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The role of VEGF-C staining in predicting regional metastasis in melanoma

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Abstract

Sentinel lymph node status is the most important prognostic factor in primary melanoma. The number of melanoma-associated lymphatic vessels has been associated with sentinel lymph node status and survival. Vascular endothelial growth factor-C (VEGF-C) is found to promote tumour-associated lymphatic vessel growth. In many human neoplasms, VEGF-C expression in neoplastic cells or tumour-associated macrophages (TAMs) has been linked to lymphatic dissemination of tumour cells. Recent studies have suggested a correlation between VEGF-C expression in primary melanoma and the presence of lymph node metastasis. We performed VEGF-C immunohistochemical staining on melanoma tissues of 113 patients with known sentinel lymph node status. We showed that both high VEGF-C expression in melanoma cells and TAMs are positively associated with the presence of a positive sentinel lymph node. No correlation with Breslow thickness, Clark invasion level or ulceration could be detected. VEGF-C expression in melanoma cells was predictive of a shorter overall and disease-free survival, without being an independent predictor of survival. Our results confirm that VEGF-C expression in primary cutaneous melanoma plays a role in the lymphatic spread of the tumour.

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References

  1. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A Jr., Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF (2001) Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635–3648

    PubMed  CAS  Google Scholar 

  2. Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, Urist M, McMasters KM, Ross MI, Kirkwood JM, Atkins MB, Thompson JA, Coit DG, Byrd D, Desmond R, Zhang Y, Liu PY, Lyman GH, Morabito A (2001) Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 19:3622–3634

    PubMed  CAS  Google Scholar 

  3. Bingle L, Brown NJ, Lewis CE (2002) The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196:254–265

    Article  PubMed  CAS  Google Scholar 

  4. Chilov D, Kukk E, Taira S, Jeltsch M, Kaukonen J, Palotie A, Joukov V, Alitalo K (1997) Genomic organization of human and mouse genes for vascular endothelial growth factor C. J Biol Chem 272:25176–25183

    Article  PubMed  CAS  Google Scholar 

  5. Clarijs R, Ruiter DJ, de Waal RM (2001) Lymphangiogenesis in malignant tumours: does it occur. J Pathol 193:143–146

    Article  PubMed  CAS  Google Scholar 

  6. Cueni LN, Detmar M (2006) New insights into the molecular control of the lymphatic vascular system and its role in disease. J Invest Dermatol 126:2167–2177

    Article  PubMed  CAS  Google Scholar 

  7. Dadras SS, Lange-Asschenfeldt B, Velasco P, Nguyen L, Vora A, Muzikansky A, Jahnke K, Hauschild A, Hirakawa S, Mihm MC, Detmar M (2005) Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes. Mod Pathol 18:1232–1242

    Article  PubMed  Google Scholar 

  8. Dadras SS, Paul T, Bertoncini J, Brown LF, Muzikansky A, Jackson DG, Ellwanger U, Garbe C, Mihm MC, Detmar M (2003) Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol 162:1951–1960

    PubMed  Google Scholar 

  9. Enholm B, Karpanen T, Jeltsch M, Kubo H, Stenback F, Prevo R, Jackson DG, Yla-Herttuala S, Alitalo K (2001) Adenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin. Circ Res 88:623–629

    PubMed  CAS  Google Scholar 

  10. Esposito I, Menicagli M, Funel N, Bergmann F, Boggi U, Mosca F, Bevilacqua G, Campani D (2004) Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol 57:630–636

    Article  PubMed  CAS  Google Scholar 

  11. Feng HC, Song YF, Wen YM (2004) [Correlation between expression of vascular endothelial growth factor-C in tumor-associated macrophages and lymphatic metastasis in oral cancer]. Ai Zheng 23:278–281

    PubMed  CAS  Google Scholar 

  12. Gershenwald JE, Thompson W, Mansfield PF, Lee JE, Colome MI, Tseng CH, Lee JJ, Balch CM, Reintgen DS, Ross MI (1999) Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 17:976–983

