucci syndrome: an international multicenter study of 161 patients.” Oncologist 16(12): 1771–1779.
Zweegers, J. and C. J. van der Vleuten (2012). “The psychosocial impact of an infantile haemangioma on children and their parents.” Arch Dis Child. [E-pub ahead of print]