Skip to main content
Top
Published in: Tumor Biology 4/2016

01-04-2016 | Original Article

Coexpression of CXCR4 and MMP9 predicts lung metastasis and poor prognosis in resected osteosarcoma

Authors: Zhiwu Ren, Shoulei Liang, Jilong Yang, Xiuxin Han, Luling Shan, Biying Wang, Tianyang Mu, Yanqin Zhang, Xueli Yang, Shunbin Xiong, Guowen Wang

Published in: Tumor Biology | Issue 4/2016

Login to get access

Abstract

Osteosarcoma is a highly aggressive bone disease with a tendency to metastasize to the lung. The 5-year survival of patients with metastatic osteosarcoma is only 20 %. Many studies have demonstrated SDF-1/CXCR4 and MMP9 play important roles in the metastasis of malignant tumors, including osteosarcoma. The aim of this study was to investigate the association of CXCR4 and MMP9 expression with clinicopathological features and pulmonary metastasis in osteosarcoma. Using tumor tissue microarrays, we analyzed the expression of CXCR4 and MMP9 among 34 primary osteosarcomas with pulmonary metastasis and 62 primary osteosarcomas without metastasis. A median time of 57.5 months (range: 6 to 171 months) follow-up was performed to evaluate tumor metastasis and the patient survival. The prognostic values were determined by univariate Kaplan-Meier survival analysis and multivariate Cox proportional hazard model analysis. The accuracy of oncologic outcome prediction was evaluated by receiver-operating characteristics (ROC) curves (AUC). The expression of CXCR4 and MMP9 was significantly correlated in tumor tissues (P = 0.026). Both CXCR4 and MMP9 were independent predictors for overall survival and metastasis-free survival by Cox multivariate analysis, and high expression for both CXCR4 and MMP9 were even more significant and better biomarkers for osteosarcoma metastasis and survival. The combination of CXCR4 and MMP9 high expression is very likely to be a valuable independent predictor of lung metastasis and survival in osteosarcoma patients.
Literature
1.
go back to reference Ritter J, Bielack SS. Osteosarcoma. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2010;21 Suppl 7:vii320–5. Ritter J, Bielack SS. Osteosarcoma. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2010;21 Suppl 7:vii320–5.
2.
go back to reference Bacci G, Rocca M, Salone M, Balladelli A, Ferrari S, Palmerini E, et al. High grade osteosarcoma of the extremities with lung metastases at presentation: Treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions. J Surg Oncol. 2008;98:415–20.CrossRefPubMed Bacci G, Rocca M, Salone M, Balladelli A, Ferrari S, Palmerini E, et al. High grade osteosarcoma of the extremities with lung metastases at presentation: Treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions. J Surg Oncol. 2008;98:415–20.CrossRefPubMed
3.
go back to reference Kager L, Zoubek A, Potschger U, Kastner U, Flege S, Kempf-Bielack B, et al. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21:2011–8.CrossRef Kager L, Zoubek A, Potschger U, Kastner U, Flege S, Kempf-Bielack B, et al. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21:2011–8.CrossRef
5.
go back to reference Teicher BA, Fricker SP. Cxcl12 (sdf-1)/cxcr4 pathway in cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2010;16:2927–31.CrossRef Teicher BA, Fricker SP. Cxcl12 (sdf-1)/cxcr4 pathway in cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2010;16:2927–31.CrossRef
6.
go back to reference Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50–6.CrossRefPubMed Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50–6.CrossRefPubMed
7.
