Abstract
The presence of interleukin (IL)-6 in peritoneal carcinomatous fluid (PCF) and its effect on immune cells composition in PCF in patients with advanced ovarian carcinoma was studied. In 21 out of 30 ovarian carcinoma patients, PCF IL-6 levels were found to exceed those seen in PCFs of patients with gastrointestinal cancer. IL-6 activity was higher in serous/mucinous than in endometrioid and undifferentiated ovarian carcinoma PCF (P = 0.05). Ovarian carcinoma PCF IL-6 activities were correlated with serum C-reactive protein levels (r = 0.65, P = 0.0000, n = 25). Ovarian carcinoma PCF leucocyte profile differed from that in blood with respect to: (i) lower percentage of NK and CD8+and (ii) higher percentage of B and CD45RO+, CD14+and HLA-DR+cells. The proportions of CD45RO+in blood were correlated with IL-6 levels in PCF. Corresponding to PCF ovarian carcinoma tumours were stained for the presence of Ki-67 antigen and p53. The highest proportions of Ki-67+cells and cells showing accumulation of p53 were seen in undifferentiated tumours. A low grade of p53 staining was seen in tumours associated with high IL-6 levels in PCF. It was evident that IL-6 production (i) depended on the histiotype of the tumour, (ii) influenced the local immune system in favour of accumulation of B, and T memory cells, and (iii) was higher in patients lacking p53 accumulation. © 2000 CancerResearch Campaign
Keywords: ovarian carcinoma, IL-6, Ki-67, p53, carcinomatous effusion, phenotype
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- Asschert J. G., Vellenga E., Hollema H., van der Zee A. G., de Vries E. G. Expression of macrophage colony-stimulating factor (M-CSF), interleukin-6, (IL-6), interleukin-1 beta (IL-1 beta), interleukin-11 (IL-11) and tumour necrosis factor-alpha (TNF-alpha) in p53-characterised human ovarian carcinomas. Eur J Cancer. 1997 Nov;33(13):2246–2251. doi: 10.1016/s0959-8049(97)00240-2. [DOI] [PubMed] [Google Scholar]
- Berek J. S., Chung C., Kaldi K., Watson J. M., Knox R. M., Martínez-Maza O. Serum interleukin-6 levels correlate with disease status in patients with epithelial ovarian cancer. Am J Obstet Gynecol. 1991 Apr;164(4):1038–1043. doi: 10.1016/0002-9378(91)90582-c. [DOI] [PubMed] [Google Scholar]
- Berger D. P., Herbstritt L., Dengler W. A., Marmé D., Mertelsmann R., Fiebig H. H. Vascular endothelial growth factor (VEGF) mRNA expression in human tumor models of different histologies. Ann Oncol. 1995 Oct;6(8):817–825. doi: 10.1093/oxfordjournals.annonc.a059322. [DOI] [PubMed] [Google Scholar]
- Blay J. Y., Rossi J. F., Wijdenes J., Menetrier-Caux C., Schemann S., Négrier S., Philip T., Favrot M. Role of interleukin-6 in the paraneoplastic inflammatory syndrome associated with renal-cell carcinoma. Int J Cancer. 1997 Jul 29;72(3):424–430. doi: 10.1002/(sici)1097-0215(19970729)72:3<424::aid-ijc9>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
- Boury N. M., Stabel T. J., Kehrli M., Jr, Taylor M. Comparison of the PK(15)- and WEHI 164 (clone 13)-based bioassays for detection of porcine tumor necrosis factor. Am J Vet Res. 1997 Oct;58(10):1115–1119. [PubMed] [Google Scholar]
- Cao X., Chen C., Zhang W., Tao Q., Yu Y., Ye T. Enhanced efficacy of combination of IL-2 gene and IL-6 gene-transfected tumor cells in the treatment of established metastatic tumors. Gene Ther. 1996 May;3(5):421–426. [PubMed] [Google Scholar]
