Abstract

Primary cutaneous T-cell lymphomas are a group of rare hematologic malignancies, derived from mature T lymphocytes and initially developing only in the skin. The most common lymphomas representing this group are mycosis fungoides and Sezary syndrome. Mycosis fungoides is an indolent disease with a chronic course and characteristic evolution of the skin lesions from erythematous patches, through plaques to tumors. Sezary syndrome is characterized by an aggressive course and a triad of symptoms (erythroderma, generalized lymphadenopathy, and the presence of atypical cells in the skin, lymph nodes and peripheral blood). The etiopathogenesis of cutaneous lymphomas is not fully understood, but a few studies on angiogenesis and lymphangiogenesis in these malignancies indicate a significant role in their development and progression. Angiogenesis is a process of formation of new blood vessels from existing ones. Lymphangiogenesis is a similar process concerning lymphatic vasculature. Development of new vessels is a complex process composed of several successive stages: migration, proliferation, and differentiation of endothelial cells, extracellular matrix degradation and formation and stabilization of new vessels, regulated by growth factors, cytokines and other proteins. Both phenomena are essential in the development and progression of solid tumors and hematological malignancies. Therapeutic strategies involving the inhibition of tumor angiogenesis and lymphangiogenesis are a promising new direction of studies in antitumor therapy, requiring further experiments.

References

• 1. Aref S., Mabed M., Zalata K., Sakarana M., El Askalany H.: The interplaybetween c-myc oncogene expression and circulating vascularendothelial growth factor (sVEGF), its antagonist receptor, solubleFlt-1 in diffuse large B cell lymphoma (DLBCL): relationship to patientoutcome. Leuk. Lymphoma, 2004; 45: 499-506
  Google Scholar
• 2. Autiero M., Waltenberger J., Communi D., Kranz A., Moons L.,Lambrechts D,. Kroll J., Plaisance S., De Mol M., Bono F., Kliche S.,Fellbrich G., Ballmer-Hofer K., Maglione D., Mayr-Beyrle U. i wsp.:Role of PIGF in the intra – and intermolecular cross talk between theVEGF receptors Flt1 and Flk1. Nat. Med., 2003; 9: 936-943
  Google Scholar
• 3. Buckstein R., Meyer R.M., Seymour L., Biagi J., Mackay H., LaurieS., Eisenhauer E.: Phase II testing of sunitinib: the National CancerInstitute of Canada Clinical Trials Group IND Program Trials IND.182- 185 Curr. Oncol., 2007; 14: 154-161
  Google Scholar
• 4. Dews M., Homayouni A., Yu D., Murphy D., Sevignani C., WentzelE., Furth E.E., Lee W.M., Enders G.H., Mendell J.T., Thomas-TikhonenkoA.: Augmentation of tumor angiogenesis by a Myc-activatedmicroRNA cluster. Nat. Genet., 2006; 38: 1060-1065
  Google Scholar
• 5. Duvic M., Dummer R., Becker J.C., Poulalhon N., Ortiz Romero P.,Grazia Bernengo M., Lebbé C., Assaf C., Squier M., Williams D., MarshoodM., Tai F., Prince H.M.: Panobinostat activity in both bexarotene-exposedand – naïve patients with refractory cutaneous T-celllymphoma: results of a phase II trial.Eur. J. Cancer, 2013; 49: 386-394
