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Expression of HLA-G in malignant mesothelioma and clinically aggressive breast carcinoma

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Abstract

The aim of the present study was to evaluate HLA-G expression in breast carcinoma and malignant mesothelioma (MM). Malignant breast carcinoma effusions (46) and corresponding solid tumors (39) and 104 MM (26 effusions, 78 solid tumors) were analyzed using immunohistochemistry (IHC). HLA-G protein and mRNA expression were further studied using immunoblotting (IB) and RT-PCR. HLA-ABC expression was analyzed using flow cytometry (FCM). IHC showed predominantly focal HLA-G expression in 12 of 46 (26%) breast carcinoma effusions and 16 of 39 (41%) solid lesions. In MM, 20 of 78 (26%) solid lesions and 14 of 26 (54%) effusions were focally HLA-G positive. Expression in MM was higher in effusions (p=0.008). IB showed more frequent HLA-G expression in MM compared with breast carcinoma effusions, while RT-PCR showed HLA-G mRNA expression in both tumors. FCM showed conserved HLA-ABC expression in 15 of 15 effusions. Breast cancer patients with HLA-G-positive tumor cells had shorter disease-free survival (mean 37 vs 85, median 25 vs 31 months), though not significantly (p=0.14). In conclusion, HLA-G is focally expressed in MM and breast carcinoma, while HLA-ABC expression is conserved. However, the up-regulated expression of HLA-G in MM effusions and its possible association with shorter disease-free survival in advanced stage of breast carcinoma suggest a possible role in immune response evasion in some tumors.

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References

  1. Algarra I, Garcia-Lora A, Cabrera T, Ruiz-Cabello F, Garrido F (2004) The selection of tumor variants with altered expression of classical and nonclassical MHC class I molecules: implications for tumor immune escape. Cancer Immunol Immunother 53:904–910

    Article  PubMed  CAS  Google Scholar 

  2. Banerjee AK, Willetts I, Robertson JF, Blamey RW (1994) Pleural effusion in breast cancer: a review of the Nottingham experience. Eur J Surg Oncol 20:33–36

    PubMed  CAS  Google Scholar 

  3. Britton M (2002) The epidemiology of mesothelioma. Semin Oncol 29:18–25

    Article  PubMed  Google Scholar 

  4. Brostjan C, Bellon T, Sobanov Y, Lopez-Botet M, Hofer E (2002) Differential expression of inhibitory and activating CD94/NKG2 receptors on NK cell clones. J Immunol Methods 264:109–119

    Article  PubMed  CAS  Google Scholar 

  5. Bukur J, Rebmann V, Grosse-Wilde H, Luboldt H, Ruebben H, Drexler I, Sutter G, Huber C, Seliger B (2003) Functional role of human leukocyte antigen-G up-regulation in renal cell carcinoma. Cancer Res 63:4107–4111

    PubMed  CAS  Google Scholar 

  6. Bukur J, Malenica B, Huber C, Seliger B (2003) Altered expression of nonclassical HLA class Ib antigens in human renal cell carcinoma and its association with impaired immune response. Hum Immunol 64:1081–1092

    Article  PubMed  CAS  Google Scholar 

  7. Davidson B (2004) Malignant effusions: from diagnosis to biology. Diagn Cytopathol 31:246–254

    Article  PubMed  Google Scholar 

  8. Davidson B, Risberg B, Kristensen G, Kvalheim G, Emilsen E, Bjåmer A, Berner A (1999) Detection of cancer cells in effusions from patients diagnosed with gynecological malignancies. Evaluation of five epithelial markers. Virchows Arch 435:43–49

    Article  PubMed  CAS  Google Scholar 

  9. Davidson B, Nielsen S, Christensen J, Asschenfeldt P, Berner A, Risberg B, Johansen P (2001) The role of desmin and N-cadherin in effusion cytology: a comparative study using established markers of mesothelial and epithelial cells. Am J Surg Pathol 25:1405–1412