go back to reference Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK. Use of the stromal cell-derived factor-1/cxcr4 pathway in prostate cancer metastasis to bone. Cancer Res. 2002;62:1832–7.PubMed Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK. Use of the stromal cell-derived factor-1/cxcr4 pathway in prostate cancer metastasis to bone. Cancer Res. 2002;62:1832–7.PubMed
8.
go back to reference Yang YC, Lee ZY, Wu CC, Chen TC, Chang CL, Chen CP. Cxcr4 expression is associated with pelvic lymph node metastasis in cervical adenocarcinoma. Int J Gynecol Cancer Off J Int Gynecol Cancer Soc. 2007;17:676–86.CrossRef Yang YC, Lee ZY, Wu CC, Chen TC, Chang CL, Chen CP. Cxcr4 expression is associated with pelvic lymph node metastasis in cervical adenocarcinoma. Int J Gynecol Cancer Off J Int Gynecol Cancer Soc. 2007;17:676–86.CrossRef
9.
go back to reference Wagner PL, Hyjek E, Vazquez MF, Meherally D, Liu YF, Chadwick PA, et al. Cxcl12 and cxcr4 in adenocarcinoma of the lung: association with metastasis and survival. J Thorac Cardiovasc Surg. 2009;137:615–21.CrossRefPubMed Wagner PL, Hyjek E, Vazquez MF, Meherally D, Liu YF, Chadwick PA, et al. Cxcl12 and cxcr4 in adenocarcinoma of the lung: association with metastasis and survival. J Thorac Cardiovasc Surg. 2009;137:615–21.CrossRefPubMed
10.
go back to reference Perissinotto E, Cavalloni G, Leone F, Fonsato V, Mitola S, Grignani G, et al. Involvement of chemokine receptor 4/stromal cell-derived factor 1 system during osteosarcoma tumor progression. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11:490–7. Perissinotto E, Cavalloni G, Leone F, Fonsato V, Mitola S, Grignani G, et al. Involvement of chemokine receptor 4/stromal cell-derived factor 1 system during osteosarcoma tumor progression. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11:490–7.
11.
go back to reference Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2:161–74.CrossRefPubMed Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2:161–74.CrossRefPubMed
12.
go back to reference Shuman Moss LA, Jensen-Taubman S, Stetler-Stevenson WG. Matrix metalloproteinases: changing roles in tumor progression and metastasis. Am J Pathol. 2012;181:1895–9.CrossRefPubMedPubMedCentral Shuman Moss LA, Jensen-Taubman S, Stetler-Stevenson WG. Matrix metalloproteinases: changing roles in tumor progression and metastasis. Am J Pathol. 2012;181:1895–9.CrossRefPubMedPubMedCentral
13.
go back to reference Baldwin RM, Haghandish N, Daneshmand M, Amin S, Paris G, Falls TJ, et al. Protein arginine methyltransferase 7 promotes breast cancer cell invasion through the induction of mmp9 expression. Oncotarget. 2015;6:3013–32.CrossRefPubMed Baldwin RM, Haghandish N, Daneshmand M, Amin S, Paris G, Falls TJ, et al. Protein arginine methyltransferase 7 promotes breast cancer cell invasion through the induction of mmp9 expression. Oncotarget. 2015;6:3013–32.CrossRefPubMed
14.
go back to reference Chen Y, Jiang T, Mao A, Xu J. Esophageal cancer stem cells express plgf to increase cancer invasion through mmp9 activation. Tumour Biol J Int Soc Oncodev Biol Med. 2014;35:12749–55.CrossRef Chen Y, Jiang T, Mao A, Xu J. Esophageal cancer stem cells express plgf to increase cancer invasion through mmp9 activation. Tumour Biol J Int Soc Oncodev Biol Med. 2014;35:12749–55.CrossRef
15.
go back to reference Huang Q, Lan F, Wang X, Yu Y, Ouyang X, Zheng F, et al. Il-1beta-induced activation of p38 promotes metastasis in gastric adenocarcinoma via upregulation of ap-1/c-fos, mmp2 and mmp9. Mol Cancer. 2014;13:18.CrossRefPubMedPubMedCentral Huang Q, Lan F, Wang X, Yu Y, Ouyang X, Zheng F, et al. Il-1beta-induced activation of p38 promotes metastasis in gastric adenocarcinoma via upregulation of ap-1/c-fos, mmp2 and mmp9. Mol Cancer. 2014;13:18.CrossRefPubMedPubMedCentral
16.