  Google Scholar
• 6. Duvic M., Talpur R., Ni X., Zhang C., Hazarika P., Kelly C., ChiaoJ.H., Reilly J.F., Ricker J.L., Richon V.M., Frankel S.R.: Phase 2 trial oforal vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractorycutaneous T-cell lymphoma (CTCL). Blood, 2007; 109: 31-39
  Google Scholar
• 7. Duvic M., Vu J.: Vorinostat: a new oral histone deacetylase inhibitorapproved for cutaneous T-cell lymphoma. Expert Opin. Investig.Drugs, 2007; 16: 1111-1120
  Google Scholar
• 8. Ferrara N., Kerbel R.S.: Angiogenesis as a therapeutic target. Nature,2005; 438: 967-974
  Google Scholar
• 9. Fink K., Boratyński J.: Rola metaloproteinaz w modyfikacj macierzyzewnątrzkomórkowej w nowotworowym wzroście inwazyjnym,w przerzutowaniu i angiogenezie. Postępy Hig. Med. Dośw.,2012; 66: 609-628
  Google Scholar
• 10. Folkman J.: Tumor angiogenesis: therapeutic implications. N.Engl. J. Med., 1971; 285: 1182-1186
  Google Scholar
• 11. Fox S.B., Leek R.D., Weekes M.P., Whitehouse R.M., Gatter K.C.,Harris A.L.: Quantitation and prognostic value of breast cancer angiogenesis:comparision of microvessel density, Chalkley count, andcomputer image analysis. J. Pathol., 1995; 177: 275-283
  Google Scholar
• 12. Fukushima N., Satoh T., Sano M., Tokunaga O.: Angiogenesisand mast cells in non-Hodgkin’s lymphoma: a strong correlationin angioimmunoblastic T-cell lymphoma. Leuk. Lymphoma, 2001;42: 709-720
  Google Scholar
• 13. Grabarska A., Dmoszyńska-Graniczka M., Nowosadzka E., StepulakA.: Histone deacetylase inhibitors – molecular mechanisms ofactions and clinical applications. Postępy Hig. Med. Dośw., 2013;67: 722-735
  Google Scholar
• 14. Grant D.S., Kibbey M.C., Kinsella J.L., Cid M.C., Kleinman H.K.:The role of basement membrane in angiogenesis and tumor growth.Path. Res. Pract., 1994; 190: 854-863
  Google Scholar
• 15. Hansen S., Grabau D.A., Sørensen F.B., Bak M., Vach W., Rose C.:The prognostic value of angiogenesis by Chalkley counting in a confirmatorystudy design on 836 breast cancer patients. Clin. CancerRes., 2000; 6: 139-146
  Google Scholar
• 16. Haugsten E.M., Wiedlocha A., Olsnes S., Wesche J.: Roles of fibroblastgrowth factor receptors in carcinogenesis. Mol. CancerRes., 2010; 8: 1439-1452
  Google Scholar
• 17. Hirakawa S., Hong Y.K., Harvey N., Schacht V., Matsuda K., LibermannT., Detmar M.: Identification of vascular lineage-specific genesby transcriptional profiling of isolated blood vascular and lymphaticendothelial cells. Am. J. Pathol., 2003; 162: 575-586
  Google Scholar
• 18. Hu G., Riordan J.F., Vallee B.L.: Angiogenin promotes invasivenessof cultured endothelial cells by stimulation of cell-associatedproteolytic activities. Proc. Natl. Acad. Sci. USA, 1994: 91: 12096-12100
  Google Scholar
• 19. Hu G.F., Riordan J.F.: Angiogenin enhances actin accelerationof plasminogen activation. Biochem. Biophys. Res. Commun., 1993;197: 682-687
  Google Scholar
• 20. Jackson D.G.: New molecular markers for the study of tumorlymphangiogenesis. Anticancer Res., 2001; 21: 4279-4283
  Google Scholar
