Abstract
Featured Articles
Gousopoulos, E., et al. (2016). “Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function.” JCI Insight 1(16): e89081.
Secondary lymphedema is a common postcancer treatment complication, but the underlying pathological processes are poorly understood and no curative treatment exists. To investigate lymphedema pathomechanisms, a top-down approach was applied, using genomic data and validating the role of a single target. RNA sequencing of lymphedematous mouse skin indicated upregulation of many T cell-related networks, and indeed depletion of CD4+ cells attenuated lymphedema. The significant upregulation of Foxp3, a transcription factor specifically expressed by regulatory T cells (Tregs), along with other Treg-related genes, implied a potential role of Tregs in lymphedema. Indeed, increased infiltration of Tregs was identified in mouse lymphedematous skin and in human lymphedema specimens. To investigate the role of Tregs during disease progression, loss-of-function and gain-of-function studies were performed. Depletion of Tregs in transgenic mice with Tregs expressing the primate diphtheria toxin receptor and green fluorescent protein (Foxp3-DTR-GFP) mice led to exacerbated edema, concomitant with increased infiltration of immune cells and a mixed TH1/TH2 cytokine profile. Conversely, expansion of Tregs using IL-2/anti-IL-2 mAb complexes significantly reduced lymphedema development. Therapeutic application of adoptively transferred Tregs upon lymphedema establishment reversed all of the major hallmarks of lymphedema, including edema, inflammation, and fibrosis, and also promoted lymphatic drainage function. Collectively, our results reveal that Treg application constitutes a potential new curative treatment modality for lymphedema.
The authors studied the mechanisms involved in lymphedema by first assessing the genes that were up- or down-regulated in lymphedema, and they found predominantly upregulated inflammation and T cell–related genes. Using a mouse tail model of surgically induced lymphedema, increased CD4+ T cells were identified in the lymphedema tissue, Depletion of CD4+T cells reduced lymphedema and improved lymphatic function. They studied the role of regulatory T-cells (Tregs), concluding they ameliorate lymphedema. Via IL-2c treatment, Treg increased and abrogated the development of lymphedema. By adoptive cell transfer of Tregs in lymphedematous mice, they noted improvement in the lymphedema, with smaller lymphatic vessels, decreased inflammatory cytokines, reduced fibrosis, and improved lymphatic function. These studies offer promise in new targets to prevent and/or ameliorate lymphedema.
Basic Science
Ahn, H. and J. H. Park (2016). “Liposomal delivery systems for intestinal lymphatic drug transport.” Biomater Res 20: 36.
Banerji, S., et al. (2016). “Homodimerization of the lymph vessel endothelial receptor LYVE-1 through a redox-labile disulfide is critical for hyaluronan binding in lymphatic endothelium.” J Biol Chem 291(48): 25004–25018.
Bianchi, R., et al. (2016). “Postnatal deletion of podoplanin in lymphatic endothelium results in blood filling of the lymphatic system and impairs dendritic cell migration to lymph nodes.” Arterioscler Thromb Vasc Biol.
Chen, W. S., et al. (2016). “Pathological lymphangiogenesis is modulated by galectin-8-dependent crosstalk between podoplanin and integrin-associated VEGFR-3.” Nat Commun 7: 11302.
Hong, J., et al. (2016). “Inhibition of phagocytosis and pyroptosis of macrophages promotes Bartonella invasion into the bloodstream through lymphatic circulation.” J Infect Dis. [E-Pub Oct 31]
Hosono, K., et al. (2016). “Signaling of prostaglandin E receptors, EP3 and EP4 facilitates wound healing and lymphangiogenesis with enhanced recruitment of M2 macrophages in mice.” PLoS One 11(10): e0162532.
Lymphangiogenesis plays an important role in homeostasis, metabolism, and immunity, and also occurs during wound-healing. Here, we examined the roles of prostaglandin E2 (PGE2) receptor (EP) signaling in enhancement of lymphangiogenesis in wound healing processes. The hole-punch was made in the ears of male C57BL/6 mice using a metal ear punch. Healing process and lymphangiogenesis together with macrophage recruitment were analyzed in EP knockout mice. Lymphangiogenesis was up-regulated in the granulation tissues at the margins of punched-hole wounds in mouse ears, and this increase was accompanied by increased expression levels of COX-2 and microsomal prostaglandin E synthase-1. Administration of celecoxib, a COX-2 inhibitor, suppressed lymphangiogenesis in the granulation tissues and reduced the induction of the pro-lymphangiogenic factors, vascular endothelial growth factor (VEGF) -C and VEGF-D. Topical applications of selective EP receptor agonists enhanced the expressions of lymphatic vessel endothelial hyaluronan receptor-1 and VEGF receptor-3. The wound-healing processes and recruitment of CD11b-positive macrophages, which produced VEGF-C and VEGF-D, were suppressed under COX-2 inhibition. Mice lacking either EP3 or EP4 exhibited reduced wound-healing, lymphangiogenesis and recruitment of M2 macrophages, compared with wild type mice. Proliferation of cultured human lymphatic endothelial cells was not detected under PGE2 stimulation. Lymphangiogenesis and recruitment of M2 macrophages that produced VEGF-C/D were suppressed in mice treated with a COX-2 inhibitor or lacking either EP3 or EP4 during wound healing. COX-2 and EP3/EP4 signaling may be novel targets to control lymphangiogenesis in vivo.
Iftakhar, E. K. I., et al. (2016). “Gene-expression profiling of different arms of lymphatic vasculature identifies candidates for manipulation of cell traffic.” Proc Natl Acad Sci U S A 113(38): 10643–10648.