    PubMed  CAS  Google Scholar 

  13. Goldman J, Le TX, Skobe M, Swartz MA (2005) Overexpression of VEGF-C causes transient lymphatic hyperplasia but not increased lymphangiogenesis in regenerating skin. Circ Res 96:1193–1199

    Article  PubMed  CAS  Google Scholar 

  14. He Y, Karpanen T, Alitalo K (2004) Role of lymphangiogenic factors in tumor metastasis. Biochim Biophys Acta 1654:3–12

    PubMed  CAS  Google Scholar 

  15. He Y, Kozaki K, Karpanen T, Koshikawa K, Yla-Herttuala S, Takahashi T, Alitalo K (2002) Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst 94:819–825

    PubMed  CAS  Google Scholar 

  16. Hirakawa S, Brown LF, Kodama S, Paavonen K, Alitalo K, Detmar M (2007) VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood 109:1010–1017

    Article  PubMed  CAS  Google Scholar 

  17. Jackowski S, Janusch M, Fiedler E, Marsch WC, Ulbrich EJ, Gaisbauer G, Dunst J, Kerjaschki D, Helmbold P (2007) Radiogenic lymphangiogenesis in the skin. Am J Pathol 171:338–348

    Article  PubMed  Google Scholar 

  18. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K (1997) Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276:1423–1425

    Article  PubMed  CAS  Google Scholar 

  19. Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K (1996) A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 15:1751

    PubMed  CAS  Google Scholar 

  20. Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, Saksela O, Kalkkinen N, Alitalo K (1997) Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J 16:3898–3911

    Article  PubMed  CAS  Google Scholar 

  21. Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, Jeltsch M, Jackson DG, Talikka M, Rauvala H, Betsholtz C, Alitalo K (2004) Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 5:74–80

    Article  PubMed  CAS  Google Scholar 

  22. Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Yla-Herttuala S, Jaattela M, Alitalo K (2001) Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 61:1786–1790

    PubMed  CAS  Google Scholar 

  23. Kukk E, Lymboussaki A, Taira S, Kaipainen A, Jeltsch M, Joukov V, Alitalo K (1996) VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development. Development 122:3829–3837

    PubMed  CAS  Google Scholar 

  24. Landi G, Polverelli M, Moscatelli G, Morelli R, Landi C, Fiscelli O, Erbazzi A (2000) Sentinel lymph node biopsy in patients with primary cutaneous melanoma: study of 455 cases. J Eur Acad Dermatol Venereol 14:35–45

    Article  PubMed  CAS  Google Scholar 

  25. Lee J, Gray A, Yuan J, Luoh SM, Avraham H, Wood WI (1996) Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. Proc Natl Acad Sci U S A 93:1988–1992

    Article  PubMed  CAS  Google Scholar 

  26. Lin J, Lalani AS, Harding TC, Gonzalez M, Wu WW, Luan B, Tu GH, Koprivnikar K, VanRoey MJ, He Y, Alitalo K, Jooss K (2005) Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor. Cancer Res 65:6901–6909

    Article  PubMed  CAS  Google Scholar 

  27. Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, Wise L, Mercer A, Kowalski H, Kerjaschki D, Stacker SA, Achen MG, Alitalo K (2001) Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J 20:4762–4773

    Article  PubMed  CAS  Google Scholar 

  28. Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, Orci L, Alitalo K, Christofori G, Pepper MS (2001) Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 20:672–682

    Article  PubMed  CAS  Google Scholar 

  29. Massi D, Puig S, Franchi A, Malvehy J, Vidal-Sicart S, Gonzalez-Cao M, Baroni G, Ketabchi S, Palou J, Santucci M (2006) Tumour lymphangiogenesis is a possible predictor of sentinel lymph node status in cutaneous melanoma: a case–control study. J Clin Pathol 59:166–173