• 21. Jackson D.G., Prevo R., Clasper S., Banerji S.: LYVE-1, the lymphaticsystem and tumor lymphangiogenesis. Trends Immunol.,2001; 22: 317-321
  Google Scholar
• 22. Jankowska-Konsur A., Maj J., Woźniak Z., Baran E.: Ocena angiogenezyu chorych na ziarniniaka grzybiastego. Post. Dermatol.Alergol., 2009; 26: 186-189
  Google Scholar
• 23. Kaelin W.G.Jr.: The von Hippel-Lindau tumor suppressor proteinand clear cell renal carcinoma. Clin. Cancer Res., 2007; 13: 680s-684s
  Google Scholar
• 24. Karpova M.B., Fujii K., Jenni D., Dummer R., Urosevic-MaiwaldM.: Evaluation of lymphangiogenic markers in Sézary syndrome.Leuk. Lymphoma, 2011; 52: 491-501
  Google Scholar
• 25. Kim Y.H., Demierre M.F., Kim E.J., Lerner A., Rook A.H., Duvic M.,Robak T., Samtsov A., McCulloch W., Chen S.C., Waksman J., NicholsJ., Whittaker S.: Clinically meaningful reduction in pruritus in patientswith cutaneous T-cell lymphoma treated with romidepsin.Leuk. Lymphoma, 2013; 54: 284-289
  Google Scholar
• 26. Krejsgaard T., Vetter-Kauczok C.S., Woetmann A., Lovato P.,Labuda T., Eriksen K.W., Zhang Q., Becker J.C., Ødum N.: Jak3 – andJNK-dependent vascular endothelial growth factor expression incutaneous T-cell lymphoma. Leukemia, 2006; 20: 1759-1766
  Google Scholar
• 27. Kwon H.J.,. Kim G.E, Lee Y.T., Jeong M.S., Kang I., Yang D., YeoE.J.: Inhibition of platelet-derived growth factor receptor tyrosinekinase and downstream signaling pathways by Compound C. Cell.Signal., 2013; 25: 883-897
  Google Scholar
• 28. Levine A.M., Tulpule A., Quinn D.I., Gorospe G.3rd, Smith D.L.,Hornor L., Boswell W.D., Espina B.M., Groshen S.G., Masood R., GillP.S.: Phase I study of antisense oligonucleotide against vascular endothelialgrowth factor: decrease in plasma vascular endothelialgrowth factor with potential clinical efficacy. J. Clin. Oncol., 2006;24: 1712-1719
  Google Scholar
• 29. Lymboussaki A., Partanen T.A., Olofsson B., Thomas-CrusellsJ., Fletcher C.D,. de Waal R.M., Kaipainen A., Alitalo K.: Expressionof the vascular endothelial growth factor C receptor VEGFR-3 inlymphatic endothelium of the skin and in vascular tumors. Am. J.Pathol., 1998; 153: 395-403
  Google Scholar
• 30. Ma S.P., Lin M., Liu H.N., Yu J.X.: Lymphangiogenesis in nonHodgkin’slymphoma and its correlation with cyclooxygenase-2 andvascular endothelial growth factor-C. Oncol. Lett., 2012; 4: 695-700
  Google Scholar
• 31. Mayerhofer M., Valent P., Sperr W.R., Griffin J.D., Sillaber C.: BCR/ABL induces expression of vascular endothelial growth factor andits transcriptional activator, hypoxia inducible factor-1a, througha pathway involving phosphoinositide 3-kinase and the mammaliantarget of rapamycin. Blood, 2002; 100: 3767-3775
  Google Scholar
• 32. Mazur G., Woźniak Z., Wróbel T., Maj J., Kuliczkowski K.: Increasedangiogenesis in cutaneous T-cell Lymphomas. Pathol. Oncol.Res., 2004; 10: 34-36
  Google Scholar
• 33. Mignatti P., Rifkin D.B.: Biology and biochemistry of proteinasesin tumor invasion. Physiol. Rev., 1993; 73: 161-195
  Google Scholar