Afferent lymphatic vessels bring antigens and diverse populations of leukocytes to draining lymph nodes, whereas efferent lymphatics allow only lymphocytes and antigens to leave the nodes. Despite the fundamental importance of afferent vs. efferent lymphatics in immune response and cancer spread, the molecular characteristics of these different arms of the lymphatic vasculature are largely unknown. The objective of this work was to explore molecular differences behind the distinct functions of afferent and efferent lymphatic vessels, and find possible molecules mediating lymphocyte traffic. We used laser-capture microdissection and cell sorting to isolate lymphatic endothelial cells (LECs) from the subcapsular sinus (SS, afferent) and lymphatic sinus (LS, efferent) for transcriptional analyses. The results reveal marked differences between afferent and efferent LECs and identify molecules on lymphatic vessels. Further characterizations of Siglec-1 (CD169) and macrophage scavenger receptor 1 (MSR1/CD204), show that they are discriminatively expressed on lymphatic endothelium of the SS but not on lymphatic vasculature of the LS. In contrast, endomucin (EMCN) is present on the LS endothelium and not on lymphatic endothelium of the SS. Moreover, both murine and human MSR1 on lymphatic endothelium of the SS bind lymphocytes and in in vivo studies MSR1 regulates entrance of lymphocytes from the SS to the lymph node parenchyma. In conclusion, this paper reports surprisingly distinct molecular profiles for afferent and efferent lymphatics and a function for MSR1. These results may open avenues to explore some of the now-identified molecules as targets to manipulate the function of lymphatic vessels.
Kang, G. J., et al. (2016). “Integrin alpha 9 blockade suppresses lymphatic valve formation and promotes transplant survival.” Invest Ophthalmol Vis Sci 57(14): 5935–5939.
Kwon, S. and E. M. Sevick-Muraca (2016). “Effect of lidocaine with and without epinephrine on lymphatic contractile activity in mice in vivo.” J Anesth 30(6): 1091–1094.
Lau, C. L., et al. (2016). “Lymphatic filariasis elimination in American Samoa: Evaluation of molecular xenomonitoring as a surveillance tool in the endgame.” PLoS Negl Trop Dis 10(11): e0005108.
Lee, L. K., et al. (2016). “LYVE1 marks the divergence of yolk sac definitive hemogenic endothelium from the primitive erythroid lineage.” Cell Rep 17(9): 2286–2298.
Lee, Y. G. and G. Y. Koh (2016). “Coordinated lymphangiogenesis is critical in lymph node development and maturation.” Dev Dyn 245(12): 1189–1197.
BACKGROUND: Lymph node (LN) formation requires multiple but coordinated signaling from intrinsic and extrinsic cellular components during embryogenesis. However, the contribution and role of lymphatic vessels (LVs) in LN formation and maturation are poorly defined. Here, using lymphatic-specific reporters, Prox1-GFP mice and Vegfc+/LacZ mice, we analyzed migration, assembly, and ingrowth of lymphatic endothelial cells (LECs) in LNs during pre- and postnatal development. RESULTS: Prox1+ LECs form string-like connections rather than lymph sac-like structures until E14.5, but the LEC coverage around LN anlagen completes before birth. Compared to wild-type littermates, Vegfc+/LacZ mice had markedly smaller LNs in neonates and adults, presumably due to the decrease in LTi cell clusters and migrating Prox1+ LECs during embryogenesis. In addition, Vegfc-haploinsufficiency or inhibition of VEGFR3 signaling led to an impairment of LN LV ingrowth, resulting in a significant decrease in LN volume. These data indicate that VEGF-C/VEGFR3 signaling plays a substantial role in normal LN formation through proper migration and organization of LECs. CONCLUSIONS: Taken together, our results provide compelling evidence that the contribution of LVs through VEGF-C/VEGFR3 signaling is critical in LN development and maturation. Developmental Dynamics 245:1189–1197, 2016. (c) 2016 Wiley Periodicals, Inc.
Liu, X., et al. (2016). “Semaphorin 3G provides a repulsive guidance cue to lymphatic endothelial cells via neuropilin-2/plexinD1.” Cell Rep 17(9): 2299–2311.
The vertebrate circulatory system is composed of closely related blood and lymphatic vessels. It has been shown that lymphatic vascular patterning is regulated by blood vessels during development, but its molecular mechanisms have not been fully elucidated. Here, we show that the artery-derived ligand semaphorin 3G (Sema3G) and the endothelial cell receptor PlexinD1 play a role in lymphatic vascular patterning. In mouse embryonic back skin, genetic inactivation of Sema3G or PlexinD1 results in abnormal artery-lymph alignment and reduced lymphatic vascular branching. Conditional ablation in mice demonstrates that PlexinD1 is primarily required in lymphatic endothelial cells (LECs). In vitro analyses show that Sema3G binds to neuropilin-2 (Nrp2), which forms a receptor complex with PlexinD1. Sema3G induces cell collapse in an Nrp2/PlexinD1-dependent manner. Our findings shed light on a molecular mechanism by which LECs are distributed away from arteries and form a branching network during lymphatic vascular development.
Lohrberg, M. and J. Wilting (2016). “The lymphatic vascular system of the mouse head.” Cell Tissue Res 366(3): 667–677.
Mary, K. A., et al. (2016). “Scope of detectability of circulating antigens of human lymphatic filarial parasite Wuchereria bancrofti with smaller amount of serum by Og4C3 assay: its application in lymphatic filariasis elimination programme.” J Parasit Dis 40(4): 1622–1626.