    Article  PubMed  CAS  Google Scholar 

  10. Davidson B, Dong HP, Berner A, Christensen J, Nielsen S, Johansen P, Bryne M, Asschenfeldt P, Risberg B (2002) Detection of malignant epithelial cells in effusions using flow cytometric immunophenotyping: an analysis of 92 cases. Am J Clin Pathol 118:85–92

    Article  PubMed  Google Scholar 

  11. Davidson B, Risberg R, Reich R, Berner A (2003) Effusion cytology in ovarian cancer—new molecular methods as aids to diagnosis and prognosis. Clin Lab Med 23:729–754

    Article  PubMed  Google Scholar 

  12. Davidson B, Reich R, Lazarovici P, Flørenes VA, Risberg B, Nielsen S, Sert B, Bedrossian C (2004) Expression of the nerve growth factor receptors TrkA and p75 in malignant mesothelioma. Lung Cancer 44:159–165

    Article  PubMed  Google Scholar 

  13. Davidson B, Reich R, Lazarovici P, Flørenes VA, Nielsen S, Nesland JM (2004) Altered expression and activation of the nerve growth factor receptors TrkA and p75 provide the first evidence of tumor progression to effusion in breast carcinoma. Breast Cancer Res Treat 83:119–128

    Article  PubMed  CAS  Google Scholar 

  14. Davidson B, Vintman L, Zcharia E, Bedrossian C, Berner A, Nielsen S, Ilan N, Vlodavsky I, Reich R (2004) Heparanase and basic fibroblast growth factor are co-expressed in malignant mesothelioma. Clin Exp Metastasis 21:469–476

    Article  PubMed  CAS  Google Scholar 

  15. Davidson B, Konstantinovsky S, Nielsen S, Dong HP, Berner A, Vyberg M, Reich R (2004) Altered expression of metastasis-associated and regulatory molecules in effusions from breast cancer patients—a novel model for tumor progression. Clin Cancer Res 10:7335–7346

    Article  PubMed  CAS  Google Scholar 

  16. Davidson B, Bukholt Elstrand M, McMaster MT, Berner A, Kurman RJ, Risberg B, Trope CG, Shih IM (2005) HLA-G expression in effusions is a possible marker of tumor susceptibility to chemotherapy in ovarian carcinoma. Gynecol Oncol 96:42–47

    Article  PubMed  CAS  Google Scholar 

  17. Dieterich M, Goodman SN, Rojas-Corona RR, Emralino AB, Jimenez-Joseph D, Sherman ME (1994) Multivariate analysis of prognostic features in malignant pleural effusions from breast cancer patients. Acta Cytol 38:945–952

    PubMed  CAS  Google Scholar 

  18. Dutta N, Majumder D, Gupta A, Mazumder DNG, Banerjee S (2005) Analysis of human lymphocyte antigen class I expression in gastric cancer by reverse transcriptase-polymerase chain reaction. Hum Immunol 66:164–169

    Article  PubMed  CAS  Google Scholar 

  19. Hausheer FH, Yarbro JW (1985) Diagnosis and treatment of malignant pleural effusion. Semin Oncol 12:54–75

    PubMed  CAS  Google Scholar 

  20. Hofmeister V, Weiss EH (2003) HLA-G modulates immune responses by diverse receptor interactions. Semin Cancer Biol 13:317–323

    Article  PubMed  CAS  Google Scholar 

  21. Ibrahim EC, Guerra N, Lacombe MJ, Angevin E, Chouaib S, Carosella ED, Caignard A, Paul P (2001) Tumor-specific up-regulation of the nonclassical class I HLA-G antigen expression in renal carcinoma. Cancer Res 61:6838–6845

    PubMed  CAS  Google Scholar 

  22. Ibrahim EC, Aractingi S, Allory Y, Borrini F, Dupuy A, Duvillard P, Carosella ED, Avril MF, Paul P (2004) Analysis of HLA antigen expression in benign and malignant melanocytic lesions reveals that upregulation of HLA-G expression correlates with malignant transformation, high inflammatory infiltration and HLA-A1 genotype. Int J Cancer 108:243–250

