Interleukin-6 is an autocrine growth factor in human prostate cancer.

Prostate cancer is the most common cancer in American men and the second leading cause of cancer deaths in this group. We have found that interleukin (IL)-6 protein concentrations are increased approximately 18-fold in clinically localized prostate cancers when compared to normal prostate tissue. Normal and neoplastic prostatic epithelial cells in culture, with the exception of LNCaP cells, secrete IL-6. Addition of exogenous IL-6 to primary epithelial cells in culture or the LNCaP prostate cancer cell line leads to phosphorylation of Stat-3 and increases in net cell proliferation. The concentration of IL-6 receptor is increased eightfold in the prostate cancer tissues and is increased in the cancer cells by immunohistochemistry. The increased expression of IL-6 receptor is correlated with increased proliferation of prostate cancer cells in vivo as assessed by Ki67 immunohistochemistry. These findings strongly support the hypothesis that IL-6 acts as a significant autocrine growth factor in vivo for primary, androgen-dependent prostate cancers.

[1]  M. Ittmann,et al.  FGF9 is an autocrine and paracrine prostatic growth factor expressed by prostatic stromal cells , 1999, Journal of cellular physiology.

[2]  J. Fu,et al.  Effect of interleukin-6 on the growth of human lung cancer cell line. , 1998, Chinese medical journal.

[3]  I. Pastan,et al.  Interleukin 6 receptor mRNA in prostate carcinomas and benign prostate hyperplasia. , 1994, The Journal of urology.

[4]  J. M. Lin,et al.  Interleukin-6 activates phosphatidylinositol-3 kinase, which inhibits apoptosis in human prostate cancer cell lines. , 2000, The Prostate.

[5]  R. Oyasu,et al.  Interleukin-6 as a paracrine and autocrine growth factor in human prostatic carcinoma cells in vitro. , 1997, Cancer research.

[6]  H. Klocker,et al.  Immunohistochemical localization of interleukin‐6 and its receptor in benign, premalignant and malignant prostate tissue , 2000, The Journal of pathology.

[7]  D. Tweardy,et al.  Interleukin‐6 induces prostate cancer cell growth accompanied by activation of Stat3 signaling pathway , 2000, The Prostate.

[8]  P. Heinrich,et al.  The soluble human IL-6 receptor. Mutational characterization of the proteolytic cleavage site. , 1994, Journal of immunology.

[9]  J. Darnell,et al.  Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. , 1994, Science.

[10]  G. Wise,et al.  Cytokine variations in patients with hormone treated prostate cancer. , 2000, The Journal of urology.

[11]  Y. Horiguchi,et al.  Serum interleukin 6 as a prognostic factor in patients with prostate cancer. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[12]  B. Bonavida,et al.  Interleukin-6 induces G1 arrest through induction of p27(Kip1), a cyclin-dependent kinase inhibitor, and neuron-like morphology in LNCaP prostate tumor cells. , 1999, Biochemical and biophysical research communications.

[13]  M. Murai,et al.  Autocrine growth promotion by multiple hematopoietic growth factors in the established renal cell carcinoma line KU-19–20 , 2000, Cell and Tissue Research.

[14]  M. Ittmann,et al.  FGF7 and FGF2 are increased in benign prostatic hyperplasia and are associated with increased proliferation. , 1999, The Journal of urology.

[15]  H. Kung,et al.  Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells , 1998, Nature.

[16]  J. Oh,et al.  A soluble interleukin 6 receptor isolated from conditioned medium of human breast cancer cells is encoded by a differentially spliced mRNA. , 1996, Cytokine.

[17]  J. Simons,et al.  Interleukin-6: a candidate mediator of human prostate cancer morbidity. , 1995, Urology.

[18]  J. Simons,et al.  Characterization of the role of IL‐6 in the progression of prostate cancer , 1999, The Prostate.

[19]  A. Falus,et al.  ROLE OF INTERLEUKIN‐6 IN THE PATHOGENESIS OF MULTIPLE MYELOMA , 2000, Cell biology international.

[20]  R. Bataille,et al.  A combination of anti‐interleukin 6 murine monoclonal antibody with dexamethasone and high‐dose melphalan induces high complete response rates in advanced multiple myeloma , 2000, British journal of haematology.

[21]  T. Savarese,et al.  Increased expression of the interleukin-11 receptor and evidence of STAT3 activation in prostate carcinoma. , 2001, The American journal of pathology.

[22]  T. Chung,et al.  Interleukin‐6 activates phosphatidylinositol‐3 kinase, which inhibits apoptosis in human prostate cancer cell lines , 2000 .

[23]  M. Ittman,et al.  Expression of fibroblast growth factors (FGFs) and FGF receptors in human prostate. , 1997, The Journal of urology.

[24]  H. Klocker,et al.  Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor. , 1998, Cancer research.

[25]  W. Farrar,et al.  Interleukin 6 activates androgen receptor-mediated gene expression through a signal transducer and activator of transcription 3-dependent pathway in LNCaP prostate cancer cells. , 2000, Cancer research.