• 34. Miyagaki T., Sugaya M., Suga H., Akamata K., Ohmatsu H., FujitaH., Asano Y., Tada Y., Kadono T., Sato S.: Angiogenin levels areincreased in lesional skin and sera in patients with erythrodermiccutaneous T cell lymphoma. Arch. Dermatol. Res., 2012; 304: 401-406
  Google Scholar
• 35. Nerlich A.G., Schleicher E.: Identification of lymph and bloodcapillaries by immunohistochemical staining for various basementmembrane components. Histochemistry, 1991; 96: 449-453
  Google Scholar
• 36. Nicosia R.F., Tchao R., Leighton J.: Interactions between newlyformed endothelial channels and carcinoma cells in plasma clotculture. Clin. Exp. Metastasis, 1986; 4: 91-104
  Google Scholar
• 37. Noureen N., Rashid H., Kalsoom S.: Identification of type-specificanticancer histone deacetylase inhibitors: road to success. CancerChemother. Pharmacol., 2010; 66: 625-633
  Google Scholar
• 38. O’Connor O.A., Wright J., Moskowitz C., Muzzy J., MacGregorCortelliB., Stubblefield M., Straus D., Portlock C., Hamlin P., Choi E.,Dumetrescu O., Esseltine D., Trehu E., Adams J., Schenkein D., ZelenetzA.D.: Phase II clinical experience with the novel proteasomeinhibitor bortezomib in patients with indolent non-Hodgkin’s lymphomaand mantle cell lymphoma. J. Clin. Oncol., 2005; 23: 676-684
  Google Scholar
• 39. Olsen E., Vonderheid E., Pimpinelli N., Willemze R., Kim Y., KnoblerR., Zackheim H., Duvic M., Estrach T., Lamberg S., Wood G.,Dummer R., Ranki A., Burg G., Heald P. i wsp.: Revisions to the stagingand classification of mycosis fungoides and Sezary syndrome:a proposal of the International Society for Cutaneous Lymphomas(ISCL) and the cutaneous lymphoma task force of the European Organizationof Research and Treatment of Cancer (EORTC). Blood,2007; 110: 1713-1722
  Google Scholar
• 40. Olsen E.A., Kim Y.H., Kuzel T.M., Pacheco T.R., Foss F.M., ParkerS., Frankel S.R., Chen C., Ricker J.L., Arduino J.M., Duvic M.: Phase IIbmulticenter trial of vorinostat in patients with persistent, progressive,or treatment refractory cutaneous T-cell lymphoma. J. Clin.Oncol., 2007; 25: 3109-3115
  Google Scholar
• 41. Paydas S., Seydaoglu G., Ergin M., Erdogan S., Yavuz S.: The prognosticsignificance of VEGF-C and VEGF-A in non-Hodgkin lymphomas.Leuk. Lymphoma, 2009; 50: 366-373
  Google Scholar
• 42. Pedersen I.H., Willerslev-Olsen A., Vetter-Kauczok C., KrejsgaardT., Lauenborg B., Kopp K.L., Geisler C., Bonefeld C.M., Zhang Q., Wasik M.A., Dabelsteen S., Woetmann A., Becker J.C., Odum N.:Vascular endothelial growth factor receptor-3 expression in mycosisfungoides. Leuk. Lymphoma, 2013; 54: 819-826
  Google Scholar
• 43. Piekarz R.L., Frye R., Turner M., Wright J.J., Allen S.L., KirschbaumM.H., Zain J., Prince H.M., Leonard J.P., Geskin L.J., Reeder C.,Joske D., Figg W.D., Gardner E.R., Steinberg S.M. i wsp.: Phase II multiinstitutionaltrial of the histone deacetylase inhibitor romidepsin asmonotherapy for patients with cutaneous T-cell lymphoma. J.Clin.Oncol., 2009; 27: 5410-5417
  Google Scholar
• 44. Pileri A., Agostinelli C., Righi S., Fuligni F., Bacci F., Sabattini E.,Patrizi A., Pileri S.A., Piccaluga PP.: A vascular endothelial growthfactor A (VEGF-A) expression in mycosis fungoides. Histopathology,2015; 66: 173-181
