Lymphatic malformations and lymphatic-derived tumors commonly involve the head and neck, where they may be associated with bony abnormalities and other systemic symptoms. The reasons for the association between these disorders and local skeletal changes are largely unknown, but such changes may cause significant disease-related morbidity. Ongoing work in molecular and developmental biology is beginning to uncover potential reasons for the bony abnormalities found in head and neck lymphatic disease; this article summarizes current knowledge on possible mechanisms underlying this association.
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References
1.
PerkinsJA, ManningSC, TemperoRM, CunninghamMJ, EdmondsJLJr, HofferFA, EgbertMA. Lymphatic malformations: Review of current treatment. Otolaryngol Head Neck Surg, 2010; 142:795–803.
LeeS, FinnL, SzeRW, PerkinsJA, SieKC. Gorham Stout syndrome (disappearing bone disease): Two additional case reports and a review of the literature. Arch Otolaryngol Head Neck Surg, 2003; 129:1340–1343.
4.
OsborneTE, LevinLS, TilghmanDM, HallerJA. Surgical correction of mandibulofacial deformities secondary to large cervical cystic hygromas. J Oral Maxillofac Surg, 1987; 45:1015–1021.
LuP, TakaiK, WeaverVM, WerbZ. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol., 2011Dec13,12:pii:a005058, 10.1101/cghperspect.a005058.
JinZW, NakamuraT, YuHC, KimuraW, MurakamiG, ChoBH. Fetal anatomy of peripheral lymphatic vessels: A D2-40 immunohistochemical study using an 18-week human fetus (CRL 155mm)J Anat, 2010; 216:671–682.
9.
OTM, KwakR, PortnofJE, BerkeDM, LipariB, WanerM. Analysis of skeletal mandibular abnormalities associated with cervicofacial lymphatic malformations. Laryngoscope, 2011; 121:91–101.
10.
ZukerbergLR, NickoloffBJ, WeissSW. Kaposiform hemangioendothelioma of infancy and childhood: An aggressive neoplasm associated with Kasabach-Merritt syndrome and lymphangiomatosis. Am J Surg Pathol, 1993; 17:321–328.
11.
FranchiA, BertoniF, BacchiniP, MourmourasV, MiraccoC. CD105/endoglin expression in Gorham disease of bone. J Clin Pathol, 2009; 62:163–167.
12.
CushingSL, IshakG, PerkinsJA, RubinsteinJT. Gorham-Stout syndrome of the petrous apex causing chronic cerebrospinal fluid leak. Otol Neurotol, 2010; 31:789–792.
13.
TemperoRM, HannibalM, FinnLS, ManningSC, CunninghamML, PerkinsJA. Lymphocytopenia in children with lymphatic malformations. Arch Otolaryngol Head Neck Surg, 2006; 132:93–97.
14.
PerkinsJA, TemperoRM, HannibalMC, ManningSC. Clinical outcomes in lymphocytopenic lymphatic malformation patients. Lymphat Res Biol, 2007; 5:169–174.
15.
HallAP, WestwoodFR, WadsworthPF. Review of the effects of anti-angiogenic compounds on the epiphyseal growth plate. Toxicol Pathol, 2006; 34:131–147.
16.
DaleyWP, PetersSB, LarsenM. Extracellular matrix dynamics in development and regenerative medicine. J Cell Sci, 2007; 121:255–264.
17.
DavisGE, SengerDR. Endothelial extracellular matrix: Biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circ Res, 2055; 97:1093–1107.
18.
MaesC, KobayashiT, SeligMK, TorrekensS, RothSI, MackemS, CarmelietG, KronenbergHM. Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev Cell, 2010; 19:329–344.
19.
WiltingJ, BeckerJ. Two endothelial cell lines derived from the somite. Anat Embryol (Berl), 2006; 211:57–63.
20.
DalalS, BerryAM, CullinaneCJ, ManghamDC, GrimerR, LewisIJ, JohnstonC, LaurenceV, BurchillSA. Vascular endothelial growth factor: A therapeutic target for tumors of the Ewing's sarcoma family. Clin Cancer Res, 2055; 11:2364–2378.
21.