    Article  PubMed  CAS  Google Scholar 

  30. Nicosia RF (1998) What is the role of vascular endothelial growth factor-related molecules in tumor angiogenesis. Am J Pathol 153:11–16

    PubMed  CAS  Google Scholar 

  31. Oh SJ, Jeltsch MM, Birkenhager R, McCarthy JE, Weich HA, Christ B, Alitalo K, Wilting J (1997) VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Dev Biol 188:96–109

    Article  PubMed  CAS  Google Scholar 

  32. Olofsson B, Jeltsch M, Eriksson U, Alitalo K (1999) Current biology of VEGF-B and VEGF-C. Curr Opin Biotechnol 10:528–535

    Article  PubMed  CAS  Google Scholar 

  33. Paavonen K, Horelli-Kuitunen N, Chilov D, Kukk E, Pennanen S, Kallioniemi OP, Pajusola K, Olofsson B, Eriksson U, Joukov V, Palotie A, Alitalo K (1996) Novel human vascular endothelial growth factor genes VEGF-B and VEGF-C localize to chromosomes 11q13 and 4q34, respectively. Circulation 93:1079–1082

    PubMed  CAS  Google Scholar 

  34. Papoutsi M, Siemeister G, Weindel K, Tomarev SI, Kurz H, Schachtele C, Martiny-Baron G, Christ B, Marme D, Wilting J (2000) Active interaction of human A375 melanoma cells with the lymphatics in vivo. Histochem Cell Biol 114:373–385

    PubMed  CAS  Google Scholar 

  35. Pepper MS (2001) Lymphangiogenesis and tumor metastasis: myth or reality? Clin Cancer Res 7:462–468

    PubMed  CAS  Google Scholar 

  36. Saaristo A, Veikkola T, Enholm B, Hytonen M, Arola J, Pajusola K, Turunen P, Jeltsch M, Karkkainen MJ, Kerjaschki D, Bueler H, Yla-Herttuala S, Alitalo K (2002) Adenoviral VEGF-C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes. FASEB J 16:1041–1049

    Article  PubMed  CAS  Google Scholar 

  37. Salven P, Lymboussaki A, Heikkila P, Jaaskela-Saari H, Enholm B, Aase K, von Euler G, Eriksson U, Alitalo K, Joensuu H (1998) Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors. Am J Pathol 153:103–108

    PubMed  CAS  Google Scholar 

  38. Schietroma C, Cianfarani F, Lacal PM, Odorisio T, Orecchia A, Kanitakis J, D’Atri S, Failla CM, Zambruno G (2003) Vascular endothelial growth factor-C expression correlates with lymph node localization of human melanoma metastases. Cancer 98:789–797

    Article  PubMed  CAS  Google Scholar 

  39. Schoppmann SF, Birner P, Stockl J, Kalt R, Ullrich R, Caucig C, Kriehuber E, Nagy K, Alitalo K, Kerjaschki D (2002) Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 161:947–956

    PubMed  CAS  Google Scholar 

  40. Schoppmann SF, Fenzl A, Nagy K, Unger S, Bayer G, Geleff S, Gnant M, Horvat R, Jakesz R, Birner P (2006) VEGF-C expressing tumor-associated macrophages in lymph node positive breast cancer: impact on lymphangiogenesis and survival. Surgery 139:839–846

    Article  PubMed  Google Scholar 

  41. Shields JD, Borsetti M, Rigby H, Harper SJ, Mortimer PS, Levick JR, Orlando A, Bates DO (2004) Lymphatic density and metastatic spread in human malignant melanoma. Br J Cancer 90:693–700

    Article  PubMed  CAS  Google Scholar 

  42. Shimizu K, Kubo H, Yamaguchi K, Kawashima K, Ueda Y, Matsuo K, Awane M, Shimahara Y, Takabayashi A, Yamaoka Y, Satoh S (2004) Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer. Cancer Sci 95:328–333

