nach oben

Erschienen in:

19.03.2018 | Original Article

Interleukin-6 receptor inhibitor suppresses bone metastases in a breast cancer cell line

verfasst von: Hiroki Wakabayashi, Takahiko Hamaguchi, Nobuto Nagao, Sho Kato, Takahiro Iino, Tomoki Nakamura, Akihiro Sudo

Erschienen in: Breast Cancer | Ausgabe 5/2018

Einloggen, um Zugang zu erhalten

Abstract

Background

Interleukin-6 (IL-6) is a potent inflammatory cytokine that appears to play a key role in cancer growth and metastasis. In the present study, the effects of IL-6 receptor (IL-6R) on breast cancer aggressiveness and bone metastases were investigated.

Methods

MDA-MB-231 (MDA-231) cells were treated in the presence or absence of anti-human IL-6 receptor (IL-6R) monoclonal antibody and examined with respect to cell survival. The expressions of signal transducer and activator of transcription 3 (Stat3), vascular endothelial growth factor (VEGF), and receptor activator of NF-κB (RANK) were analyzed by SDS-PAGE and immunoblotting. MDA-231 cells were injected into the left ventricle of mice, and then anti-human IL-6R monoclonal antibody or saline was administered intraperitoneally for 28 days. After 28 days, the incidence of bone metastases was evaluated in the hind limbs by radiography and histology.

Results

Anti-human IL-6R monoclonal antibody reduced bone metastases in an animal model injected with MDA-231 cells on radiological and histomorphometric analyses. The mechanism of bone metastasis inhibition involved inhibited cell proliferation and decreased expressions of phospho-Stat3, VEGF, and RANK in MDA-231 cells.

Conclusions

The results of the present study suggest that inhibition of IL-6 signaling may become a preventive therapeutic option for breast cancer and bone metastases.

Nur mit Berechtigung zugänglich

Henderson BE, Ross RK, Pike MC. Hormonal chemoprevention of cancer in women. Science. 1993;259(5095):633–8.CrossRefPubMed

Taira N, Arai M, Ikeda M, Iwasaki M, Okamura H, Takamatsu K, Nomura T, Yamamoto S, Ito Y, Mukai H. The Japanese Breast Cancer Society clinical practice guidelines for epidemiology and prevention of breast cancer, 2015 edition. Breast Cancer. 2016;23(3):343–56.CrossRefPubMed

Greenberg PA, Hortobagyi GN, Smith TL, Ziegler LD, Frye DK, Buzdar AU. Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol. 1996;14(8):2197–205.CrossRefPubMed

Coleman RE, Rubens RD. The clinical course of bone metastases from breast cancer. Br J Cancer. 1987;55(1):61–6.CrossRefPubMedPubMedCentral

Manders K, van de Poll-Franse LV, Creemers GJ, Vreugdenhil G, van der Sangen MJ, Nieuwenhuijzen GA, Roumen RM, Voogd AC. Clinical management of women with metastatic breast cancer: a descriptive study according to age group. BMC Cancer. 2006;6(6):179.CrossRefPubMedPubMedCentral

Coleman RE. Adjuvant bisphosphonates in breast cancer: are we witnessing the emergence of a new therapeutic strategy? Eur J Cancer. 2009;45(11):1909–15.CrossRefPubMed

Barton MK. Denosumab an option for patients with bone metastasis from breast cancer. CA Cancer J Clin. 2011;61(3):135–6.CrossRefPubMed

Aihara T, Toyama T, Takahashi M, Yamamoto Y, Hara F, Akabane H, Fujisawa T, Ishikawa T, Nagai S, Nakamura R, Tsurutani J, Ito Y, Mukai H. The Japanese Breast Cancer Society Clinical Practice Guideline for systemic treatment of breast cancer, 2015 edition. Breast Cancer. 2016;23(3):329–42.CrossRefPubMed

Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30(7):1073–81.CrossRefPubMed

10.

Heikkilä K, Ebrahim S, Lawlor DA. Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. Eur J Cancer. 2008;44(7):937–45.CrossRefPubMed

11.

Salgado R, Junius S, Benoy I, Van Dam P, Vermeulen P, Van Marck E, Huget P, Dirix LY. Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int J Cancer. 2003;103(5):642–6.CrossRefPubMed

12.

Yokoe T, Iino Y, Morishita Y. Trends of IL-6 and IL-8 levels in patients with recurrent breast cancer: preliminary report. Breast Cancer. 2000;7(3):187–90.CrossRefPubMed

13.

Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer. 2005;41(16):2502–12.CrossRefPubMed

14.

Malinowska K, Neuwirt H, Cavarretta IT, Bektic J, Steiner H, Dietrich H, Moser PL, Fuchs D, Hobisch A, Culig Z. Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor. Endocr Relat Cancer. 2009;16(1):155–69.CrossRefPubMed

15.

Sasser AK, Sullivan NJ, Studebaker AW, Hendey LF, Axel AE, Hall BM. Interleukin-6 is a potent growth factor for ER-alpha-positive human breast cancer. FASEB J. 2007;21(13):3763–70.CrossRefPubMed

16.

Chiu JJ, Sgagias MK, Cowan KH. Interleukin 6 acts as a paracrine growth factor in human mammary carcinoma cell lines. Clin Cancer Res. 1996;2(1):215–21.PubMed

17.

Yamashita JI, Ogawa M. Medroxyprogesterone acetate and cancer cachexia: interleukin-6 involvement. Breast Cancer. 2000;7(2):130–5.CrossRefPubMed

18.

Liu S, Ishikawa H, Li FJ, Ma Z, Otsuyama K, Asaoku H, Abroun S, Zheng X, Tsuyama N, Obata M, Kawano MM. Dehydroepiandrosterone can inhibit the proliferation of myeloma cells and the interleukin-6 production of bone marrow mononuclear cells from patients with myeloma. Cancer Res. 2005;65(6):2269–76.CrossRefPubMed

19.

Liu S, Ma Z, Cai H, Li Q, Rong W, Kawano M. Inhibitory effect of baicalein on IL-6-mediated signaling cascades in human myeloma cells. Eur J Haematol. 2010;84(2):137–44.CrossRefPubMed

20.

Kishimoto T. Interleukin-6: discovery of a pleiotropic cytokine. Arthritis Res Ther. 2006;8(Suppl. 2):S2.CrossRefPubMedPubMedCentral

21.

Yoshio-Hoshino N, Adachi Y, Aoki C, Pereboev A, Curiel DT, Nishimoto N. Establishment of a new interleukin-6 (IL-6) receptor inhibitor applicable to the gene therapy for IL-6-dependent tumor. Cancer Res. 2007;67(3):871–5.CrossRefPubMed

22.

Oguro T, Ishibashi K, Sugino T, Hashimoto K, Tomita S, Takahashi N, Yanagida T, Haga N, Aikawa K, Suzutani T, Yamaguchi O, Kojima Y. Humanised antihuman IL-6R antibody with interferon inhibits renal cell carcinoma cell growth in vitro and in vivo through suppressed SOCS3 expression. Eur J Cancer. 2013;49(7):1715–24.CrossRefPubMed

23.

Hamaguchi T, Wakabayashi H, Matsumine A, Sudo A, Uchida A. TNF inhibitor suppresses bone metastasis in a breast cancer cell line. Biochem Biophys Res Commun. 2011;407(3):525–30.CrossRefPubMed

24.

Araki K, Wakabayashi H, Shintani K, Morikawa J, Matsumine A, Kusuzaki K, Sudo A, Uchida A. Decorin suppresses bone metastasis in a breast cancer cell line. Oncology. 2009;77(2):92–9.CrossRefPubMed

25.

Ara T, Declerck YA. Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer. 2010;46(7):1223–31.CrossRefPubMedPubMedCentral

26.

Maruthanila VL, Elancheran R, Kunnumakkara AB, Kabilan S, Kotoky J. Recent development of targeted approaches for the treatment of breast cancer. Breast Cancer. 2017;24(2):191–219.CrossRefPubMed

27.

Gautam S, Roy S, Ansari MN, Saeedan AS, Saraf SA, Kaithwas G. DuCLOX-2/5 inhibition: a promising target for cancer chemoprevention. Breast Cancer. 2017;24(2):180–90.CrossRefPubMed

28.

Santini D, Perrone G, Roato I, Godio L, Pantano F, Grasso D, Russo A, Vincenzi B, Fratto ME, Sabbatini R, Della Pepa C, Porta C, Del Conte A, Schiavon G, Berruti A, Tomasino RM, Papotti M, Papapietro N, Onetti Muda A, Denaro V, Tonini G. Expression pattern of receptor activator of NFκB (RANK) in a series of primary solid tumors and related bone metastases. J Cell Physiol. 2011;226(3):780–4.CrossRefPubMed

29.

Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest. 2007;117:1175–83.CrossRefPubMedPubMedCentral

30.

Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3(9):651–62.CrossRefPubMed

31.

Scherzad A, Steber M, Gehrke T, Rak K, Froelich K, Schendzielorz P, Hagen R, Kleinsasser N, Hackenberg S. Human mesenchymal stem cells enhance cancer cell proliferation via IL-6 secretion and activation of ERK1/2. Int J Oncol. 2015;47(1):391–7.CrossRefPubMed

32.

Shi Y, Hsu JH, Hu L, Gera J, Lichtenstein A. Signal pathways involved in activation of p70S6K and phosphorylation of 4E-BP1 following exposure of multiple myeloma tumor cells to interleukin-6. J Biol Chem. 2002;277:15712–20.CrossRefPubMed

33.

Hong DS, Angelo LS, Kurzrock R. Interleukin-6 and its receptor in cancer: implications for translational therapeutics. Cancer. 2007;110(9):1911–28.CrossRefPubMed

34.

Zheng Y, Basel D, Chow SO, Fong-Yee C, Kim S, Buttgereit F, Dunstan CR, Zhou H, Seibel MJ. Targeting IL-6 and RANKL signaling inhibits prostate cancer growth in bone. Clin Exp Metastasis. 2014;31(8):921–33.CrossRefPubMed

35.

Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov. 2007;6(4):273–86.CrossRefPubMed

36.

Tzeng HE, Tsai CH, Chang ZL, Su CM, Wang SW, Hwang WL, Tang CH. Interleukin-6 induces vascular endothelial growth factor expression and promotes angiogenesis through apoptosis signal-regulating kinase 1 in human osteosarcoma. Biochem Pharmacol. 2013;85(4):531–40.CrossRefPubMed

37.

Arihiro K, Oda H, Kaneko M, Inai K. Cytokines facilitate chemotactic motility of breast carcinoma cells. Breast Cancer. 2000;7(3):221–30.CrossRefPubMed

38.

Ahmad N, Ammar A, Storr SJ, Green AR, Rakha E, Ellis IO, Martin SG. IL-6 and IL-10 are associated with good prognosis in early stage invasive breast cancer patients. Cancer Immunol Immunother. 2017. https://doi.org/10.1007/s00262-017-2106-8.CrossRefPubMedPubMedCentral

39.

James JJ, Evans AJ, Pinder SE, Gutteridge E, Cheung KL, Chan S, Robertson JF. Bone metastases from breast carcinoma: histopathological-radiological correlations and prognostic features. Br J Cancer. 2003;89(4):660–5.CrossRefPubMedPubMedCentral

40.

Kassem M, Khosla S, Spelsberg TC, Riggs BL. Cytokine production in the bone marrow microenvironment: failure to demonstrate estrogen regulation in early postmenopausal women. J Clin Endocrinol Metab. 1996;81(2):513–8.PubMed

Titel: Interleukin-6 receptor inhibitor suppresses bone metastases in a breast cancer cell line
verfasst von: Hiroki Wakabayashi
Takahiko Hamaguchi
Nobuto Nagao
Sho Kato
Takahiro Iino
Tomoki Nakamura
Akihiro Sudo
Publikationsdatum: 19.03.2018
Verlag: Springer Japan
Erschienen in: Breast Cancer / Ausgabe 5/2018
Print ISSN: 1340-6868
Elektronische ISSN: 1880-4233
DOI: https://doi.org/10.1007/s12282-018-0853-9

Neu im Fachgebiet Onkologie

24.04.2024 | DGIM 2024 | Nachrichten

Springer Medizin

Interleukin-6 receptor inhibitor suppresses bone metastases in a breast cancer cell line

Abstract

Background

Methods

Results

Conclusions

Neu im Fachgebiet Onkologie

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Update Onkologie

Springer Medizin

Abstract

Background

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 5/2018

Assessing residual cancer cells using MRI and US after preoperative chemotherapy in primary breast cancer to omit surgery

Evaluation of the dislocation and long-term sonographic detectability of a hydrogel-based breast biopsy site marker

Feasibility study of contralateral risk-reducing mastectomy with breast reconstruction for breast cancer patients with BRCA mutations in Japan

Applying new Magee equations for predicting the Oncotype Dx recurrence score

LncRNA PlncRNA-1 overexpression inhibits the growth of breast cancer by upregulating TGF-β1 and downregulating PHGDH

HER2 genomic amplification in circulating tumor DNA and estrogen receptor positivity predict primary resistance to trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer

Neu im Fachgebiet Onkologie

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Update Onkologie