  Google Scholar
• 45. Prevo R., Banerji S., Ferguson D.J., Clasper S., Jackson D.G.: MouseLYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium.J. Biol. Chem., 2001; 276: 19420-19430
  Google Scholar
• 46. Pro B., Younes A., Albitar M., Dang N.H., Samaniego F., RomagueraJ., McLaughlin P., Hagemeister F.B., Rodriguez M.A., ClemonsM., Cabanillas F.: Thalidomide for patients with recurrent lymphoma.Cancer, 2004; 100: 1186-1189
  Google Scholar
• 47. Rak J., Filmus J., Kerbel R.S.: Reciprocal paracrine interactionsbetween tumour cells and endothelial cells: the ‘angiogenesis progression’hypothesis. Eur. J. Cancer, 1996; 32A: 2438-2450
  Google Scholar
• 48. Rak J., Mitsuhashi Y., Bayko L., Filmus J., Shirasawa S., SasazukiT., Kerbel R.S.: Mutant ras oncogenes upregulate VEGF/VPF expression:implications for induction and inhibition of tumor of tumorangiogenesis. Cancer Res., 1995; 55: 4575-4580
  Google Scholar
• 49. Rasheed H., Tolba Fawzi M.M., Abdel-Halim M.R., Eissa A.M., MohammedSalem N., Mahfouz S.: Immunohistochemical study of theexpression of matrix metalloproteinase-9 in skin lesions of mycosisfungoides. Am. J. Dermatopathol., 2010; 32: 162-169
  Google Scholar
• 50. Rodriguez-Niedenführ M., Papoutsi M., Christ B., Nicolaides K.H.,von Kaisenberg C.S., Tomarev S.I., Wilting J.: Prox1 is a marker ofectodermal placodes, endodermal compartments, lymphatic endotheliumand lymphangioblasts. Anat. Embryol., 2001; 204: 399-406
  Google Scholar
• 51. Rueda A., Olmos D., Vicioso L., Quero C., Gallego E., PajaresHacheroB.I., Mendiola M., Casanova M., Álvarez M., Provencio M.,Alba E.: Role of vascular endothelial growth factor C in classicalHodgkin lymphoma. Leuk. Lymphoma, 2015; 7: 1-9
  Google Scholar
• 52. Salven P., Orpana A, Teerenhovi L., Joensuu H.: Simultaneouselevation in the sera concentrations of angiogenic growth factorsVEGF and bFGF is independent predictor of poor prognosis in nonHodgkin’slymphoma: a single institution study of 200 patients.Blood, 2000; 96: 3712-3718
  Google Scholar
• 53. Salven P., Teerenhovi L., Joensuu H.: A high pretreatment serumbasic fibroblast growth factor concentration is an independentpredictor of poor prognosis in non-Hodgkin’s lymphoma. Blood,1999; 94: 3334-3339
  Google Scholar
• 54. Schneider-Stock R., Ocker M.: Epigenetic therapy in cancer: molecularbackground and clinical development of histone deacetylaseand DNA methyltransferase inhibitors. IDrugs, 2007; 10: 557-561
  Google Scholar
• 55. Sokołowska-Wojdyło M., Lech-Marańda E., Placek W., Meder J.,Zaucha J.M., Walewski J.: Leczenie pierwotnych chłoniaków skóry.Rekomendacje Sekcji Chłoniaków Skóry Polskiej Grupy BadawczejChłoniaków (PLRG). Przegl. Dermatol., 2010; 97: 225-242
  Google Scholar
• 56. Stopeck A.T., Unger J.M., Rimsza L.M., Bellamy W.T., IannoneM., Persky D.O., Leblanc M., Fisher R.I., Miller T.P.: A phase II trialof single agent bevacizumab in patients with relapsed, aggressivenon-Hodgkin lymphoma: Southwest oncology group study S0108.Leuk. Lymphoma, 2009; 50: 728-735