    Article  CAS  Google Scholar 

  23. Korkola JE, DeVries S, Fridlyand J, Hwang ES, Estep AL, Chen YY, Chew KL, Dairkee SH, Jensen RM, Waldman FM (2003) Differentiation of lobular versus ductal breast carcinomas by expression microarray analysis. Cancer Res 63:7167–7175

    PubMed  CAS  Google Scholar 

  24. Lefebvre S, Antoine M, Uzan S, McMaster M, Dausset J, Carosella ED, Paul P (2002) Specific activation of the non-classical class I histocompatibility HLA-G antigen and expression of the ILT2 inhibitory receptor in human breast cancer. J Pathol 196:266–274

    Article  PubMed  CAS  Google Scholar 

  25. Martinez-Moragon E, Aparicio J, Sanchis J, Menendez R, Cruz Rogado M, Sanchis F (1998) Malignant pleural effusion: prognostic factors for survival and response to chemical pleurodesis in a series of 120 cases. Respiration 65:108–113

    Article  PubMed  CAS  Google Scholar 

  26. Maelandsmo GM, Hovig E, Skrede M, Engebraaten O, Florenes VA, Myklebost O, Grigorian M, Lukanidin E, Scanlon KJ, Fodstad O (1996) Reversal of the in vivo metastatic phenotype of human tumor cells by an anti-CAPL (mts1) ribozyme. Cancer Res 56:5490–5498

    PubMed  CAS  Google Scholar 

  27. Malmberg KJ, Levitsky V, Norell H, de Matos CT, Carlsten M, Schedvins K, Rabbani H, Moretta A, Soderstrom K, Levitskaya J, Kiessling R (2002) IFN-gamma protects short-term ovarian carcinoma cell lines from CTL lysis via a CD94/NKG2A-dependent mechanism. J Clin Invest 110:1515–1523

    PubMed  CAS  Google Scholar 

  28. McMaster MT, Librach CL, Zhou Y, Lim KH, Janatpour MJ, DeMars R, Kovats S, Damsky C, Fisher SJ (1995) Human placental HLA-G expression is restricted to differentiated cytotrophoblasts. J Immunol 154:3771–3778

    PubMed  CAS  Google Scholar 

  29. McMaster M, Zhou Y, Shorter S, Kapasi K, Geraghty D, Lim KH, Fisher SJ (1998) HLA-G isoforms produced by placental cytotrophoblasts and found in amniotic fluid are due to unusual glycosylation. J Immunol 160:5922–5928

    PubMed  CAS  Google Scholar 

  30. Moretta L, Biassoni R, Bottino C, Cantoni C, Pende D, Mingari MC, Moretta A (2002) Human NK cells and their receptors. Microbes Infect 4:1539–1544

    Article  PubMed  CAS  Google Scholar 

  31. Palmisano GL, Pistillo MP, Fardin P, Capanni P, Nicolo G, Salvi S, Spina B, Pasciucco G, Ferrara GB (2002) Analysis of HLA-G expression in breast cancer tissue. Hum Immunol 63:969–976

    Article  PubMed  CAS  Google Scholar 

  32. Paul P, Rouas-Freiss N, Khalil-Daher I, Moreau P, Riteau B, Le Gal FA, Avril MF, Dausset J, Guillet JG, Carosella ED (1998) HLA-G expression in melanoma: a way for tumor cells to escape from immunosurveillance. Proc Natl Acad Sci U S A 95:4510–4515

    Article  PubMed  CAS  Google Scholar 

  33. Paul P, Cabestre FA, Le Gal FA, Khalil-Daher I, Le Danff C, Schmid M, Mercier S, Avril MF, Dausset J, Guillet JG, Carosella ED (1999) Heterogeneity of HLA-G gene transcription and protein expression in malignant melanoma biopsies. Cancer Res 59:1954–1960

    PubMed  CAS  Google Scholar 

  34. Paul P, Rouas-Freiss N, Moreau P, Cabestre FA, Menier C, Khalil-Daher I, Pangault C, Onno M, Fauchet R, Martinez-Laso J, Morales P, Villena AA, Giacomini P, Natali PG, Frumento G, Ferrara GB, McMaster M, Fisher S, Schust D, Ferrone S, Dausset J, Geraghty D, Carosella ED (2000) HLA-G, -E, -F preworkshop: tools and protocols for analysis of non-classical class I genes transcription and protein expression. Hum Immunol 61:1177–1195

