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Activin A circulating levels in patients with bone metastasis from breast or prostate cancer

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Abstract

Recent studies have highlighted that Activin A, a member of the transforming growth factor-β (TGF-β) superfamily, may be involved in the regulation of osteoblastic activity and in osteoclast differentiation. Therefore, we have investigated the clinical significance of its circulating levels in patients with bone metastasis. Activin A serum concentrations were determined, by a commercially available enzyme-linked immunosorbent assay kit, in 72 patients with breast cancer (BC) or prostatic cancer (PC) with (BM+) or without (BM−) bone metastases, in 15 female patients with age-related osteoporosis (OP), in 20 patients with benign prostatic hypertrophy (BPH) and in 48 registered healthy blood donors (HS) of both sex (25 female and 23 male). Activin A serum concentrations were significantly increased in BC or PC patients as compared to OP (P < 0.0001) or BPH (P = 0.045), respectively, or to sex matched HS (P < 0.0001). Additionally, these levels resulted more elevated in PC patients as compared to BC patients (P = 0.032). Interestingly, Activin A was significantly higher in BM+ patients than in BM− patients (BC, P = 0.047; PC, P = 0.016). In BC patients, a significant correlation was observed only between Activin A and number of bone metastases (P = 0.0065) while, in PC patients, Activin A levels were strongly correlated with the Gleason score (P = 0.011) or PSA levels (P = 0.0001) and, to a lessen extent, with the number of bone metastases (P = 0.056). Receiver operating characteristic curve (ROC) analysis showed a fair diagnostic accuracy of Activin A to discriminate between BM+ and BM− patients (BC: AUC = 0.71 ± 0.09, P = 0.03; PC: AUC = 0.73 ± 0.081, P = 0.005). These findings indicate that Activin A may be implicated in the pathogenesis of bone metastasis. Therefore, this cytokine may be considered a novel potential target for a more selective therapeutic approach in the treatment of skeletal metastasis and may be also useful as additional biochemical marker of metastatic bone disease.

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Abbreviations

AUC:

Area under the curve

BC:

Breast cancer

BPH:

Benign prostatic hypertrophy

BM+:

Bone metastasis

BM−:

No metastasis

ELISA:

Enzyme-linked immunosorbent assay

HS:

Healthy subjects

OP:

Primary osteoporosis

PC:

Prostate cancer

PSA:

Prostate specific antigen

ROC:

Receiver operating characteristic curve

TGF-β:

Transforming growth factor-β

References

  1. Luisi S, Florio P, Reis FM, Petraglia F (2001) Expression and secretion of Activin A: possible physiological and clinical implications. Eur J Endocrinol 145:225–236

    Article  PubMed  CAS  Google Scholar 

  2. Tsuchida K (2004) Activins, myostatin and related TGF-β family members as novel therapeutic targets for endocrine, metabolic and immune disorders. Curr Drug Targets Immune Endocr Metabol Disord 4:157–166

    Article  PubMed  CAS  Google Scholar 

  3. Risbridger GP, Schmitt JF, Robertson DM (2001) Activins and inhibins in endocrine and other tumors. Endocr Rev 22(6):836–858

    Article  PubMed  CAS  Google Scholar 

  4. Chen Y-G, Lui HM, Lin S-H et’al (2002) Regulation of cell proliferation, apoptosis and carcinogenesis by activin. Exp Biol Med 227(2):75–88

    CAS  Google Scholar 

  5. Werner S, Alzheimer C (2006) Roles of activin in tissue repair, fibrosis and inflammatory disease. Cytokine Growth Factor Rev (in press) DOI: 10.1016/j.cytogfr.2006.01.001

  6. Fuller K, Bayley KE, Chambers TJ (2000) Activin A is an essential cofactor for osteoclast induction. Biochem Biophys Res Comm 268:2–7

    Article  PubMed  CAS  Google Scholar 

  7. Sugatani T, Alvarez UM, Hruska KA (2003) Activin A stimulates IkB-α/NFkB and RANK expression for osteoclast differentiation, but not AKT survival pathway in osteoclast precursors. J Cell Biochem 90:59–67