go back to reference Wang X, Lu H, Urvalek AM, Li T, Yu L, Lamar J, et al. Klf8 promotes human breast cancer cell invasion and metastasis by transcriptional activation of mmp9. Oncogene. 2011;30:1901–11.CrossRefPubMed Wang X, Lu H, Urvalek AM, Li T, Yu L, Lamar J, et al. Klf8 promotes human breast cancer cell invasion and metastasis by transcriptional activation of mmp9. Oncogene. 2011;30:1901–11.CrossRefPubMed
17.
go back to reference Chinni SR, Sivalogan S, Dong Z, Filho JC, Deng X, Bonfil RD, et al. Cxcl12/cxcr4 signaling activates akt-1 and mmp-9 expression in prostate cancer cells: The role of bone microenvironment-associated cxcl12. Prostate. 2006;66:32–48.CrossRefPubMed Chinni SR, Sivalogan S, Dong Z, Filho JC, Deng X, Bonfil RD, et al. Cxcl12/cxcr4 signaling activates akt-1 and mmp-9 expression in prostate cancer cells: The role of bone microenvironment-associated cxcl12. Prostate. 2006;66:32–48.CrossRefPubMed
18.
go back to reference Nian WQ, Chen FL, Ao XJ, Chen ZT. Cxcr4 positive cells from lewis lung carcinoma cell line have cancer metastatic stem cell characteristics. Mol Cell Biochem. 2011;355:241–8.CrossRefPubMed Nian WQ, Chen FL, Ao XJ, Chen ZT. Cxcr4 positive cells from lewis lung carcinoma cell line have cancer metastatic stem cell characteristics. Mol Cell Biochem. 2011;355:241–8.CrossRefPubMed
19.
go back to reference Lee CC, Lai JH, Hueng DY, Ma HI, Chung Y, Sun YY, et al. Disrupting the cxcl12/cxcr4 axis disturbs the characteristics of glioblastoma stem-like cells of rat rg2 glioblastoma. Cancer Cell Int. 2013;13:85.CrossRefPubMedPubMedCentral Lee CC, Lai JH, Hueng DY, Ma HI, Chung Y, Sun YY, et al. Disrupting the cxcl12/cxcr4 axis disturbs the characteristics of glioblastoma stem-like cells of rat rg2 glioblastoma. Cancer Cell Int. 2013;13:85.CrossRefPubMedPubMedCentral
20.
go back to reference Marchesi F, Monti P, Leone BE, Zerbi A, Vecchi A, Piemonti L, et al. Increased survival, proliferation, and migration in metastatic human pancreatic tumor cells expressing functional cxcr4. Cancer Res. 2004;64:8420–7.CrossRefPubMed Marchesi F, Monti P, Leone BE, Zerbi A, Vecchi A, Piemonti L, et al. Increased survival, proliferation, and migration in metastatic human pancreatic tumor cells expressing functional cxcr4. Cancer Res. 2004;64:8420–7.CrossRefPubMed
21.
go back to reference Brand S, Dambacher J, Beigel F, Olszak T, Diebold J, Otte JM, et al. Cxcr4 and cxcl12 are inversely expressed in colorectal cancer cells and modulate cancer cell migration, invasion and mmp-9 activation. Exp Cell Res. 2005;310:117–30.CrossRefPubMed Brand S, Dambacher J, Beigel F, Olszak T, Diebold J, Otte JM, et al. Cxcr4 and cxcl12 are inversely expressed in colorectal cancer cells and modulate cancer cell migration, invasion and mmp-9 activation. Exp Cell Res. 2005;310:117–30.CrossRefPubMed
22.
go back to reference Samara GJ, Lawrence DM, Chiarelli CJ, Valentino MD, Lyubsky S, Zucker S, et al. Cxcr4-mediated adhesion and mmp-9 secretion in head and neck squamous cell carcinoma. Cancer Lett. 2004;214:231–41.CrossRefPubMed Samara GJ, Lawrence DM, Chiarelli CJ, Valentino MD, Lyubsky S, Zucker S, et al. Cxcr4-mediated adhesion and mmp-9 secretion in head and neck squamous cell carcinoma. Cancer Lett. 2004;214:231–41.CrossRefPubMed
23.
go back to reference Murphy PM. Chemokines and the molecular basis of cancer metastasis. N Engl J Med. 2001;345:833–5.CrossRefPubMed Murphy PM. Chemokines and the molecular basis of cancer metastasis. N Engl J Med. 2001;345:833–5.CrossRefPubMed
24.
go back to reference Oda Y, Yamamoto H, Tamiya S, Matsuda S, Tanaka K, Yokoyama R, et al. Cxcr4 and vegf expression in the primary site and the metastatic site of human osteosarcoma: Analysis within a group of patients, all of whom developed lung metastasis. Modern Pathol Off J US Can Acad Pathol Inc. 2006;19:738–45. Oda Y, Yamamoto H, Tamiya S, Matsuda S, Tanaka K, Yokoyama R, et al. Cxcr4 and vegf expression in the primary site and the metastatic site of human osteosarcoma: Analysis within a group of patients, all of whom developed lung metastasis. Modern Pathol Off J US Can Acad Pathol Inc. 2006;19:738–45.