Miranda Garces, M., et al. (2016). “Intratissue lymphovenous communications in the mechanism of action of vascularized lymph node transfer.” J Surg Oncol. E-Pub Nov 25
Moldobaeva, A., et al. (2016). “Lymphangiogenesis in rat asthma model.” Angiogenesis. EPub Oct 27
Mucka, P., et al. (2016). “Inflammation and lymphedema are exacerbated and prolonged by neuropilin 2 deficiency.” Am J Pathol 186(11): 2803–2812.
The vasculature influences the progression and resolution of tissue inflammation. Capillaries express vascular endothelial growth factor (VEGF) receptors, including neuropilins (NRPs), which regulate interstitial fluid flow. NRP2, a receptor of VEGFA and semaphorin (SEMA) 3F ligands, is expressed in the vascular and lymphatic endothelia. Previous studies have demonstrated that blocking VEGF receptor 2 attenuates VEGFA-induced vascular permeability. The inhibition of NRP2 was hypothesized to decrease vascular permeability as well. Unexpectedly, massive tissue swelling and edema were observed in Nrp2-/- mice compared with wild-type littermates after delayed-type hypersensitivity reactions. Vascular permeability was twofold greater in inflamed blood vessels in Nrp2-deficient mice compared to those in Nrp2-intact littermates. The addition of exogenous SEMA3F protein inhibited vascular permeability in Balb/cJ mice, suggesting that the loss of endogenous Sema3F activity in the Nrp2-deficient mice was responsible for the enhanced vessel leakage. Functional lymphatic capillaries are necessary for draining excess fluid after inflammation; however, Nrp2-mutant mice lacked superficial lymphatic capillaries, leading to 2.5-fold greater fluid retention and severe lymphedema after inflammation. In conclusion, Nrp2 deficiency increased blood vessel permeability and decreased lymphatic vessel drainage during inflammation, highlighting the importance of the NRP2/SEMA3F pathway in the modulation of tissue swelling and resolution of postinflammatory edema.
Nikolic, I., et al. (2016). “Immunohistochemical heterogeneity of the endothelium of blood and lymphatic vessels in the developing human liver and in adulthood.” Cells Tissues Organs. EPub Nov 27
Nizamutdinova, I. T., et al. (2016). “Mast cells and histamine are triggering the NF-kappaB-mediated reactions of adult and aged perilymphatic mesenteric tissues to acute inflammation.” Aging (Albany NY). EPub Nov 21
This study aimed to establish mechanistic links between the aging-associated changes in the functional status of mast cells and the altered responses of mesenteric tissue and mesenteric lymphatic vessels (MLVs) to acute inflammation. We used an in vivo model of acute peritoneal inflammation induced by lipopolysaccharide treatment of adult (9-month) and aged (24-month) F-344 rats. We analyzed contractility of isolated MLVs, mast cell activation, activation of nuclear factor-kappaB (NF-kappaB) without and with stabilization of mast cells by cromolyn or blockade of all types of histamine receptors and production of 27 major pro-inflammatory cytokines in adult and aged perilymphatic mesenteric tissues and blood. We found that the reactivity of aged contracting lymphatic vessels to LPS-induced acute inflammation was abolished and that activated mast cells trigger NF-kappaB signaling in the mesentery through release of histamine. The aging-associated basal activation of mesenteric mast cells limits acute inflammatory NF-kappaB activation in aged mesentery. We conclude that proper functioning of the mast cell/histamine/NF-kappaB axis is necessary for reactions of the lymphatic vessels to acute inflammatory stimuli as well as for interaction and trafficking of immune cells near and within the collecting lymphatics.
Ochsenbein, A. M., et al. (2016). “Regulation of lymphangiogenesis in the diaphragm by macrophages and VEGFR-3 signaling.” Angiogenesis 19(4): 513–524.
Perfahl, H., et al. (2016). “3D hybrid modelling of vascular network formation.” J Theor Biol. EPub Nov 24
Rodionova, O. M., et al. (2016). “Effect of Herbal Homeopathic Monopreparations on the Rate of Tissue Lymphatic Drainage in Healthy Mice.” Bull Exp Biol Med 161(6): 786–787.
Ruddle, N. H. (2016). “High endothelial venules and lymphatic vessels in tertiary lymphoid organs: Characteristics, functions, and regulation.” Front Immunol 7: 491.
High endothelial venules (HEVs) and lymphatic vessels (LVs) are essential for the function of the immune system, by providing communication between the body and lymph nodes (LNs), specialized sites of antigen presentation and recognition. HEVs bring in naive and central memory cells and LVs transport antigen, antigen-presenting cells, and lymphocytes in and out of LNs. Tertiary lymphoid organs (TLOs) are accumulations of lymphoid and stromal cells that arise and organize at ectopic sites in response to chronic inflammation in autoimmunity, microbial infection, graft rejection, and cancer. TLOs are distinguished from primary lymphoid organs - the thymus and bone marrow, and secondary lymphoid organs (SLOs) - the LNs, spleen, and Peyer's patches, in that they arise in response to inflammatory signals, rather than in ontogeny. TLOs usually do not have a capsule but are rather contained within the confines of another organ. Their structure, cellular composition, chemokine expression, and vascular and stromal support resemble SLOs and are the defining aspects of TLOs. T and B cells, antigen-presenting cells, fibroblast reticular cells, and other stromal cells and vascular elements including HEVs and LVs are all typical components of TLOs. A key question is whether the HEVs and LVs play comparable roles and are regulated similarly to those in LNs. Data are presented that support this concept, especially with regard to TLO HEVs. Emerging data suggest that the functions and regulation of TLO LVs are also similar to those in LNs. These observations support the concept that TLOs are not merely cellular accumulations but are functional entities that provide sites to generate effector cells, and that their HEVs and LVs are crucial elements in those activities.