RiaR, VaccaA, RussoF, CirulliT, MassaiaM, TosiP, CavoM, GuidolinD, RibattiD, DammaccoF. A VEGF-dependent autocrine loop mediates proliferation and capillarogenesis in bone marrow endothelial cells of patients with multiple myeloma. Thromb Haemost, 2004; 92:1438–1445.
22.
ReddyK, CaoY, ZhouZ, YuL, JiaSF, KleinermanES. VEGF165 expression in the tumor microenvironment influences the differentiation of bone marrow-derived pericytes that contribute to the Ewing's sarcoma vasculature. Angiogenesis, 2008; 11:257–267.
23.
GrunewaldM, AvrahamI, DorY, Bachar-LustigE, ItinA, YungS, ChimentiS, LandsmanL, AbramovitchR, KeshetE. VEGF-induced adult neovascularization: Recruitment, retention, and role of accessory cells. Cell, 2006; 124:175–189.
24.
StratmanAN, DavisMJ, DavisGE. VEGF and FGF prime vascular tube morphogenesis and sprouting directed by hematopoietic stem cell cytokines. Blood, 2011; 117:3709–3719.
25.
TanakaY, AbeM, HiasaM, OdaA, AmouH, NakanoA, TakeuchiK, KitazoeK, KidoS, InoueD, MoriyamaK, HashimotoT, OzakiS, MatsumotoT. Myeloma cell–osteoclast interaction enhances angiogenesis together with bone resorption: A role for vascular endothelial cell growth factor and osteopontin. Clin Cancer Res, 2007; 13:816–823.
26.
JacobsenKA, Al-AqlZS, WanC, FitchJL, StapletonSN, MasonZD, ColeRM, GilbertSR, ClemensTL, MorganEF, EinhornTA, GerstenfeldLC. Bone formation during distraction osteogenesis is dependent on both VEGFR1 and VEGFR2 signaling. J Bone Miner Res, 2008; 23:596–609.
SalvenP, MustjokiS, AlitaloR, AlitaloK, RafiiS. VEGFR-3 and CD133 identify a population of CD34+ lymphatic/vascular endothelial precursor cells. Blood, 2003; 101:168–172.
34.
NyA, KochM, VandeveldeW, SchneiderM, FischerC, Diez-JuanA, NevenE, GeudensI, MaityS, MoonsL, PlaisanceS, LambrechtsD, CarmelietP, DewerchinM. Role of VEGF-D and VEGFR-3 in developmental lymphangiogenesis, a chemicogenetic study in Xenopus tadpoles. Blood, 2008; 112:1740–1749.
35.
CursiefenC, ChenL, BorgesLP, JacksonD, CaoJ, RadziejewskiC, D'AmorePA, DanaMR, WiegandSJ, StreileinJW. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest, 2004; 113:1040–1050.
36.
KilicN, Oliveira-FerrerL, Neshat0, VahidS, IrmakS, Obst-PernbergK, WurmbachJ-H, LogesS, KilicE, WeilJ, LaukeH, TilkiD, SingerBB, ErgunS. Lymphatic reprogramming of microvascular endothelial cells by CEA-related cell adhesion molecule-1 via interaction with VEGFR-3 and Prox1. Blood, 2007; 110:4223–4233.
37.
JellG, KerjaschkiD, RevellP, Al-SaffarN. Lymphangiogenesis in the bone-implant interface of orthopedic implants: Importance and consequence. J Biomed Mater Res, 2006; 77A:119–127.
38.
WiltingJ, ButtlerK, RosslerJ, NorgallS, SchweigererL, WeichHA, PapoutsiM. Embryonic development and malformation of lymphatic vessels. Novartis Found Symp, 2007; 283:220–227.
39.
KellyK, HutchinsonG, Nebenius-OosthuizenD, SmithAJ, BartschJW, HoriuchiK, RittgerA, ManovaK, DochertyAJ, BlobelCP. Metalloprotease-disintegrin ADAM8: Expression analysis and targeted deletion in mice. Dev Dyn, 2005; 232:221–231.
40.
BennuruS, NutmanTB. Lymphangiogenesis and lymphatic remodeling induced by filarial parasites: Implications for pathogenesis. PLoS Pathog, 2009; 5:e1000688.
41.