- Cattoretti G., Becker M. H., Key G., Duchrow M., Schlüter C., Galle J., Gerdes J. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol. 1992 Dec;168(4):357–363. doi: 10.1002/path.1711680404. [DOI] [PubMed] [Google Scholar]
- Chang S. G., Lee S. J., Lee S. J., Kimi J. I., Jung J. C., Kim J. H., Hoffman R. M. Interleukin-6 production in primary histoculture by normal human kidney and renal tumor tissues. Anticancer Res. 1997 Jan-Feb;17(1A):113–115. [PubMed] [Google Scholar]
- Eskandari M. K., Nguyen D. T., Kunkel S. L., Remick D. G. WEHI 164 subclone 13 assay for TNF: sensitivity, specificity, and reliability. Immunol Invest. 1990 Feb;19(1):69–79. doi: 10.3109/08820139009042026. [DOI] [PubMed] [Google Scholar]
- Fennelly D. Dose intensity in advanced ovarian cancer: have we answered the question? Clin Cancer Res. 1995 Jun;1(6):575–582. [PubMed] [Google Scholar]
- Freedman R. S., Tomasovic B., Templin S., Atkinson E. N., Kudelka A., Edwards C. L., Platsoucas C. D. Large-scale expansion in interleukin-2 of tumor-infiltrating lymphocytes from patients with ovarian carcinoma for adoptive immunotherapy. J Immunol Methods. 1994 Jan 3;167(1-2):145–160. doi: 10.1016/0022-1759(94)90084-1. [DOI] [PubMed] [Google Scholar]
- Gastl G., Plante M., Finstad C. L., Wong G. Y., Federici M. G., Bander N. H., Rubin S. C. High IL-6 levels in ascitic fluid correlate with reactive thrombocytosis in patients with epithelial ovarian cancer. Br J Haematol. 1993 Mar;83(3):433–441. doi: 10.1111/j.1365-2141.1993.tb04668.x. [DOI] [PubMed] [Google Scholar]
- Giannios J., Ioannidou-Mouzaka L. Molecular aspects of breast and ovarian cancer. Eur J Gynaecol Oncol. 1997;18(5):387–393. [PubMed] [Google Scholar]
- Gotlieb W. H., Watson J. M., Rezai A., Johnson M., Martínez-Maza O., Berek J. S. Cytokine-induced modulation of tumor suppressor gene expression in ovarian cancer cells: up-regulation of p53 gene expression and induction of apoptosis by tumor necrosis factor-alpha. Am J Obstet Gynecol. 1994 Apr;170(4):1121–1130. doi: 10.1016/s0002-9378(94)70106-7. [DOI] [PubMed] [Google Scholar]
- Hsu S. M., Waldron J. W., Jr, Hsu P. L., Hough A. J., Jr Cytokines in malignant lymphomas: review and prospective evaluation. Hum Pathol. 1993 Oct;24(10):1040–1057. doi: 10.1016/0046-8177(93)90183-h. [DOI] [PubMed] [Google Scholar]
- Hutchins D., Steel C. M. Regulation of ICAM-1 (CD54) expression in human breast cancer cell lines by interleukin 6 and fibroblast-derived factors. Int J Cancer. 1994 Jul 1;58(1):80–84. doi: 10.1002/ijc.2910580114. [DOI] [PubMed] [Google Scholar]
- Karimine N., Nanbara S., Arinaga S., Asoh T., Ueo H., Akiyoshi T. Lymphokine-activated killer cell activity of peripheral blood, spleen, regional lymph node, and tumor infiltrating lymphocytes in gastric cancer patients. J Surg Oncol. 1994 Mar;55(3):179–185. doi: 10.1002/jso.2930550310. [DOI] [PubMed] [Google Scholar]
- Kishimoto T. The biology of interleukin-6. Blood. 1989 Jul;74(1):1–10. [PubMed] [Google Scholar]
- Kutteh W. H., Kutteh C. C. Quantitation of tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 in the effusions of ovarian epithelial neoplasms. Am J Obstet Gynecol. 1992 Dec;167(6):1864–1869. doi: 10.1016/0002-9378(92)91788-c. [DOI] [PubMed] [Google Scholar]
- Luca M., Huang S., Gershenwald J. E., Singh R. K., Reich R., Bar-Eli M. Expression of interleukin-8 by human melanoma cells up-regulates MMP-2 activity and increases tumor growth and metastasis. Am J Pathol. 1997 Oct;151(4):1105–1113. [PMC free article] [PubMed] [Google Scholar]
