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The American Journal of Pathology logoLink to The American Journal of Pathology
. 1996 Apr;148(4):1055–1063.

Immunihistochemical detection of Bcl-2 in AIDS-associated and classical Kaposi's sarcoma.

C B Morris 1, R Gendelman 1, A J Marrogi 1, M Lu 1, J M Lockyer 1, W Alperin-Lea 1, B Ensoli 1
PMCID: PMC1861530  PMID: 8644847

Abstract

Kaposi's Sarcoma (KS) is an angioproliferative disease that is characterized by proliferation of spindle-shaped cells predominantly of vascular endothelial cell origin, neoangiogenesis, inflammatory cell infiltration, and edema. Although the lesions of classical KS and AIDS-associated KS (AIDS-KS) share common histological features, AIDS-KS occurs at a markedly higher frequency with a more aggressive clinical course. Immunohistochemical analyses of 26 evolutionarily staged AIDS-KS lesions derived from HIV-infected patients demonstrate significant cytoplasmic levels of Bcl-2, a protooncogene known to prolong cellular viability and to antagonize apoptosis. Bcl-2 expression increases as the pathological stage of KS advances. Immunohistochemical analyses of classical KS lesions demonstrate prevalent expression of Bcl-2 as well, indicating that upregulation of Bcl-2 may be important in the pathogenesis of both classical and AIDS-associated KS. Coexpression of Bcl-2 and factor VIII-related antigen in spindle-shaped cells present within KS lesions suggests that Bcl-2 is upregulated within the vascular endothelial spindle-shaped cells of KS. The consequences of upregulated Bcl-2 expression within KS lesions may be prolonged spindle cell viability which, when coupled with dysregulated cellular proliferation due in part to synergistic activities of inflammatory and angiogenic cytokines and HIV-1 Tat protein, may result in the maintenance, growth, and progression of KS.