    Article  PubMed  CAS  Google Scholar 

  8. Sakai R, Yuzuru E (2001) Involvement of activin in the regulation of bone metabolism. Mol Cell Endocrinol 180:183–188

    Article  PubMed  CAS  Google Scholar 

  9. Harrison GA, Gray PC, Vale WW et’al (2005) Antagonists of activin signaling: mechanisms and potential biological applications. Trends Endocrinol Metab 16(2):73–78

    Article  PubMed  CAS  Google Scholar 

  10. Reinholz M, Iturria SJ, Ingle JN, Roche PC (2002) Differential gene expression of TGF-β family members and osteopontin in breast tumor tissue: analysis by real-time quantitative PCR. Breast Cancer Res Treat 74:255–269

    Article  PubMed  CAS  Google Scholar 

  11. Reis F, Cobellis L, Tameirão LC et’al (2002) Serum and tissue expression of activin A in postmenopausal women with breast cancer. J Clin Endocrinol Metab 87(5):2277–2282

    Article  PubMed  CAS  Google Scholar 

  12. Dowling CR, Risbridger GP (2004) The role of inhibins and activins in prostate cancer pathogenesis. Endocr Relat Cancer 7:243–256

    Article  Google Scholar 

  13. Robertson DM, Burger HG, Fuller PJ (2004) Inhibin/activin and ovarian cancer. Endocr Relat Cancer 11:35–49

    Article  PubMed  CAS  Google Scholar 

  14. Wildi S, Kleeff J, Maruyama H et’al (2001) Overexpression of activin A in stage IV colorectal cancer. Gut 49:409–417

    Article  PubMed  CAS  Google Scholar 

  15. Yuen MF, Norris S, Evans LW et’al (2002) Transforming growth factor-beta 1, activin and follistatin in patients with hepatocellular carcinoma and patients with alcoholic cirrhosis. Scand J Gastroenterol 37(2):233–238

    Article  PubMed  CAS  Google Scholar 

  16. Pirisi M, Fabris C, Luisi S et’al (2000) Evaluation of circulating activin-A as a serum marker of hepatocellular carcinoma. Cancer Detect Prev 24(2):150–155

    PubMed  CAS  Google Scholar 

  17. Kleeff J, Ishiwata T, Friess H et’al (1998) Concomitant over-expression of activin/inhibin β subunits and their receptors in human pancreatic cancer. Int J Cancer 77:860–868

    Article  PubMed  CAS  Google Scholar 

  18. Schulte KM, Jonas C, Krebs R, Roher HD (2001) Activin A and activin receptors in thyroid cancer. Thyroid 11(1):3–14

    Article  PubMed  CAS  Google Scholar 

  19. Yoshinaga K, Mimori K, Yamashita K et’al (2003) Clinical significance of the expression of activin A in esophageal carcinoma. Int J Oncol 22(1):75–80

    PubMed  CAS  Google Scholar 

  20. Schramm A, von Schuetz V, Christiansen H et’al (2005) High activin A expression in human neuroblastoma: suppression of malignant potential and correlation with favourable clinical outcome. Oncogene. 24(4):680–687

    Article  PubMed  CAS  Google Scholar 

  21. Matsuyama S, Iwadate M, Kondo M et’al (2003) SB-431542 and Gleevec inhibit transforming growth factor-beta-induced proliferation of human osteosarcoma cells. Cancer Res 63(22):7791–7798

    PubMed  CAS  Google Scholar 

  22. Sakai R, Eto Y, Hirafuji M, Shinoda H (2000) Activin release from bone coupled to bone resorption in organ culture of neonatal mouse calvaria. Bone 26:235–240

    Article  PubMed  CAS  Google Scholar 

  23. Roodman GD (2004) Mechanism of bone metastasis. N Eng J Med 350:1655–1664

    Article  CAS  Google Scholar 

  24. World Medical Association Declaration of Helsinki (1997) Recommendations guiding physicians in biomedical research involving human subjects. JAMA 277:925–926