    Article  PubMed  CAS  Google Scholar 

  43. Skobe M, Hamberg LM, Hawighorst T, Schirner M, Wolf GL, Alitalo K, Detmar M (2001) Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. Am J Pathol 159:893–903

    PubMed  CAS  Google Scholar 

  44. Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M (2001) Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 7:192–198

    Article  PubMed  CAS  Google Scholar 

  45. Stacker SA, Williams RA, Achen MG (2004) Lymphangiogenic growth factors as markers of tumor metastasis. APMIS 112:539–549

    Article  PubMed  CAS  Google Scholar 

  46. Straume O, Jackson DG, Akslen LA (2003) Independent prognostic impact of lymphatic vessel density and presence of low-grade lymphangiogenesis in cutaneous melanoma. Clin Cancer Res 9:250–256

    PubMed  CAS  Google Scholar 

  47. Takizawa H, Kondo K, Fujino H, Kenzaki K, Miyoshi T, Sakiyama S, Tangoku A (2006) The balance of VEGF-C and VEGFR-3 mRNA is a predictor of lymph node metastasis in non-small cell lung cancer. Br J Cancer 95:75–79

    Article  PubMed  CAS  Google Scholar 

  48. Thiele W, Sleeman JP (2006) Tumor-induced lymphangiogenesis: a target for cancer therapy? J Biotechnol 124:224–241

    Article  PubMed  CAS  Google Scholar 

  49. Tobler NE, Detmar M (2006) Tumor and lymph node lymphangiogenesis—impact on cancer metastasis. J Leukoc Biol 80:691–696

    Article  PubMed  CAS  Google Scholar 

  50. Valencak J, Heere-Ress E, Kopp T, Schoppmann SF, Kittler H, Pehamberger H (2004) Selective immunohistochemical staining shows significant prognostic influence of lymphatic and blood vessels in patients with malignant melanoma. Eur J Cancer 40:358–364

    Article  PubMed  CAS  Google Scholar 

  51. Veikkola T, Jussila L, Makinen T, Karpanen T, Jeltsch M, Petrova TV, Kubo H, Thurston G, McDonald DM, Achen MG, Stacker SA, Alitalo K (2001) Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J 20:1223–1231

    Article  PubMed  CAS  Google Scholar 

  52. Wagner JD, Corbett L, Park HM, Davidson D, Coleman JJ, Havlik RJ, Hayes JT 2nd (2000) Sentinel lymph node biopsy for melanoma: experience with 234 consecutive procedures. Plast Reconstr Surg 105:1956–1966

    Article  PubMed  CAS  Google Scholar 

  53. Was H (2005) [Characterization of markers and growth factors for lymphatic endothelium]. Postepy Biochem 51:209–214

    PubMed  CAS  Google Scholar 

  54. Wissmann C, Detmar M (2006) Pathways targeting tumor lymphangiogenesis. Clin Cancer Res 12:6865–6868

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors thank Mrs. R. Heyse and Mrs. S. D’Hont for their technical support and assistance in completing this study. This study was supported by the National Fund for Scientific Research-Flanders, grant number G.0128.06.

Barbara Boone is a research fellow of the National Fund for Scientific Research-Flanders, grant number G.0128.06.

Conflict of interest statement

We declare that we have no conflict of interest.

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Authors and Affiliations

  1. Department of Dermatology, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium

    Barbara Boone, Jo Lambert & Lieve Brochez

  2. Department of Pathology, UMC Sint-Radboud, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, The Netherlands

    Willeke Blokx & Dirk Ruiter

  3. Department of Public Health, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium

    Dirk De Bacquer

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  1. Barbara Boone
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Correspondence to Barbara Boone.

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Boone, B., Blokx, W., De Bacquer, D. et al. The role of VEGF-C staining in predicting regional metastasis in melanoma. Virchows Arch 453, 257–265 (2008). https://doi.org/10.1007/s00428-008-0641-6

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  • DOI: https://doi.org/10.1007/s00428-008-0641-6

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