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Selected References

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  1. Barillari G., Buonaguro L., Fiorelli V., Hoffman J., Michaels F., Gallo R. C., Ensoli B. Effects of cytokines from activated immune cells on vascular cell growth and HIV-1 gene expression. Implications for AIDS-Kaposi's sarcoma pathogenesis. J Immunol. 1992 Dec 1;149(11):3727–3734. [PubMed] [Google Scholar]
  2. Barillari G., Gendelman R., Gallo R. C., Ensoli B. The Tat protein of human immunodeficiency virus type 1, a growth factor for AIDS Kaposi sarcoma and cytokine-activated vascular cells, induces adhesion of the same cell types by using integrin receptors recognizing the RGD amino acid sequence. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7941–7945. doi: 10.1073/pnas.90.17.7941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Buonaguro L., Barillari G., Chang H. K., Bohan C. A., Kao V., Morgan R., Gallo R. C., Ensoli B. Effects of the human immunodeficiency virus type 1 Tat protein on the expression of inflammatory cytokines. J Virol. 1992 Dec;66(12):7159–7167. doi: 10.1128/jvi.66.12.7159-7167.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chang Y., Cesarman E., Pessin M. S., Lee F., Culpepper J., Knowles D. M., Moore P. S. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994 Dec 16;266(5192):1865–1869. doi: 10.1126/science.7997879. [DOI] [PubMed] [Google Scholar]
  5. Chiou S. K., Rao L., White E. Bcl-2 blocks p53-dependent apoptosis. Mol Cell Biol. 1994 Apr;14(4):2556–2563. doi: 10.1128/mcb.14.4.2556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chor P. J., Santa Cruz D. J. Kaposi's sarcoma. A clinicopathologic review and differential diagnosis. J Cutan Pathol. 1992 Feb;19(1):6–20. doi: 10.1111/j.1600-0560.1992.tb01553.x. [DOI] [PubMed] [Google Scholar]
  7. Donehower L. A., Bradley A. The tumor suppressor p53. Biochim Biophys Acta. 1993 Aug 23;1155(2):181–205. doi: 10.1016/0304-419x(93)90004-v. [DOI] [PubMed] [Google Scholar]
  8. Ensoli B., Barillari G., Gallo R. C. Pathogenesis of AIDS-associated Kaposi's sarcoma. Hematol Oncol Clin North Am. 1991 Apr;5(2):281–295. [PubMed] [Google Scholar]
  9. Ensoli B., Barillari G., Salahuddin S. Z., Gallo R. C., Wong-Staal F. Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients. Nature. 1990 May 3;345(6270):84–86. doi: 10.1038/345084a0. [DOI] [PubMed] [Google Scholar]
  10. Ensoli B., Buonaguro L., Barillari G., Fiorelli V., Gendelman R., Morgan R. A., Wingfield P., Gallo R. C. Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. J Virol. 1993 Jan;67(1):277–287. doi: 10.1128/jvi.67.1.277-287.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ensoli B., Gendelman R., Markham P., Fiorelli V., Colombini S., Raffeld M., Cafaro A., Chang H. K., Brady J. N., Gallo R. C. Synergy between basic fibroblast growth factor and HIV-1 Tat protein in induction of Kaposi's sarcoma. Nature. 1994 Oct 20;371(6499):674–680. doi: 10.1038/371674a0. [DOI] [PubMed] [Google Scholar]
  12. Ensoli B., Nakamura S., Salahuddin S. Z., Biberfeld P., Larsson L., Beaver B., Wong-Staal F., Gallo R. C. AIDS-Kaposi's sarcoma-derived cells express cytokines with autocrine and paracrine growth effects. Science. 1989 Jan 13;243(4888):223–226. doi: 10.1126/science.2643161. [DOI] [PubMed] [Google Scholar]
  13. Fiorelli V., Gendelman R., Samaniego F., Markham P. D., Ensoli B. Cytokines from activated T cells induce normal endothelial cells to acquire the phenotypic and functional features of AIDS-Kaposi's sarcoma spindle cells. J Clin Invest. 1995 Apr;95(4):1723–1734. doi: 10.1172/JCI117849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Friedman-Kien A. E. Disseminated Kaposi's sarcoma syndrome in young homosexual men. J Am Acad Dermatol. 1981 Oct;5(4):468–471. doi: 10.1016/s0190-9622(81)80010-2. [DOI] [PubMed] [Google Scholar]
  15. Geiger K. D., Gurushanthaiah D., Howes E. L., Lewandowski G. A., Reed J. C., Bloom F. E., Sarvetnick N. E. Cytokine-mediated survival from lethal herpes simplex virus infection: role of programmed neuronal death. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3411–3415. doi: 10.1073/pnas.92.8.3411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gottlieb G. J., Ackerman A. B. Kaposi's sarcoma: an extensively disseminated form in young homosexual men. Hum Pathol. 1982 Oct;13(10):882–892. doi: 10.1016/s0046-8177(82)80047-6. [DOI] [PubMed] [Google Scholar]
  17. Haverkos H. W., Drotman D. P. Prevalence of Kaposi's sarcoma among patients with AIDS. N Engl J Med. 1985 Jun 6;312(23):1518–1518. [PubMed] [Google Scholar]