Salvi, V., et al. (2016). “Dendritic cell-derived VEGF-A plays a role in inflammatory angiogenesis of human secondary lymphoid organs and is driven by the coordinated activation of multiple transcription factors.” Oncotarget 7(26): 39256–39269.
Shin, M., et al. (2016). “Vegfc acts through ERK to induce sprouting and differentiation of trunk lymphatic progenitors.” Development 143(20): 3785–3795.
Vascular endothelial growth factor C (Vegfc) activates its receptor, Flt4, to induce lymphatic development. However, the signals that act downstream of Flt4 in this context in vivo remain unclear. To understand Flt4 signaling better, we generated zebrafish bearing a deletion in the Flt4 cytoplasmic domain that eliminates tyrosines Y1226 and 1227. Embryos bearing this deletion failed to initiate sprouting or differentiation of trunk lymphatic vessels and did not form a thoracic duct. Deletion of Y1226/7 prevented ERK phosphorylation in lymphatic progenitors, and ERK inhibition blocked trunk lymphatic sprouting and differentiation. Conversely, endothelial autonomous ERK activation rescued lymphatic sprouting and differentiation in flt4 mutants. Interestingly, embryos bearing the Y1226/7 deletion formed a functional facial lymphatic network enabling them to develop normally to adulthood. By contrast, flt4 null larvae displayed hypoplastic facial lymphatics and severe lymphedema. Thus, facial lymphatic vessels appear to be the first functional lymphatic network in the zebrafish, whereas the thoracic duct is initially dispensable for lymphatic function. Moreover, distinct signaling pathways downstream of Flt4 govern lymphatic morphogenesis and differentiation in different anatomical locations.
Ulvmar, M. H. and T. Makinen (2016). “Heterogeneity in the lymphatic vascular system and its origin.” Cardiovasc Res 111(4): 310–321.
Wang, Y., et al. (2016). “Syndecan 4 controls lymphatic vasculature remodeling during mouse embryonic development.” Development 143(23): 4441–4451.
Worley, D. R., et al. (2016). “Docetaxel accumulates in lymphatic circulation following subcutaneous delivery compared to intravenous delivery in rats.” Anticancer Res 36(10): 5071–5078.
Yu, Z. Y., et al. (2016). “Abnormal mural cell recruitment in lymphatic capillaries: a common pathological feature in chronic lymphedematous skin?” Microcirculation 23(7): 495–502.
Zawieja, S. D., et al. (2016). “Macrophage alterations within the mesenteric lymphatic tissue are associated with impairment of lymphatic pump in metabolic syndrome.” Microcirculation 23(7): 558–570.
Zheng, M., et al. (2016). “The selective distribution of LYVE-1-expressing endothelial cells and reticular cells in the reticulo-endothelial system (RES).” Biomed Res 37(3): 187–198.
Clinical
Amirjamshidi, A., et al. (2016). “Painful sporadic osteolysis of the parietal bone 'Gorham's disease'.” Br J Neurosurg 30(6): 687–688.
Beijnen, U. E., et al. (2016). “Beckwith-Wiedemann Syndrome and primary lymphedema of the lower extremity.” Pediatr Dermatol. EPub Oct 25
Chandrasena, N. T., et al. (2016). “Surveillance for transmission of lymphatic filariasis in Colombo and Gampaha districts of Sri Lanka following mass drug administration.” Trans R Soc Trop Med Hyg. EPub Nov 5
Crawford, J., et al. (2016). “Expanding the genotypic spectrum of CCBE1 mutations in Hennekam syndrome.” Am J Med Genet A 170(10): 2694–2697.
Ganal-Antonio, A. K., et al. (2016). “Disappearing bone disease of the humerus and the cervico-thoracic spine: a case report with 42-year follow-up.” Spine J 16(2): e67–75.
Hellyer, J., et al. (2016). “Pregnancy complicated by Gorham-Stout Disease and refractory chylothorax.” AJP Rep 6(4): e355-e358.
Hur, S., et al. (2016). “Early experience in the management of postoperative lymphatic leakage using lipiodol lymphangiography and adjunctive glue embolization.” J Vasc Interv Radiol 27(8): 1177–1186 e1171.
Inoue, M., et al. (2016). “Lymphatic Intervention for Various Types of Lymphorrhea: Access and Treatment.” Radiographics 36(7): 2199–2211.
Itkin, M. (2016). “Invited commentary: Lymphatic (or “forgotten”) circulation has to be rediscovered.” Radiographics 36(7): 2212–2213.
Itkin, M. G., et al. (2016). “Diagnosis and treatment of lymphatic plastic bronchitis in adults using advanced lymphatic imaging and percutaneous embolization.” Ann Am Thorac Soc 13(10): 1689–1696.
Keppler-Noreuil, K. M., et al. (2016). “Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies.” Am J Med Genet C Semin Med Genet. EPub Nov 18
Kilbreath, S. L., et al. (2016). “Bioimpedance spectroscopy does have a valid and evidence-based role in detection and monitoring of lymphoedema.” J Surg Oncol. EPub Nov 4
Nathan, N., et al. (2017). “Mosaic disorders of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway.” Dermatol Clin 35(1): 51–60.
Onoda, S., et al. (2016). “Relationship of the number and size of superficial groin lymph nodes with the stage of secondary lymphatic edema.” J Surg Oncol. EPub Oct 6
Patil, A. R., et al. (2016). “Disorders of the lymphatic system of the abdomen.” Clin Radiol 71(10): 941–952.
Putta, T., et al. (2016). “Young patient with generalized lymphangiomatosis: Differentiating the differential.” Indian J Radiol Imaging 26(3): 411–415.