- Machelon V., Nomé F., Durand-Gasselin I., Emilie D. Tumor necrosis factor-alpha induces interleukin-6 mRNA and protein in human granulosa luteinizing cells via protein tyrosine kinase without involving ceramide. Mol Cell Endocrinol. 1997 Feb 7;126(2):173–184. doi: 10.1016/s0303-7207(96)03985-8. [DOI] [PubMed] [Google Scholar]
- Matsuda M., Petersson M., Lenkei R., Taupin J. L., Magnusson I., Mellstedt H., Anderson P., Kiessling R. Alterations in the signal-transducing molecules of T cells and NK cells in colorectal tumor-infiltrating, gut mucosal and peripheral lymphocytes: correlation with the stage of the disease. Int J Cancer. 1995 Jun 9;61(6):765–772. doi: 10.1002/ijc.2910610605. [DOI] [PubMed] [Google Scholar]
- Offner F. A., Obrist P., Stadlmann S., Feichtinger H., Klingler P., Herold M., Zwierzina H., Hittmair A., Mikuz G., Abendstein B. IL-6 secretion by human peritoneal mesothelial and ovarian cancer cells. Cytokine. 1995 Aug;7(6):542–547. doi: 10.1006/cyto.1995.0073. [DOI] [PubMed] [Google Scholar]
- Papadopoulos N. G., Dedoussis G. V., Baxevanis C. N., Papamichail M. Bioassay vs. immunoassay for quantification of interleukin-6 in biological fluids. J Clin Lab Anal. 1995;9(4):234–237. doi: 10.1002/jcla.1860090404. [DOI] [PubMed] [Google Scholar]
- Plante M., Rubin S. C., Wong G. Y., Federici M. G., Finstad C. L., Gastl G. A. Interleukin-6 level in serum and ascites as a prognostic factor in patients with epithelial ovarian cancer. Cancer. 1994 Apr 1;73(7):1882–1888. doi: 10.1002/1097-0142(19940401)73:7<1882::aid-cncr2820730718>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
- Runnebaum I. B. Basics of cancer gene therapy. Anticancer Res. 1997 Jul-Aug;17(4B):2887–2890. [PubMed] [Google Scholar]
- Schöndorf T., Engel H., Lindemann C., Kolhagen H., von Rücker A. A., Mallmann P. Cellular characteristics of peripheral blood lymphocytes and tumour-infiltrating lymphocytes in patients with gynaecological tumours. Cancer Immunol Immunother. 1997 Apr;44(2):88–96. doi: 10.1007/s002620050360. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takatsuki F., Okano A., Suzuki C., Chieda R., Takahara Y., Hirano T., Kishimoto T., Hamuro J., Akiyama Y. Human recombinant IL-6/B cell stimulatory factor 2 augments murine antigen-specific antibody responses in vitro and in vivo. J Immunol. 1988 Nov 1;141(9):3072–3077. [PubMed] [Google Scholar]
- Unutmaz D., Pileri P., Abrignani S. Antigen-independent activation of naive and memory resting T cells by a cytokine combination. J Exp Med. 1994 Sep 1;180(3):1159–1164. doi: 10.1084/jem.180.3.1159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Willemse P. H., de Vries E. G., Mulder N. H., Aalders J. G., Bouma J., Sleijfer D. T. Intraperitoneal human recombinant interferon alpha-2b in minimal residual ovarian cancer. Eur J Cancer. 1990 Mar;26(3):353–358. doi: 10.1016/0277-5379(90)90233-j. [DOI] [PubMed] [Google Scholar]
- Wimmenauer S., Keller H., Rahner S., Kirste G., Von Bergwelt M., Meyer A., Von Kleist S., Farthmann E. H. Phenotypical and functional characteristics of tumor-infiltrating lymphocytes from colon carcinomas stimulated with rIL-2 and rIL-4 in vitro: comparison with lymphocytes of the normal colon mucosa and the peripheral blood. Anticancer Res. 1994 May-Jun;14(3A):963–968. [PubMed] [Google Scholar]