    Article  PubMed  CAS  Google Scholar 

  35. Real LM, Cabrera T, Collado A, Jimenez P, Garcia A, Ruiz-Cabello F, Garrido F (1999) Expression of HLA-G in human tumors is not a frequent event. Int J Cancer 81:512–518

    Article  PubMed  CAS  Google Scholar 

  36. Singer G, Kurman RJ, McMaster M, Shih I-M (2002) HLA-G immunoreactivity is specific for intermediate trophoblast in gestational trophoblastic disease and can serve as a useful marker in differential diagnosis. Am J Surg Pathol 26:914–920

    Article  PubMed  Google Scholar 

  37. Singer G, Rebmann V, Chen YC, Liu HT, Ali SZ, Reinsberg J, McMaster MT, Pfeiffer K, Chan DW, Wardelmann E, Grosse-Wilde H, Cheng CC, Kurman RJ, Shih IM (2003) HLA-G is a potential tumor marker in malignant ascites. Clin Cancer Res 9:4460–4464

    PubMed  CAS  Google Scholar 

  38. Urosevic M, Kurrer MO, Kamarashev J, Mueller B, Weder W, Burg G, Stahel RA, Dummer R, Trojan A (2001) Human leukocyte antigen G up-regulation in lung cancer associates with high-grade histology, human leukocyte antigen class I loss and interleukin-10 production. Am J Pathol 159:817–824

    PubMed  CAS  Google Scholar 

  39. Urosevic M, Willers J, Mueller B, Kempf W, Burg G, Dummer R (2002) HLA-G protein up-regulation in primary cutaneous lymphomas is associated with interleukin-10 expression in large cell T-cell lymphomas and indolent B-cell lymphomas. Blood 99:609–617

    Article  PubMed  CAS  Google Scholar 

  40. van der Ven K, Pfeiffer K, Skrablin S (2000) HLA-G polymorphisms and molecule function—questions and more questions—a review. Placenta 21(Suppl A):S86–S92

    PubMed  Google Scholar 

  41. van Ruth S, Baas P, Zoetmulder FAN (2003) Surgical treatment of malignant pleural mesothelioma. Chest 123:551–561

    Article  PubMed  Google Scholar 

  42. Wilkes JD, Fidias P, Vaickus L, Perez RP (1995) Malignancy-related pericardial effusion. 127 cases from the Roswell Park Center Institute. Cancer 76:1377–1387

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We gratefully acknowledge the competent technical help of Ms. Inger-Liv Nordli, Ms. Mai Nguyen, Ms. Ann Larsen, and Ms. Esther Hasper (IHC) and Mr. Arild Holth (FCM) at the Department of Pathology, Norwegian Radium Hospital.

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Authors and Affiliations

  1. Department of Pathology, Norwegian Radium Hospital, University of Oslo, Montebello, 0310, Oslo, Norway

    Lilach Kleinberg, Vivi Ann Flørenes, Martina Skrede, Hiep Phuc Dong, Jahn M. Nesland & Ben Davidson

  2. Department of Pathology, Aalborg Hospital, Aalborg, Denmark

    Søren Nielsen

  3. Department of Stomatology, University of California, San Francisco, CA, USA

    Michael T. McMaster

  4. Department of Pathology, Gynecology and Oncology, Johns Hopkins University Medical Institutions, Baltimore, MD, USA

    Ie-Ming Shih

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  1. Lilach Kleinberg
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Correspondence to Ben Davidson.

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Kleinberg, L., Flørenes, V.A., Skrede, M. et al. Expression of HLA-G in malignant mesothelioma and clinically aggressive breast carcinoma. Virchows Arch 449, 31–39 (2006). https://doi.org/10.1007/s00428-005-0144-7

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  • DOI: https://doi.org/10.1007/s00428-005-0144-7

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