    Google Scholar 

  25. Lambert-Messerlian GM, DePasquale SE, Maybruck WM et’al (1999) Secretion of Activin A in recurrent epithelial ovarian carcinoma. Gynecol Oncol 74:93–97

    Article  PubMed  CAS  Google Scholar 

  26. Chang H, Brown CW, Matzuk MM (2002) Genetic analysis of the mammalian transforming growth factor-β- superfamily. Endocr Rev 23:787–823

    Article  PubMed  CAS  Google Scholar 

  27. Rossi MR, Ionov Y, Bakin AV, Cowell JK (2005) Truncating mutations in the ACVR2 gene attenuates activin signalling in prostate cancer cells. Cancer Genet Cytogenet 163:123–129

    Article  PubMed  CAS  Google Scholar 

  28. Jeruss JS, Sturgis CD, Rademaker AW, Woodruff TK (2003) Down-regulation of activin, activin receptors and Smads in high grade breast cancer. Cancer Res 63:783–790

    Google Scholar 

  29. Carey JL, Sasur LM, Kawakubo H et’al (2004) Mutually antagonistic effects of androgen and activin in the regulation of prostate cancer cell growth. Mol Endocrinol 18:696–707

    Article  PubMed  CAS  Google Scholar 

  30. Hyuga S, Kawasaki N, Hashimoto O et’al (2000) Possible role of hepatocyte growth factor/scatter factor and activin A produced by the target organ in liver metastasis. Cancer Lett 153:137–143

    Article  PubMed  CAS  Google Scholar 

  31. Koeneman K, Yeung F, Chung WK (1999) Osteomimetic properties of prostate cancer cells: a hypothesis supporting the predilection of prostate cancer metastasis and growth in the bone environment. Prostate 39:246–261

    Article  PubMed  CAS  Google Scholar 

  32. Keller E, Brown J (2004) Prostate cancer bone metastases promote both osteolytic and osteoblastic activity. J Cell Biochem 91:718–729

    Article  PubMed  CAS  Google Scholar 

  33. Fujii Y, Kawakami S, Okada Y et’al (2004) Regulation of prostate-specific antigen by Activin A in prostate cancer LNCaP cells. Am J Physiol Endocrinol Metab 286(6):E927–E931

    Article  PubMed  CAS  Google Scholar 

  34. Cardillo MR, Petrangeli E, Perracchio L et’al (2000) Transforming growth factor-beta expression in prostate neoplasia. Anal Quant Cytol Histol 22(1):1–10

    PubMed  CAS  Google Scholar 

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Acknowledgement

This work was supported, in part, by funds (ex quota 60%) from Italian Ministry of Education, University and Research (MIUR).

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Authors and Affiliations

  1. Laboratory of Experimental Chemotherapy, Department of Surgery and Oncology, Policlinico Universitario P. Giaccone, Via del Vespro 129, 90127, Palermo, Italy

    Gaetano Leto, Francesca M. Tumminello, Carla Flandina & Marilena Crescimanno

  2. Section of Clinical Oncology, Department of Surgery and Oncology, Policlinico Universitario P. Giaccone, 90127, Palermo, Italy

    Lorena Incorvaia, Giuseppe Badalamenti & Nicola Gebbia

  3. Department of Clinical Medicine and Emerging Diseases, Policlinico Universitario P. Giaccone, 90127, Palermo, Italy

    Giovambattista Rini

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  1. Gaetano Leto
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  2. Lorena Incorvaia
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  3. Giuseppe Badalamenti
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  4. Francesca M. Tumminello
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Correspondence to Gaetano Leto.

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Leto, G., Incorvaia, L., Badalamenti, G. et al. Activin A circulating levels in patients with bone metastasis from breast or prostate cancer. Clin Exp Metastasis 23, 117–122 (2006). https://doi.org/10.1007/s10585-006-9010-5

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  • DOI: https://doi.org/10.1007/s10585-006-9010-5

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