  Google Scholar
• 57. Su J.L., Yen C.J., Chen P.S., Chuang S.E., Hong C.C., Kuo I.H., ChenH.Y., Hung M.C., Kuo M.L.: The role of the VEGF-C/VEGFR-3 axis incancer progression. Br. J. Cancer, 2007; 96: 541-545
  Google Scholar
• 58. Tzankov A., Heiss S., Ebner S., Sterlacci W., Schaefer G., AugustinF., Fiegl M., Dirnhofer S.: Angiogenesis in nodal B-cell lymphomas:a high throughput study. J. Clin. Pathol., 2007; 60: 476-482
  Google Scholar
• 59. Vacca A., Ribatti D., Roncali L., Ranieri G., Serio G., Silvestris F.,Dammacco F.: Bone marrow angiogenesis and progression in multiplemyeloma. Br. J. Haematol., 1994; 87: 503-508
  Google Scholar
• 60. Vacca A., Moretti S., Ribatti D., Pellegrino A., Pimpinelli N., BianchiB., Bonifazi E., Ria R., Serio G., Dammacco F.: Progression ofmycosis fungoides is associated with changes in angiogenesis andexpression of the matrix metalloproteinases 2 and 9. Eur. J. Cancer,1997; 33: 1685-1692
  Google Scholar
• 61. Whittaker S.J., Demierre M.F., Kim E.J., Rook A.H., Lerner A.,Duvic M., Scarisbrick J., Reddy S., Robak T., Becker J.C., Samtsov A.,McCulloch W., Kim Y.H.: Final results from a multicenter, international,pivotal study of romidepsin in refractory cutaneous T-celllymphoma. J. Clin. Oncol., 2010; 28: 4485-4491
  Google Scholar
• 62. Wigle J.T., Harvey N., Detmar M., Lagutina I., Grosveld G., GunnM.D., Jackson D.G., Oliver G.: An essential role for Prox1 in the inductionof the lymphatic endothelial cell phenotype. EMBO J., 2002;21: 1505-1513
  Google Scholar
• 63. Willemze R., Jaffe E.S., Burg G., Cerroni L., Berti E., SwerdlowS.H., Ralfkiaer E., Chimenti S., Diaz-Perez J.L., Duncan L.M., GrangeF., Harris N.L., Kempf W., Kerl H., Kurrer M. i wsp.: WHO-EORTC classificationfor cutaneous lymphomas. Blood, 2005; 105: 3768-3785
  Google Scholar
• 64. Witzig T.E., Vose J.M., Zinzani P.L., Reeder C.B., Buckstein R.,Polikoff J.A., Bouabdallah R., Haioun C., Tilly H., Guo P., PietronigroD., Ervin-Haynes A.L., Czuczman M.S.: An international phase II trialof single-agent lenalidomide for relapsed or refractory aggressiveB-cell non-Hodgkin’s lymphoma. Ann. Oncol., 2011; 22: 1622-1627
  Google Scholar
• 65. Wołowiec D.: Angiogeneza i limfangiogeneza w chłoniakachzłośliwych nieziarniczych. Acta Haematol. Polonica, 2011; 42: 357-365
  Google Scholar
• 66. Wosztyl A., Korycka-Wołowiec A.: Angiogeneza i limfangiogenezaoraz ich znaczenie w nieziarniczych chłoniakach złośliwych.Acta Haematologica Polonica, 2010; 41: 21-33
  Google Scholar
• 67. Wróbel T., Mazur G., Usnarska-Zubkiewicz L., Kuliczkowski K.:Vascular endothelial growth factor (VEGF) serum concentration innon-Hodgkins lymphoma patients. Pol. Arch. Med. Wewn., 2004;112: 919-923
  Google Scholar
• 68. Yancopoulos G.D., Davis S., Gale N.W., Rudge J.S., Wiegand S.J.,Holash J.: Vascular-specific growth factors and blood vessel formation.Nature, 2000; 407: 242-248
  Google Scholar
• 69. Younes A.: Angiogenesis in lymphoma – a short review. Curr.Mol. Med., 2005; 5: 609-613
  Google Scholar

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