MarlerJJ, FishmanSJ, KilroySM, FangJ, UptonJ, MullikenJB, BurrowsPE, ZurakowskiD, FolkmanJ, MosesMA. Increased expression of urinary matrix metalloproteinases parallels the extent and activity of vascular anomalies. Pediatrics, 2005; 116:38–45.
42.
OrtegaN, BehonickD, StickensD, WerbZ. How proteases regulate bone morphogenesis. Ann NY Acad Sci, 2003; 995:109–116.
43.
LieuS, HansenE, DediniR, BehonickD, WerbZ, MiclauT, MarcucioR, ColnotC. Impaired remodeling phase of fracture repair in the absence of matrix metalloproteinase-2. Dis Model Mech, 2011; 4:203–211.
44.
CaoX, ChenD. The BMP signaling and in vivo bone formation. Gene, 2005; 357:1–8.
45.
BoydNL, DharaSK, RekayaR, GodbeyEA, HasneenK, RaoRR, WestFDIII, GerweBA, SticeSL. BMP4 promotes formation of primitive vascular networks in human embryonic stem cell-derived embryoid bodies. Exp Biol Med, 2007; 232:833–843.
46.
BressanM, DavisP, TimmerJ, HerzlingerD, MikawaT. Notochord-derived BMP antagonists inhibit endothelial cell generation and network formation. Dev Biol, 2009; 326:101–111.
47.
KloenP, DiPaolaM, BorensO, RichmondJ, PerinoG, HelfetDL, GoumansMJ. BMP signaling components are expressed in human fracture callus. Bone, 2003; 33:362–371.
48.
LesiakM, Augusciak-DumaA, SzydloA, SieronA. Blocking angiogenesis with peptides that inhibit the activity of procollagen C-endopeptidase. Pharmacol Rep, 2009; 61:468–476.
49.
ZhaoM, HarrisSE, HornD, GengZ, NishimuraR, MundyG, ChenD. Bone morphogenetic protein receptor signaling is necessary for normal murine postnatal bone formation. J Cell Biol, 2002; 157:1049–1060.
50.
WigleJT, OliverG. Prox1 function is required for the development of the murine lymphatic system. Cell, 1999; 98:769–778.
51.
HongY-K, HarveyN, NohY-H, SchachtV, HirakawaS, DetmarM, OliverG. Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn, 2002; 225:351–357.
52.
YoshimatsuY, YamazakiT, MihiraH, ItohT, SuehiroJ, YukiK, HaradaK, MorikawaM, IwataC, MinamiT, MorishitaY, KodamaT, MiyazonoK, WatabeT. Ets family members induce lymphangiogenesis through physical and functional interaction with Prox1. J Cell Sci, 2011; 124:2753–2762.
MaruyaamaK, AsaiJ, IiM, ThorneT, LosordoDW, D'AmorePA. Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing. Am J Pathol, 2007; 1270:1178–1191.
55.
MurakamiM, ZhengY, HirashimaM, SudaT, MoritaY, OoeharaJ, EmaH, FongG-H, ShibuyaM. VEGFR1 tyrosine kinase signaling promotes lymphangiogenesis as well as angiogenesis indirectly via macrophage recruitment. Arterioscler Thromb Vasc Biol, 2008; 28:658–664.
56.
De BenedettiF. The impact of chronic inflammation on the growing skeleton: Lessons from interleukin-6 transgenic mice. Horm Res, 2009; 72:26–29.
57.
TobenD, SchroederI, El KhassawnaT, MehtaM, HoffmannJE, FrischJT, SchellH, LienauJ, SerraA, RadbruchA, DudaGN. Fracture healing is accelerated in the absence of the adaptive immune system. J Bone Miner Res, 2011; 26:113–124.
58.
AikawaE, NahrendorfM, FigueiredoJL, SwirskiFK, ShtatlandT, KohlerRH, JafferFA, AikawaM, WeisslederR. Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation, 2007; 116:2841–2850.
59.
RajamannanNM, NealisTB, SubramaniamM, PandyaS, StockSR, IgnatievCI, SeboTJ, RosengartTK, EdwardsWD, McCarthyPM, BonowRO, SpelsbergTC. Calcified rheumatic valve neoangiogenesis is associated with vascular endothelial growth factor expression and osteoblast-like bone formation. Circulation, 2005; 111:3296–3301.
