Affiliation of authors: N. Auersperg (Department of Obstetrics and Gynecology), H. Ziltener (The Biomedical Research Centre and the Department of Pathology and Laboratory Medicine), The University of British Columbia, Vancouver, Canada.
Correspondence to: Nelly Auersperg, M.D., Ph.D., Department of Obstetrics and Gynecology, The University of British Columbia, B.C. Women's Hospital, 4490 Oak St., Vancouver BC V6H 3V5, Canada (e-mail: auersper{at}interchange.ubc).
In a recent issue of the Journal, Syed et al. (1) describe a comprehensive and carefully executed study aimed at defining the hormonal mechanisms that regulate STAT3-mediated interleukin 6 (IL-6) action in nontumorigenic human ovarian surface epithelial (HOSE) cells and ovarian cancer cells. The authors demonstrate, in their system, that IL-6 acts as an autocrine growth factor and mediates growth stimulation by reproductive hormones. Furthermore, they find that expression of the IL-6 receptor is greater in ovarian cancer cells than in HOSE cells. In conjunction with reports that IL-6 levels are increased in the serum and peritoneal fluid of ovarian cancer patients (2,3), these data support the concept of an important role of this cytokine in ovarian epithelial carcinogenesis.
We would like to draw attention to two points that perhaps should be clarified to further complete the picture of IL-6 action in ovarian carcinogenesis. First, we were confused by the use of the abbreviation HOSE to refer to ovarian surface epithelial cells that had been immortalized with human papillomavirus (HPV) E6/E7 and, in particular, with the term normal in the title of the paper. The abbreviation HOSE is generally interpreted as referring to human OSE (ovarian surface epithelial) cells that have not been genetically manipulated after isolation from the ovary but, rather, they represent the normal tissue of origin of ovarian cancer. OSE cells immortalized with either HPV E6/E7 (4), as in the present study by Syed et al., or simian virus 40 (SV40) large T antigen (5) are nontumorigenic but otherwise far removed from normal. These cells are highly unstable genetically (4) and have impaired p53 and retinoblastoma protein activity (6), and their responses to growth controls (e.g., in terms of serum dependence, plating efficiency, and senescence) resemble the responses of ovarian cancer cells more than those of HOSE cells. Among the normal characteristics of HOSE cells quoted by Syed et al. in their "Materials and Methods" section, the lack of tumorigenicity is the only characteristic not shared by a large number of ovarian tumors. Thus, although it is stated in their Abstract that the HOSE cells are immortalized, the implications of this step are not emphasized in the paper and, therefore, it is not clear that the authors are comparing premalignant and malignant OSE cells rather than normal and malignant cells. In particular, the term normal in the title is misleading.
Second, Syed et al. suggest, on the basis of their data and of the literature cited, that IL-6 secretion increases with malignant progression. However, they fail to comment on our 1993 study (7), in which the production of bioactive IL-6 was measured in human OSE cells recently grown from surgical specimens, SV40 large T-immortalized OSE cells, and ovarian cancer cells. IL-6 secretion was highest in cultures of normal OSE cells and was reduced nearly 10-fold in cultures of immortalized and malignant cells. Among other implications, these observations raise the possibility that molecular measurements don't necessarily parallel bioactivity. Furthermore, these observations suggest the possibility that the high levels of IL-6 in body fluids of ovarian cancer patients may be derived, at least in part, from cells of the immune system.
NOTES
Editor's note: The authors of Syed et al. declined to respond.
REFERENCES
1 Syed V, Ulinski G, Mok SC, Ho SM. Reproductive hormone-induced, STAT3-mediated interleukin 6 action in normal and malignant human ovarian surface epithelial cells. J Natl Cancer Inst 2002;94:61729.
2 Plante M, Rubin SC, Wong GY, Federici MG, Finstad CL, Gastl GA. Interleukin-6 level in serum and ascites as a prognostic factor in patients with epithelial ovarian cancer. Cancer 1994;73:18828.[Medline]
3 Tempfer C, Zeisler H, Sliutz G, Haeusler G, Hanzal E, Kainz C. Serum evaluation of interleukin 6 in ovarian cancer patients. Gynecol Oncol 1997;66:2730.[Medline]
4 Tsao SW, Wong N, Wang X, Liu Y, Wan TS, Fung LF, et al. Nonrandom chromosomal imbalances in human ovarian surface epithelial cells immortalized by HPV16-E6E7 viral oncogenes. Cancer Genet Cytogenet 2001;130:1419.[Medline]
5 Maines-Bandiera SL, Kruk PA, Auersperg N. Simian virus 40-transformed human ovarian surface epithelial cells escape normal growth controls but retain morphogenetic responses to extracellular matrix. Am J Obstet Gynecol 1992;167:72935.[Medline]
6 Schneider J, Fanning E. Mutations in the phosphorylation sites of simian virus 40 (SV40) T antigen alter its origin DNA-binding specificity for sites I or II and affect SV40 DNA replication activity. J Virol 1988;62:1598605.[Medline]
7 Ziltener HJ, Maines-Bandiera S, Schrader JW, Auersperg N. Secretion of bioactive interleukin-1, interleukin-6, and colony-stimulating factors by human ovarian surface epithelium. Biol Reprod 1993;49:63541.[Abstract]
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