Silva, A. K. and D. W. Chang (2016). “Discussion: Evaluation of the upper limb lymphatic system: A prospective lymphoscintigraphic study in melanoma patients and healthy controls.” Plast Reconstr Surg 138(6): 1332.
Weiss, R. (2016). “Cost of a lymphedema treatment mandate-10 years of experience in the Commonwealth of Virginia.” Health Econ Rev 6(1): 42.
Wong, L. L., et al. (2016). “Orbital angiogenesis and lymphangiogenesis in thyroid eye disease: An analysis of vascular growth factors with clinical correlation.” Ophthalmology 123(9): 2028–2036.
Oncology
Ahmed, M., et al. (2016). “Meta-analysis of aberrant lymphatic drainage in recurrent breast cancer.” Br J Surg 103(12): 1579–1588.
Alishekevitz, D., et al. (2016). “Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3.” Cell Rep 17(5): 1344–1356.
While chemotherapy strongly restricts or reverses tumor growth, the response of host tissue to therapy can counteract its anti-tumor activity by promoting tumor re-growth and/or metastases, thus limiting therapeutic efficacy. Here, we show that vascular endothelial growth factor receptor 3 (VEGFR3)-expressing macrophages infiltrating chemotherapy-treated tumors play a significant role in metastasis. They do so in part by inducing lymphangiogenesis as a result of cathepsin release, leading to VEGF-C upregulation by heparanase. We found that macrophages from chemotherapy-treated mice are sufficient to trigger lymphatic vessel activity and structure in naive tumors in a VEGFR3-dependent manner. Blocking VEGF-C/VEGFR3 axis inhibits the activity of chemotherapy-educated macrophages, leading to reduced lymphangiogenesis in treated tumors. Overall, our results suggest that disrupting the VEGF-C/VEGFR3 axis not only directly inhibits lymphangiogenesis but also blocks the pro-metastatic activity of macrophages in chemotherapy-treated mice.
Argenbright, C. A., et al. (2016). “Bowenwork for symptom management of women breast cancer survivors with lymphedema: A pilot study.” Complement Ther Clin Pract 25: 142–149.
PURPOSE: The objectives of this pilot study for women breast cancer survivors with lymphedema was 1) to evaluate recruitment rates, retention rates, adherence to Bowenwork (a noninvasive complementary therapy involving gentle muscle movements), home exercises, safety and comfort; 2) determine the effect of Bowenwork on quality of life (QOL), functional status, perceived pain, range of motion (ROM), arm/ankle circumference (to assess for localized and systemic changes). METHODS: Participants received 4 Bowenwork sessions with home exercises. Initial and post assessments included QOL, functional status, and pain. ROM, arm/ankle circumference and pain measures were recorded before each session. RESULTS: Twenty-one women enrolled in the study; 95% completion; adherence 100%; home exercises 95%; no adverse events. The intervention improved mental health (SF-36-MCS); breast cancer-related functional (FACT-B); increased ROM; reduced arm circumferences. P value set at <0.05. CONCLUSIONS: The Bowenwork intervention was safe and acceptable for women breast cancer survivors with lymphedema.
Basta, M. N., et al. (2016). “Reliable prediction of postmastectomy lymphedema: the Risk Assessment Tool Evaluating Lymphedema.” Am J Surg. EPub Sept 7
Benharroch, D., et al. (2016). “Lymphangiogenesis in Classical Hodgkin Lymphoma - Preliminary Study with Clinicopathological Correlations.” J Cancer 7(14): 2117–2123.
Bgatova, N. P., et al. (2016). “Expression of Molecular Markers of Angiogenesis, Lymphangiogenesis, and Proliferation Depending on the Stage of Skin Melanoma.” Bull Exp Biol Med 161(4): 542–546.
Cobec, I. M., et al. (2016). “Podoplanin as Key Player of Tumor Progression and Lymph Vessel Proliferation in Ovarian Cancer.” Anticancer Res 36(10): 5265–5272.
BACKGROUND/AIM: Podoplanin plays a key role in tumor progression and metastasis. We evaluated lymphatics proliferation rate and podoplanin expression in tumor cells of ovarian carcinoma. MATERIALS AND METHODS: Seventy-five paraffin-embedded specimens of ovarian cancer were immunohistochemically assessed in order to quantify peritumoral (LMVDP) and intratumoral (LMVDT) lymphatic microvessel density of proliferating lymphatics and for podoplanin variability in tumor cells. RESULTS AND CONCLUSION: LMVDT correlated with proliferating tumor vessels located in the peritumoral area (p = 0.024) and with the number of mature vessels located in the intratumoral area (p < 0.0001), while LMVDP correlated with peritumoral mature vessels (p < 0.000l). Proliferating tumor cells at the invasive front were highly positive for podoplanin. To the best of our knowledge, this study represents the first assessment of lymphatic endothelial cell proliferation correlated with podoplanin expression in tumor cells from ovarian cancer. Our data support podoplanin as a potential target that may help reduce ovarian cancer dissemination and lymphatic metastasis.
Gratzon, A., et al. (2016). “Clinical and Psychosocial Outcomes of Vascularized Lymph Node Transfer for the Treatment of Upper Extremity Lymphedema After Breast Cancer Therapy.” Ann Surg Oncol.
Kim, M., et al. (2016). “Identification of Prognostic Risk Factors for Transient and Persistent Lymphedema after Multimodal Treatment for Breast Cancer.” Cancer Res Treat 48(4): 1330–1337. EPub Oct 12
Kitagawa, Y., et al. (2016). “Enhanced detection of lymphovascular invasion in small rectal neuroendocrine tumors using D2-40 and Elastica van Gieson immunohistochemical analysis.” Cancer Med 5(11): 3121–3127.
Krediet, J. T., et al. (2016). “Prognostic value of the area and density of lymphatic vessels in cutaneous squamous cell carcinoma.” J Dtsch Dermatol Ges 14(11): 1114–1121.
Kwon, M. J., et al. (2016). “Lymphovascular invasion in more than one-quarter of small rectal neuroendocrine tumors.” World J Gastroenterol 22(42): 9400–9410.
Liu, Y., et al. (2016). “NOK/STYK1 promotes the genesis and remodeling of blood and lymphatic vessels during tumor progression.” Biochem Biophys Res Commun 478(1): 254–259.
Previous studies have indicated that the overexpression of NOK, also named STYK1, led to tumorigenesis and metastasis. Here, we provide evidence that increased expression of NOK/STYK1 caused marked alterations in the overall and inner structures of tumors and substantially facilitates the genesis and remodeling of the blood and lymphatic vessels during tumor progression. In particular, NOK-expressed HeLa stable cells (HeLa-K) significantly enhanced tumor growth and metastasis in xenografted nude mice. Hematoxylin and eosin (HE) staining demonstrated that the tumor tissues generated by HeLa-K cells were much more ichorous and had more interspaces than those generated by control HeLa cells (HeLa-C). The fluorescent areas stained with cluster of differentiation 31 (CD31), a marker protein for blood vessels, appeared to be in different patterns. The total blood vessels, especially the ring patterns, within the tumors of the HeLa-K group were highly enriched compared with those in the HeLa-C group. NOK-HA was demonstrated to be well colocalized with CD31 in the wall of the tubular structures within tumor tissues. Interestingly, antibody staining of the lymphatic vessel endothelial hyaluronan receptor (LYVE-1) further revealed the increase in ring (oratretic strip-like) lymphatic vessels in either the peritumoral or intratumoral areas in the HeLa-K group compared with the HeLa-C group. Consistently, the analysis of human cancerous tissue also showed that NOK was highly expressed in the walls of tubular structures. Thus, our results reveal a novel tumorigenic function of NOK to mediate the genesis and remodeling of blood and lymphatic vessels during tumor progression.
Maehana, S., et al. (2016). “Suppression of lymphangiogenesis by soluble vascular endothelial growth factor receptor-2 in a mouse lung cancer model.” Biomed Pharmacother 84: 660–665.
Mahmoud, S., et al. (2016). “Over expression of sulfatase-1 in murine hepatocarcinoma Hca-F cell line downregulates mesothelin and leads to reduction in lymphatic metastasis, both in vitro and in vivo.” Oncotarget. EPub Sept 10
Marinho Bezerra de Oliveira Moura, J., et al. (2016). “Immunohistochemical comparative analysis of lymphatic vessel density and VEGF-C expression in squamous cell carcinomas of the tongue between young and old patients.” Pathol Res Pract. EPub Nov 2
Martinez-Iglesias, O., et al. (2016). “The nuclear corepressor 1 and the thyroid hormone receptor beta suppress breast tumor lymphangiogenesis.” Oncotarget. EPub Oct 27
May, M., et al. (2016). “Is there evidence for a close connection between side of intravesical tumor location and ipsilateral lymphatic spread in lymph node-positive bladder cancer patients at radical cystectomy? Results of the PROMETRICS 2011 database.” Int Urol Nephrol. EPub Nov 28
Raica, M., et al. (2016). “Lymphangiogenesis and anti-lymphangiogenesis in cutaneous melanoma.” Anticancer Res 36(9): 4427–4435.
Rong, B., et al. (2016). “Increased level of Hsp90-beta in bronchoalveolar lavage fluid correlates with lymphatic invasion and advanced stage of lung cancer patients.” Am J Transl Res 8(10): 4147–4159.
Steinskog, E. S., et al. (2016). “Impaired lymphatic function accelerates cancer growth.” Oncotarget. EPub June 13
Increased lymphangiogenesis is a common feature of cancer development and progression, yet the influence of impaired lymphangiogenesis on tumor growth is elusive. C3HBA breast cancer and KHT-1 sarcoma cell lines were implanted orthotopically in Chy mice, harboring a heterozygous inactivating mutation of vascular endothelial growth factor receptor-3, resulting in impaired dermal lymphangiogenesis. Accelerated tumor growth was observed in both cancer models in Chy mice, coinciding with reduced peritumoral lymphangiogenesis. An impaired lymphatic washout was observed from the peritumoral area in Chy mice with C3HBA tumors, and the number of macrophages was significantly reduced. While fewer macrophages were detected, the fraction of CD163+ M2 macrophages remained constant, causing a shift towards a higher M2/M1 ratio in Chy mice. No difference in adaptive immune cells was observed between wt and Chy mice. Interestingly, levels of pro- and anti-inflammatory macrophage-associated cytokines were reduced in C3HBA tumors, pointing to an impaired innate immune response. However, IL-6 was profoundly elevated in the C3HBA tumor interstitial fluid, and treatment with the anti-IL-6 receptor antibody tocilizumab inhibited breast cancer growth. Collectively, our data indicate that impaired lymphangiogenesis weakens anti-tumor immunity and favors tumor growth at an early stage of cancer development.
Su, F., et al. (2016). “Expression of VEGF-D, SMAD4, and SMAD7 and their relationship with lymphangiogenesis and prognosis in colon cancer.” J Gastrointest Surg 20(12): 2074–2082.
Yano, S., et al. (2016). “Enhanced metastatic recurrence via lymphatic trafficking of a high-metastatic variant of human triple-negative breast cancer after surgical resection in orthotopic nude mouse models.” J Cell Biochem. EPub Sept 14
Yong, T. L., et al. (2016). “Anatomy of hepatic lymphatics and its implications in hepatic malignancies.” ANZ J Surg 86(11): 868–873.
Zheng, Y., et al. (2016). “Effect of VEGF-C siRNA and endostatin on ring formation and proliferation of esophageal squamous cell carcinoma lymphatic endothelial cells.” Onco Targets Ther 9: 6727–6732.
OBJECTIVE: To study the effects of vascular endothelial growth factor C small interfering RNA and endostatin on esophageal squamous cell carcinoma-related ring formation in vitro and proliferation of lymphatic endothelial cells. MATERIALS AND METHODS: KYSE150 cells were subjected to analysis of cell transfection and endostatin operation. The groups were as follows: negative group, blank group, negative plus endostatin group, endostatin group, SG1 group, SG2 group, SG1 plus endostatin group, and SG2 plus endostatin group. The esophageal cancer-related microlymphatic endothelial cells were three-dimensionally cultured. Cell Counting Kit-8 (CCK-8) assay was employed to detect cell proliferation. RESULTS: The negative group's three-dimensional culture result was the highest, followed by the blank group, negative plus endostatin group, endostatin group, SG2 group, SG1 group, SG1 plus endostatin group, and SG2 plus endostatin group. The quantity of living cells in the blank group was the highest, followed by the negative control, endostatin, SG2, SG1, negative plus endostatin, SG1 plus endostatin, and SG2 plus endostatin groups. CONCLUSION: Both vascular endothelial growth factor C small interfering RNA and endostatin could inhibit ring formation in esophageal squamous cell carcinoma and proliferation of lymphatic endothelial cells.
Vascular Anomalies
Boccara, O., et al. (2016). “Kaposiform Haemangioendothelioma-spectrum Lesions with Kasabach-Merritt Phenomenon: Retrospective Analysis and Long-term Outcome.” Acta Derm Venereol 96(1): 77–81.
Brinjikji, W., et al. (2016). “Prevalence and characteristics of brain arteriovenous malformations in hereditary hemorrhagic telangiectasia: a systematic review and meta-analysis.” J Neurosurg: 1–9.
Brosig, C. L., et al. (2016). “Neurodevelopmental outcomes in children with PHACE Syndrome.” Pediatr Dermatol 33(4): 415–423.
Croteau, S. E. and D. Gupta (2016). “The clinical spectrum of kaposiform hemangioendothelioma and tufted angioma.” Semin Cutan Med Surg 35(3): 147–152.
Droege, F., et al. (2016). “Improvement in hereditary hemorrhagic telangiectasia after treatment with the multi-kinase inhibitor Sunitinib.” Ann Hematol 95(12): 2077–2078.
Frommelt, P., et al. (2016). “Adverse Events in Young and Preterm Infants Receiving Topical Timolol for Infantile Hemangioma.” Pediatr Dermatol 33(4): 405–414.
Galindo-Ferreiro, A., et al. (2016). “Recurrent Orbital Inflammation Mimicking Orbital Cellulitis Associated With Orbitopalpebral Venous Lymphatic Malformation.” Ophthal Plast Reconstr Surg. EPub Nov 24
Harbi, S., et al. (2016). “Infantile Hemangioma Originates From A Dysregulated But Not Fully Transformed Multipotent Stem Cell.” Sci Rep 6: 35811.
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. To understand the process of hemangioma-genesis we characterized the progenitor hemangioma-derived stem cell (HemSC) and its lineage and non-lineage derivatives. For this purpose we performed a high-throughput (HT) phenotypic and gene expression analysis of HemSCs, and analyzed HemSC-derived tumorspheres. 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. The potential biomarkers we identified can afford the development of diagnostic tools and precision-medicine therapies to “rewire” or redirect cellular transitions at an early stage, such as signaling pathways or immune response modifiers.
Ivars, M. and P. Redondo (2016). “Efficacy of topical sirolimus (rapamycin) for the treatment of microcystic lymphatic malformations.” JAMA Dermatol. EPub Oct 26
Jenkins, D., et al. (2016). “Tuberous sclerosis complex associated with vascular anomalies or overgrowth.” Pediatr Dermatol 33(5): 536–542.
Kaseka, M. L., et al. (2016). “Predictive factors for epilepsy in pediatric patients with Sturge-Weber Syndrome.” Pediatr Neurol. EPub Aug 18
Liu, X., et al. (2016). “Long noncoding RNA expression profile of infantile hemangioma identified by microarray analysis.” Tumour Biol. EPub Oct 5
Infantile hemangioma (IH) is one of the most common vascular tumors of childhood. Long noncoding RNAs (lncRNAs) play a critical role in angiogenesis, but their involvement in hemangioma remains unknown. This study aimed to assess the expression profiles of lncRNAs in IH and adjacent normal tissue samples, exploring the biological functions of lncRNAs as well as their involvement in IH pathogenesis. The lncRNA expression profiles were determined by lncRNA microarrays. A total of 1259 and 857 lncRNAs were upregulated and downregulated in IH, respectively, at a fold change cutoff of 2.0 (p < 0.05); in addition, 1469 and 1184 messenger RNAs (mRNAs) were upregulated and downregulated, respectively (fold change cutoff of 2.0; p < 0.05). A total of 292 differentially expressed mRNAs were targeted by the lncRNAs with altered expression in hemangioma, including 228 and 64 upregulated and downregulated, respectively (cutoff of 2.0, p < 0.05). Gene ontology (GO) analyses revealed several angiogenesis-related pathways. An lncRNA-mRNA co-expression network for differentially expressed lncRNAs revealed significant associations of the lncRNAs MEG3, MEG8, FENDRR, and Linc00152 with their related mRNAs. The validation results of nine differentially expressed lncRNAs (MALAT1, MEG3, MEG8, p29066, p33867, FENDRR, Linc00152, p44557_v4, p8683) as well as two mRNAs (FOXF1, EGFL7) indicated that the microarray data correlated well with the QPCR results. Interestingly, MALAT1 knockdown induced apoptosis and S-phase cell cycle arrest in human umbilical vein endothelial cells (HUVECs). Overall, this study revealed the lncRNA expression profile of IH and that lncRNAs likely regulate several genes with important roles in angiogenesis.
Lupa, M. D. and S. K. Wise (2016). “Comprehensive management of hereditary hemorrhagic telangiectasia.” Curr Opin Otolaryngol Head Neck Surg. EPub Nov 10
Ola, R., et al. (2016). “PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia.” Nat Commun 7: 13650.
Phillips, J. D., et al. (2016). “Expression of beta-adrenergic receptor subtypes in proliferative, involuted, and propranolol-responsive infantile hemangiomas.” JAMA Facial Plast Surg. EPub Oct 13
Importance: Propranolol hydrochloride has become the primary medical treatment for problematic infantile hemangioma; however, the expression of propranolol's target receptors during growth, involution, and treatment of hemangioma remains unclear. Objective: To measure and compare the expression of beta1-, beta2-, and beta3-adrenergic receptors (ADBR1, ADBR2, and ADBR3, respectively) in proliferative (n = 10), involuted (n = 11), and propranolol-responsive (n = 12) hemangioma tissue. Design, Setting, and Participants: Infantile hemangioma specimens were harvested for molecular investigation. Messenger RNA (mRNA) expression of the ADBR1, ADBR2, and ADBR3 genes was detected by real-time polymerase chain reaction. Protein level expression was measured by Western blot and standardized with densitometry. A total of 33 specimens were collected from patients in a tertiary pediatric hospital who underwent excision of problematic hemangiomas. This study was conducted from January 18, 2011, to September 24, 2013, and data analysis was performed from February 25, 2015, to June 25, 2016. Results: Of the 33 patients included, 21 were female (64%). The mean (SD) patient age at the time of excision was 7 (2.5) months for the proliferative group lesions, 23.5 (10) months for the involuted group, and 16 (10) months for the propranolol group. The mean level of ADBR1 mRNA expression was significantly higher in proliferative hemangioma than in propranolol-responsive hemangioma (1.05 [0.56] vs 0.52 [0.36]; P = .01; 95% CI, 0.12–0.94). There was no difference in ADBR2 expression among the groups. Protein expression of ADBR3 was significantly higher in involuted (0.64 [0.12] vs 0.26 [0.04]; P < .01; 95% CI, 0.26–0.49) and propranolol-responsive hemangioma (0.66 [0.31] vs 0.26 [0.04]; P = .01; 95% CI, 0.16–0.68) compared with proliferative hemangioma. Conclusions and Relevance: These data demonstrate the variable expression of ADBR subtypes among infantile hemangiomas during growth, involution, and response to treatment. These findings may have clinical implications regarding the use of selective vs nonselective beta-blockade. Level of Evidence: 2.
Ruiz, S., et al. (2016). “A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10.” Sci Rep 5: 37366.
Soblet, J., et al. (2016). “Blue Rubber Bleb Nevus (BRBN) Syndrome is caused by somatic TEK (TIE2) mutations.” J Invest Dermatol. Aug 9
Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.
Tan, E. M., et al. (2016). “Neuropeptide Y receptor 1 is expressed by B and T lymphocytes and mast cells in infantile haemangiomas.” Acta Paediatr. EPub Nov 27
AIM: We investigated the expression of neuropeptide Y (NPY), NPY receptor 1 (NPYR1) and NPY receptor 2 (NPYR2) in infantile haemangiomas (IHs). METHODS: Immunohistochemical (IHC) staining was performed on proliferating IHs from six patients aged 4–13 (mean 8.7) months and involuted IHs from six patients aged 5–59 (mean 18.7) years, for the expression of NPY, NPYR1 and NPYR2. Protein and messenger ribonucleic acid expression corresponding to these proteins was investigated by Western blotting and NanoString analysis, respectively. RESULTS: IHC staining, Western blotting and NanoString analysis demonstrated the presence of NPYR1, but not NPYR2, within proliferating and involuted IHs. IHC staining showed NPYR1 was expressed by B and T lymphocytes expressing CD45 and mast cells expressing tryptase. IHC staining demonstrated the presence of NPY on NPYR1+ cells, but it was not detected by Western blotting or NanoString analysis. CONCLUSION: NPYR1, but not NPYR2, was present in IHs. The localisation of NPYR1 to B and T lymphocytes and mast cells suggests its role in the biology of IHs. The demonstration of NPY on the NPYR1+ cells, without active transcription, suggests that NPY was not being produced within IHs. This article is protected by copyright. All rights reserved.
Wetzel-Strong, S. E., et al. (2016). “The pathobiology of vascular malformations: insights from human and model organism genetics.” J Pathol. EPub Nov 9
Vascular malformations may arise in any of the vascular beds present in the human body. These lesions vary in location, type, and clinical severity of the phenotype. In recent years, the genetic basis of several vascular malformations has been elucidated. This review will consider how the identification of the genetic factors contributing to different vascular malformations, with subsequent functional studies in animal models, has provided a better understanding of these factors that maintain vascular integrity in vascular beds, as well as their role in the pathogenesis of vascular malformations.