25.
go back to reference Laverdiere C, Hoang BH, Yang R, Sowers R, Qin J, Meyers PA, et al. Messenger rna expression levels of cxcr4 correlate with metastatic behavior and outcome in patients with osteosarcoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11:2561–7.CrossRef Laverdiere C, Hoang BH, Yang R, Sowers R, Qin J, Meyers PA, et al. Messenger rna expression levels of cxcr4 correlate with metastatic behavior and outcome in patients with osteosarcoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11:2561–7.CrossRef
26.
go back to reference Mira E, Lacalle RA, Buesa JM, de Buitrago GG, Jimenez-Baranda S, Gomez-Mouton C, et al. Secreted mmp9 promotes angiogenesis more efficiently than constitutive active mmp9 bound to the tumor cell surface. J Cell Sci. 2004;117:1847–57.CrossRefPubMed Mira E, Lacalle RA, Buesa JM, de Buitrago GG, Jimenez-Baranda S, Gomez-Mouton C, et al. Secreted mmp9 promotes angiogenesis more efficiently than constitutive active mmp9 bound to the tumor cell surface. J Cell Sci. 2004;117:1847–57.CrossRefPubMed
28.
go back to reference Hiratsuka S, Nakamura K, Iwai S, Murakami M, Itoh T, Kijima H, et al. Mmp9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell. 2002;2:289–300.CrossRefPubMed Hiratsuka S, Nakamura K, Iwai S, Murakami M, Itoh T, Kijima H, et al. Mmp9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell. 2002;2:289–300.CrossRefPubMed
29.
go back to reference van Kempen LC, Coussens LM. Mmp9 potentiates pulmonary metastasis formation. Cancer Cell. 2002;2:251–2.CrossRefPubMed van Kempen LC, Coussens LM. Mmp9 potentiates pulmonary metastasis formation. Cancer Cell. 2002;2:251–2.CrossRefPubMed
30.
go back to reference Liang S, Ren Z, Han X, Yang J, Shan L, Li L, et al. Pla2g16 expression in human osteosarcoma is associated with pulmonary metastasis and poor prognosis. PLoS One. 2015;10:e0127236.CrossRefPubMedPubMedCentral Liang S, Ren Z, Han X, Yang J, Shan L, Li L, et al. Pla2g16 expression in human osteosarcoma is associated with pulmonary metastasis and poor prognosis. PLoS One. 2015;10:e0127236.CrossRefPubMedPubMedCentral
31.
go back to reference Meyers PA, Heller G, Healey JH, Huvos A, Applewhite A, Sun M, et al. Osteogenic sarcoma with clinically detectable metastasis at initial presentation. J Clin Oncol Off J Am Soc Clin Oncol. 1993;11:449–53.CrossRef Meyers PA, Heller G, Healey JH, Huvos A, Applewhite A, Sun M, et al. Osteogenic sarcoma with clinically detectable metastasis at initial presentation. J Clin Oncol Off J Am Soc Clin Oncol. 1993;11:449–53.CrossRef
32.
go back to reference Jaffe N, Carrasco H, Raymond K, Ayala A, Eftekhari F. Can cure in patients with osteosarcoma be achieved exclusively with chemotherapy and abrogation of surgery? Cancer. 2002;95:2202–10.CrossRefPubMed Jaffe N, Carrasco H, Raymond K, Ayala A, Eftekhari F. Can cure in patients with osteosarcoma be achieved exclusively with chemotherapy and abrogation of surgery? Cancer. 2002;95:2202–10.CrossRefPubMed
Metadata
Title
Coexpression of CXCR4 and MMP9 predicts lung metastasis and poor prognosis in resected osteosarcoma
Authors
Zhiwu Ren
Shoulei Liang
Jilong Yang
Xiuxin Han
Luling Shan
Biying Wang
Tianyang Mu
Yanqin Zhang
Xueli Yang
Shunbin Xiong
Guowen Wang
Publication date
01-04-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 4/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4352-8

Other articles of this Issue 4/2016

Tumor Biology 4/2016 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine