Lymphovascular Genomics and Proteomics, Clinical Syndromes, and Cancer Metastasis

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Cancer Metastasis Through the Lymphovascular System

Abstract

The number of genetic mutations that cause lymphedema and other diseases of the lymphatic system has significantly grown in recent years. This information has shed light on the molecular mechanisms controlling the development of the lymphatic system and has increased our understanding of the etiology of inherited and non-inherited diseases of the lymphatic system. Here, we briefly describe the different genetic mutations that cause diseases of the lymphatic system, some of which are also mutated in some cancers. Additionally, we discuss the similarities between lymphatic diseases and cancer.

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References

  1. Fang J, Dagenais SL, Erickson RP, Arlt MF, Glynn MW, Gorski JL, Seaver LH, Glover TW. Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet. 2000;67(6):1382–8. https://doi.org/10.1086/316915.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ferrell RE, Levinson KL, Esman JH, Kimak MA, Lawrence EC, Barmada MM, Finegold DN. Hereditary lymphedema: evidence for linkage and genetic heterogeneity. Hum Mol Genet. 1998;7(13):2073–8.

    Article  CAS  Google Scholar 

  3. Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, Fryns JP, Van Steensel MA, Vikkula M. Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am J Hum Genet. 2003;72(6):1470–8. https://doi.org/10.1086/375614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wigle JT, Oliver G. Prox1 function is required for the development of the murine lymphatic system. Cell. 1999;98(6):769–78. doi:S0092-8674(00)81511-1 [pii]

    Article  CAS  Google Scholar 

  5. Johnson NC, Dillard ME, Baluk P, McDonald DM, Harvey NL, Frase SL, Oliver G. Lymphatic endothelial cell identity is reversible and its maintenance requires Prox1 activity. Genes Dev. 2008;22(23):3282–91. https://doi.org/10.1101/gad.1727208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Scheuerle AE, Sweed NT, Timmons CF, Smith ED, Alcaraz WA, Shinde DN. An additional case of Hennekam lymphangiectasia-lymphedema syndrome caused by loss-of-function mutation in ADAMTS3. Am J Med Genet A. 2018;176(12):2858–61. https://doi.org/10.1002/ajmg.a.40633.

    Article  CAS  PubMed  Google Scholar 

  7. Gordon K, Schulte D, Brice G, Simpson MA, Roukens MG, van Impel A, Connell F, Kalidas K, Jeffery S, Mortimer PS, Mansour S, Schulte-Merker S, Ostergaard P. Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant Milroy-like primary lymphedema. Circ Res. 2013;112(6):956–60. https://doi.org/10.1161/CIRCRESAHA.113.300350.

    Article  CAS  PubMed  Google Scholar 

  8. Song E, Mao T, Dong H, Boisserand LSB, Antila S, Bosenberg M, Alitalo K, Thomas JL, Iwasaki A. VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours. Nature. 2020;577(7792):689–94. https://doi.org/10.1038/s41586-019-1912-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Michelini S, Paolacci S, Manara E, Eretta C, Mattassi R, Lee BB, Bertelli M. Genetic tests in lymphatic vascular malformations and lymphedema. J Med Genet. 2018;55(4):222–32. https://doi.org/10.1136/jmedgenet-2017-105064.

    Article  CAS  PubMed  Google Scholar 

  10. Sabine A, Saygili Demir C, Petrova TV. Endothelial cell responses to biomechanical forces in lymphatic vessels. Antioxid Redox Signal. 2016;25(7):451–65. https://doi.org/10.1089/ars.2016.6685.

    Article  CAS  PubMed  Google Scholar 

  11. Kazenwadel J, Betterman KL, Chong CE, Stokes PH, Lee YK, Secker GA, Agalarov Y, Demir CS, Lawrence DM, Sutton DL, Tabruyn SP, Miura N, Salminen M, Petrova TV, Matthews JM, Hahn CN, Scott HS, Harvey NL. GATA2 is required for lymphatic vessel valve development and maintenance. J Clin Invest. 2015;125(8):2979–94. https://doi.org/10.1172/JCI78888.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Petrova TV, Karpanen T, Norrmen C, Mellor R, Tamakoshi T, Finegold D, Ferrell R, Kerjaschki D, Mortimer P, Yla-Herttuala S, Miura N, Alitalo K. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat Med. 2004;10(9):974–81. https://doi.org/10.1038/nm1094nm1094.

    Article  CAS  PubMed  Google Scholar 

  13. Erickson RP, Lai LW, Mustacich DJ, Bernas MJ, Kuo PH, Witte MH. Sex-limited penetrance of lymphedema to females with CELSR1 haploinsufficiency: a second family. Clin Genet. 2019;96(5):478–82. https://doi.org/10.1111/cge.13622.

    Article  CAS  PubMed  Google Scholar 

  14. Kanady JD, Simon AM. Lymphatic communication: connexin junction, what's your function? Lymphology. 2011;44(3):95–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Kanady JD, Dellinger MT, Munger SJ, Witte MH, Simon AM. Connexin37 and Connexin43 deficiencies in mice disrupt lymphatic valve development and result in lymphatic disorders including lymphedema and chylothorax. Dev Biol. 2011;354(2):253–66. https://doi.org/10.1016/j.ydbio.2011.04.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ferrell RE, Baty CJ, Kimak MA, Karlsson JM, Lawrence EC, Franke-Snyder M, Meriney SD, Feingold E, Finegold DN. GJC2 missense mutations cause human lymphedema. Am J Hum Genet. 2010;86(6):943–8. https://doi.org/10.1016/j.ajhg.2010.04.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Brice G, Ostergaard P, Jeffery S, Gordon K, Mortimer PS, Mansour S. A novel mutation in GJA1 causing oculodentodigital syndrome and primary lymphoedema in a three generation family. Clin Genet. 2013;84(4):378–81. https://doi.org/10.1111/cge.12158.

    Article  CAS  PubMed  Google Scholar 

  18. Mustacich DJ, Kylat RI, Bernas MJ, Myles RJ, Jones JA, Kanady JD, Simon AM, Georgieva TG, Witte MH, Erickson RP, Pires PW. Abnormal lymphatic phenotype in a crispr mouse model of the human lymphedema-causing connexin47 R260c point mutation. Lymphology. 2021;54:78–91.

    Google Scholar 

  19. Finegold DN, Baty CJ, Knickelbein KZ, Perschke S, Noon SE, Campbell D, Karlsson JM, Huang D, Kimak MA, Lawrence EC, Feingold E, Meriney SD, Brufsky AM, Ferrell RE. Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment. Clin Cancer Res. 2012;18(8):2382–90. https://doi.org/10.1158/1078-0432.CCR-11-2303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Newman B, Lose F, Kedda MA, Francois M, Ferguson K, Janda M, Yates P, Spurdle AB, Hayes SC. Possible genetic predisposition to lymphedema after breast cancer. Lymphat Res Biol. 2012;10(1):2–13. https://doi.org/10.1089/lrb.2011.0024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Choi D, Park E, Jung E, Seong YJ, Hong M, Lee S, Burford J, Gyarmati G, Peti-Peterdi J, Srikanth S, Gwack Y, Koh CJ, Boriushkin E, Hamik A, Wong AK, Hong YK. ORAI1 activates proliferation of lymphatic endothelial cells in response to laminar flow through Kruppel-like factors 2 and 4. Circ Res. 2017;120(9):1426–39. https://doi.org/10.1161/CIRCRESAHA.116.309548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nonomura K, Lukacs V, Sweet DT, Goddard LM, Kanie A, Whitwam T, Ranade SS, Fujimori T, Kahn ML, Patapoutian A. Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation. Proc Natl Acad Sci U S A. 2018;115(50):12817–22. https://doi.org/10.1073/pnas.1817070115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang Y, Baeyens N, Corti F, Tanaka K, Fang JS, Zhang J, ** Y, Coon B, Hirschi KK, Schwartz MA, Simons M. Syndecan 4 controls lymphatic vasculature remodeling during mouse embryonic development. Development. 2016;143(23):4441–51. https://doi.org/10.1242/dev.140129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yang Y, Cha B, Motawe ZY, Srinivasan RS, Scallan JP. VE-cadherin is required for lymphatic valve formation and maintenance. Cell Rep. 2019;28(9):2397–412. e2394. https://doi.org/10.1016/j.celrep.2019.07.072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Boucher CA, Sargent CA, Ogata T, Affara NA. Breakpoint analysis of turner patients with partial Xp deletions: implications for the lymphoedema gene location. J Med Genet. 2001;38(9):591–8. https://doi.org/10.1136/jmg.38.9.591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lee BB, Andrade M, Antignani PL, Boccardo F, Bunke N, Campisi C, Damstra R, Flour M, Forner-Cordero I, Gloviczki P, Laredo J, Partsch H, Piller N, Michelini S, Mortimer P, Rabe E, Rockson S, Scuderi A, Szolnoky G, Villavicencio JL, International Union of P (2013) Diagnosis and treatment of primary lymphedema. Consensus document of the International Union of Phlebology (IUP)-2013. Int Angiol 32 (6):541–574.

    Google Scholar 

  27. Makinen T, Adams RH, Bailey J, Lu Q, Ziemiecki A, Alitalo K, Klein R, Wilkinson GA. PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev. 2005;19(3):397–410. https://doi.org/10.1101/gad.330105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li D, Wenger TL, Seiler C, March ME, Gutierrez-Uzquiza A, Kao C, Bhoj E, Tian L, Rosenbach M, Liu Y, Robinson N, Behr M, Chiavacci R, Hou C, Wang T, Bakay M, Pellegrino da Silva R, Perkins JA, Sleiman P, Levine MA, Hicks PJ, Itkin M, Dori Y, Hakonarson H. Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly. Hum Mol Genet. 2018;27(18):3233–45. https://doi.org/10.1093/hmg/ddy218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Martin-Almedina S, Martinez-Corral I, Holdhus R, Vicente A, Fotiou E, Lin S, Petersen K, Simpson MA, Hoischen A, Gilissen C, Jeffery H, Atton G, Karapouliou C, Brice G, Gordon K, Wiseman JW, Wedin M, Rockson SG, Jeffery S, Mortimer PS, Snyder MP, Berland S, Mansour S, Makinen T, Ostergaard P. EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis. J Clin Invest. 2016;126(8):3080–8. https://doi.org/10.1172/JCI85794.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Dellinger M, Hunter R, Bernas M, Gale N, Yancopoulos G, Erickson R, Witte M. Defective remodeling and maturation of the lymphatic vasculature in Angiopoietin-2 deficient mice. Dev Biol. 2008;319(2):309–20. https://doi.org/10.1016/j.ydbio.2008.04.024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Souma T, Thomson BR, Heinen S, Carota IA, Yamaguchi S, Onay T, Liu P, Ghosh AK, Li C, Eremina V, Hong YK, Economides AN, Vestweber D, Peters KG, ** J, Quaggin SE. Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP. Proc Natl Acad Sci U S A. 2018;115(6):1298–303. https://doi.org/10.1073/pnas.1714446115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Leppanen VM, Brouillard P, Korhonen EA, Sipila T, Jha SK, Revencu N, Labarque V, Fastre E, Schlogel M, Ravoet M, Singer A, Luzzatto C, Angelone D, Crichiutti G, D'Elia A, Kuurne J, Elamaa H, Koh GY, Saharinen P, Vikkula M, Alitalo K. Characterization of ANGPT2 mutations associated with primary lymphedema. Sci Transl Med. 2020;12(560) https://doi.org/10.1126/scitranslmed.aax8013.

  33. Wassef M, Blei F, Adams D, Alomari A, Baselga E, Berenstein A, Burrows P, Frieden IJ, Garzon MC, Lopez-Gutierrez JC, Lord DJ, Mitchel S, Powell J, Prendiville J, Vikkula M, Committee. IBaS. Vascular anomalies classification: recommendations from the International Society for the Study of vascular anomalies. Pediatrics. 2015;136(1):e203–14. https://doi.org/10.1542/peds.2014-3673.

    Article  PubMed  Google Scholar 

  34. Trenor CC 3rd, Chaudry G. Complex lymphatic anomalies. Semin Pediatr Surg. 2014;23(4):186–90. https://doi.org/10.1053/j.sempedsurg.2014.07.006.

    Article  PubMed  Google Scholar 

  35. Boscolo E, Coma S, Luks VL, Greene AK, Klagsbrun M, Warman ML, Bischoff J. AKT hyper-phosphorylation associated with PI3K mutations in lymphatic endothelial cells from a patient with lymphatic malformation. Angiogenesis. 2015;18(2):151–62. https://doi.org/10.1007/s10456-014-9453-2.

    Article  CAS  PubMed  Google Scholar 

  36. Osborn AJ, Dickie P, Neilson DE, Glaser K, Lynch KA, Gupta A, Dickie BH. Activating PIK3CA alleles and lymphangiogenic phenotype of lymphatic endothelial cells isolated from lymphatic malformations. Hum Mol Genet. 2015;24(4):926–38. https://doi.org/10.1093/hmg/ddu505.

    Article  CAS  PubMed  Google Scholar 

  37. Lala S, Mulliken JB, Alomari AI, Fishman SJ, Kozakewich HP, Chaudry G. Gorham-Stout disease and generalized lymphatic anomaly-clinical, radiologic, and histologic differentiation. Skelet Radiol. 2013;42:917–24. https://doi.org/10.1007/s00256-012-1565-4.

    Article  Google Scholar 

  38. Luks VL, Kamitaki N, Vivero MP, Uller W, Rab R, Bovee JV, Rialon KL, Guevara CJ, Alomari AI, Greene AK, Fishman SJ, Kozakewich HP, Maclellan RA, Mulliken JB, Rahbar R, Spencer SA, Trenor CC 3rd, Upton J, Zurakowski D, Perkins JA, Kirsh A, Bennett JT, Dobyns WB, Kurek KC, Warman ML, SA MC, Murillo R. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatrics. 2015;166(4):1048–54. e1041–1045. https://doi.org/10.1016/j.jpeds.2014.12.069.

    Article  CAS  Google Scholar 

  39. Rodriguez-Laguna L, Agra N, Ibanez K, Oliva-Molina G, Gordo G, Khurana N, Hominick D, Beato M, Colmenero I, Herranz G, Torres Canizalez JM, Rodriguez Pena R, Vallespin E, Martin-Arenas R, Del Pozo A, Villaverde C, Bustamante A, Ayuso C, Lapunzina P, Lopez-Gutierrez JC, Dellinger MT, Martinez-Glez V. Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly. J Exp Med. 2019;216(2):407–18. https://doi.org/10.1084/jem.20181353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Adams DM, Trenor CC 3rd, Hammill AM, Vinks AA, Patel MN, Chaudry G, Wentzel MS, Mobberley-Schuman PS, Campbell LM, Brookbank C, Gupta A, Chute C, Eile J, McKenna J, Merrow AC, Fei L, Hornung L, Seid M, Dasgupta AR, Dickie BH, Elluru RG, Lucky AW, Weiss B, Azizkhan RG. Efficacy and safety of Sirolimus in the treatment of complicated vascular anomalies. Pediatrics. 2016;137(2):1–10. https://doi.org/10.1542/peds.2015-3257.

    Article  Google Scholar 

  41. Ricci KW, Hammill AM, Mobberley-Schuman P, Nelson SC, Blatt J, Bender JLG, McCuaig CC, Synakiewicz A, Frieden IJ, Adams DM. Efficacy of systemic sirolimus in the treatment of generalized lymphatic anomaly and Gorham-Stout disease. Pediatr Blood Cancer. 2019;66(5):e27614. https://doi.org/10.1002/pbc.27614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Strychowsky JE, Rahbar R, O'Hare MJ, Irace AL, Padua H, Trenor CC 3rd. Sirolimus as treatment for 19 patients with refractory cervicofacial lymphatic malformation. Laryngoscope. 2018;128(1):269–76. https://doi.org/10.1002/lary.26780.

    Article  CAS  PubMed  Google Scholar 

  43. Li D, March ME, Gutierrez-Uzquiza A, Kao C, Seiler C, Pinto E, Matsuoka LS, Battig MR, Bhoj EJ, Wenger TL, Tian L, Robinson N, Wang T, Liu Y, Weinstein BM, Swift M, Jung HM, Kaminski CN, Chiavacci R, Perkins JA, Levine MA, Sleiman PMA, Hicks PJ, Strausbaugh JT, Belasco JB, Dori Y, Hakonarson H. ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor. Nat Med. 2019;25(7):1116–22. https://doi.org/10.1038/s41591-019-0479-2.

    Article  CAS  PubMed  Google Scholar 

  44. Croteau SE, Kozakewich HP, Perez-Atayde AR, Fishman SJ, Alomari AI, Chaudry G, Mulliken JB, Trenor CC 3rd. Kaposiform lymphangiomatosis: a distinct aggressive lymphatic anomaly. J Pediatr. 2014;164(2):383–8. https://doi.org/10.1016/j.jpeds.2013.10.013.

    Article  PubMed  Google Scholar 

  45. Ozeki M, Fu**o A, Matsuoka K, Nosaka S, Kuroda T, Fukao T. Clinical features and prognosis of generalized lymphatic anomaly, Kaposiform Lymphangiomatosis, and Gorham-Stout disease. Pediatr Blood Cancer. 2016;63(5):832–8. https://doi.org/10.1002/pbc.25914.

    Article  PubMed  Google Scholar 

  46. Manevitz-Mendelson E, Leichner GS, Barel O, Davidi-Avrahami I, Ziv-Strasser L, Eyal E, Pessach I, Rimon U, Barzilai A, Hirshberg A, Chechekes K, Amariglio N, Rechavi G, Yaniv K, Greenberger S. Somatic NRAS mutation in patient with generalized lymphatic anomaly. Angiogenesis. 2018;21(2):287–98. https://doi.org/10.1007/s10456-018-9595-8.

    Article  CAS  PubMed  Google Scholar 

  47. Barclay SF, Inman KW, Luks VL, McIntyre JB, Al-Ibraheemi A, Church AJ, Perez-Atayde AR, Mangray S, Jeng M, Kreimer SR, Walker L, Fishman SJ, Alomari AI, Chaudry G, Trenor Iii CC, Adams D, Kozakewich HPW, Kurek KC. A somatic activating NRAS variant associated with kaposiform lymphangiomatosis. Genet Med. 2019;21(7):1517–24. https://doi.org/10.1038/s41436-018-0390-0.

    Article  CAS  PubMed  Google Scholar 

  48. Ozeki M, Aoki Y, Nozawa A, Yasue S, Endo S, Hori Y, Matsuoka K, Niihori T, Funayama R, Shirota M, Nakayama K, Fukao T. Detection of NRAS mutation in cell-free DNA biological fluids from patients with kaposiform lymphangiomatosis. Orphanet J Rare Dis. 2019;14(1):215. https://doi.org/10.1186/s13023-019-1191-5.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Foster JB, Li D, March ME, Sheppard SE, Adams DM, Hakonarson H, Dori Y. Kaposiform lymphangiomatosis effectively treated with MEK inhibition. EMBO Mol Med. 2020:e12324. https://doi.org/10.15252/emmm.202012324.

  50. Dellinger MT, Garg N, Olsen BR. Viewpoints on vessels and vanishing bones in Gorham-Stout disease. Bone. 2014;63:47–52. https://doi.org/10.1016/j.bone.2014.02.011.

    Article  PubMed  Google Scholar 

  51. Gorham LW, Stout AP. Massive osteolysis (acute spontaneous absorption of bone, phantom bone, disappearing bone); its relation to hemangiomatosis. J Bone Joint Surg Am. 1955;37-A(5):985–1004.

    Article  CAS  Google Scholar 

  52. Nozawa A, Ozeki M, Niihori T, Suzui N, Miyazaki T, Aoki Y. A somatic activating KRAS variant identified in an affected lesion of a patient with Gorham-Stout disease. J Hum Genet. 2020; https://doi.org/10.1038/s10038-020-0794-y.

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Erickson, R.P., Dellinger, M.T. (2022). Lymphovascular Genomics and Proteomics, Clinical Syndromes, and Cancer Metastasis. In: Leong, S.P., Nathanson, S.D., Zager, J.S. (eds) Cancer Metastasis Through the Lymphovascular System. Springer, Cham. https://doi.org/10.1007/978-3-030-93084-4_23

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