  18. Henderson S., Rowe M., Gregory C., Croom-Carter D., Wang F., Longnecker R., Kieff E., Rickinson A. Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell. 1991 Jun 28;65(7):1107–1115. doi: 10.1016/0092-8674(91)90007-l. [DOI] [PubMed] [Google Scholar]
  19. Hockenbery D. M., Zutter M., Hickey W., Nahm M., Korsmeyer S. J. BCL2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):6961–6965. doi: 10.1073/pnas.88.16.6961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hockenbery D., Nuñez G., Milliman C., Schreiber R. D., Korsmeyer S. J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990 Nov 22;348(6299):334–336. doi: 10.1038/348334a0. [DOI] [PubMed] [Google Scholar]
  21. Hsu S. M., Raine L., Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981 Apr;29(4):577–580. doi: 10.1177/29.4.6166661. [DOI] [PubMed] [Google Scholar]
  22. Levine A. M. AIDS-related malignancies: the emerging epidemic. J Natl Cancer Inst. 1993 Sep 1;85(17):1382–1397. doi: 10.1093/jnci/85.17.1382. [DOI] [PubMed] [Google Scholar]
  23. Lowe S. W., Ruley H. E. Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis. Genes Dev. 1993 Apr;7(4):535–545. doi: 10.1101/gad.7.4.535. [DOI] [PubMed] [Google Scholar]
  24. Lunardi-Iskandar Y., Gill P., Lam V. H., Zeman R. A., Michaels F., Mann D. L., Reitz M. S., Jr, Kaplan M., Berneman Z. N., Carter D. Isolation and characterization of an immortal neoplastic cell line (KS Y-1) from AIDS-associated Kaposi's sarcoma. J Natl Cancer Inst. 1995 Jul 5;87(13):974–981. doi: 10.1093/jnci/87.13.974. [DOI] [PubMed] [Google Scholar]
  25. Mann D. A., Frankel A. D. Endocytosis and targeting of exogenous HIV-1 Tat protein. EMBO J. 1991 Jul;10(7):1733–1739. doi: 10.1002/j.1460-2075.1991.tb07697.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Miles S. A., Rezai A. R., Salazar-González J. F., Vander Meyden M., Stevens R. H., Logan D. M., Mitsuyasu R. T., Taga T., Hirano T., Kishimoto T. AIDS Kaposi sarcoma-derived cells produce and respond to interleukin 6. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4068–4072. doi: 10.1073/pnas.87.11.4068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nuñez G., London L., Hockenbery D., Alexander M., McKearn J. P., Korsmeyer S. J. Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J Immunol. 1990 May 1;144(9):3602–3610. [PubMed] [Google Scholar]
  28. Oren M. p53: the ultimate tumor suppressor gene? FASEB J. 1992 Oct;6(13):3169–3176. doi: 10.1096/fasebj.6.13.1397838. [DOI] [PubMed] [Google Scholar]
  29. Regezi J. A., MacPhail L. A., Daniels T. E., DeSouza Y. G., Greenspan J. S., Greenspan D. Human immunodeficiency virus-associated oral Kaposi's sarcoma. A heterogeneous cell population dominated by spindle-shaped endothelial cells. Am J Pathol. 1993 Jul;143(1):240–249. [PMC free article] [PubMed] [Google Scholar]
  30. Strasser A., Harris A. W., Cory S. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell. 1991 Nov 29;67(5):889–899. doi: 10.1016/0092-8674(91)90362-3. [DOI] [PubMed] [Google Scholar]
  31. Szekely L., Selivanova G., Magnusson K. P., Klein G., Wiman K. G. EBNA-5, an Epstein-Barr virus-encoded nuclear antigen, binds to the retinoblastoma and p53 proteins. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5455–5459. doi: 10.1073/pnas.90.12.5455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Vogelstein B., Kinzler K. W. p53 function and dysfunction. Cell. 1992 Aug 21;70(4):523–526. doi: 10.1016/0092-8674(92)90421-8. [DOI] [PubMed] [Google Scholar]
  33. Wang X. W., Forrester K., Yeh H., Feitelson M. A., Gu J. R., Harris C. C. Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2230–2234. doi: 10.1073/pnas.91.6.2230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wang Y., Szekely L., Okan I., Klein G., Wiman K. G. Wild-type p53-triggered apoptosis is inhibited by bcl-2 in a v-myc-induced T-cell lymphoma line. Oncogene. 1993 Dec;8(12):3427–3431. [PubMed] [Google Scholar]
  35. Zambetti G. P., Levine A. J. A comparison of the biological activities of wild-type and mutant p53. FASEB J. 1993 Jul;7(10):855–865. doi: 10.1096/fasebj.7.10.8344485. [DOI] [PubMed] [Google Scholar]
  36. Zauli G., Gibellini D., Milani D., Mazzoni M., Borgatti P., La Placa M., Capitani S. Human immunodeficiency virus type 1 Tat protein protects lymphoid, epithelial, and neuronal cell lines from death by apoptosis. Cancer Res. 1993 Oct 1;53(19):4481–4485. [PubMed] [Google Scholar]
  37. el-Habashi A., el-Morsi B., Freeman S. M., el-Didi M., Marrogi A. J. Tumor oncogenic expression in malignant effusions as a possible method to enhance cytologic diagnostic sensitivity. An immunocytochemical study of 87 cases. Am J Clin Pathol. 1995 Feb;103(2):206–214. doi: 10.1093/ajcp/103.2.206. [DOI] [PubMed] [Google Scholar]

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