Differential Secretome Analysis Reveals CST6 As a Suppressor of Breast Cancer Bone Metastasis

Overview

Journal Cell Res

Specialty Cell Biology

Date 2012 Jun 13

PMID 22688893

Citations 31

Authors

Lei Jin

Yan Zhang

Hui Li

Ling Yao

Da Fu

Xuebiao Yao

Lisa X Xu

Xiaofang Hu

Guohong Hu

Affiliations

Soon will be listed here.

Abstract

Bone metastasis is a frequent complication of breast cancer and a common cause of morbidity and mortality from the disease. During metastasis secreted proteins play crucial roles in the interactions between cancer cells and host stroma. To characterize the secreted proteins that are associated with breast cancer bone metastasis, we preformed a label-free proteomic analysis to compare the secretomes of four MDA-MB-231 (MDA231) derivative cell lines with varied capacities of bone metastasis. A total of 128 proteins were found to be consistently up-/down-regulated in the conditioned medium of bone-tropic cancer cells. The enriched molecular functions of the altered proteins included receptor binding and peptidase inhibition. Through additional transcriptomic analyses of breast cancer cells, we selected cystatin E/M (CST6), a cysteine protease inhibitor down-regulated in bone-metastatic cells, for further functional studies. Our results showed that CST6 suppressed the proliferation, colony formation, migration and invasion of breast cancer cells. The suppressive function against cancer cell motility was carried out by cancer cell-derived soluble CST6. More importantly, ectopic expression of CST6 in cancer cells rescued mice from overt osteolytic metastasis and deaths in the animal study, while CST6 knockdown markedly enhanced cancer cell bone metastasis and shortened animal survival. Overall, our study provided a systemic secretome analysis of breast cancer bone tropism and established secreted CST6 as a bona fide suppressor of breast cancer osteolytic metastasis.

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References

Zhang J, Shridhar R, Dai Q, Song J, Barlow S, Yin L . Cystatin m: a novel candidate tumor suppressor gene for breast cancer. Cancer Res. 2004; 64(19):6957-64. DOI: 10.1158/0008-5472.CAN-04-0819. View

Kim T, Zhong S, Fields C, Kim J, Robertson K . Epigenomic profiling reveals novel and frequent targets of aberrant DNA methylation-mediated silencing in malignant glioma. Cancer Res. 2006; 66(15):7490-501. DOI: 10.1158/0008-5472.CAN-05-4552. View

Minn A, Gupta G, Siegel P, Bos P, Shu W, Giri D . Genes that mediate breast cancer metastasis to lung. Nature. 2005; 436(7050):518-24. PMC: 1283098. DOI: 10.1038/nature03799. View

Condeelis J, Pollard J . Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006; 124(2):263-6. DOI: 10.1016/j.cell.2006.01.007. View

Kaplan R, Riba R, Zacharoulis S, Bramley A, Vincent L, Costa C . VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005; 438(7069):820-7. PMC: 2945882. DOI: 10.1038/nature04186. View

Zhong L, Roybal J, Chaerkady R, Zhang W, Choi K, Alvarez C . Identification of secreted proteins that mediate cell-cell interactions in an in vitro model of the lung cancer microenvironment. Cancer Res. 2008; 68(17):7237-45. PMC: 2562343. DOI: 10.1158/0008-5472.CAN-08-1529. View

Rivenbark A, Jones W, Coleman W . DNA methylation-dependent silencing of CST6 in human breast cancer cell lines. Lab Invest. 2006; 86(12):1233-42. DOI: 10.1038/labinvest.3700485. View

Korpal M, Yan J, Lu X, Xu S, Lerit D, Kang Y . Imaging transforming growth factor-beta signaling dynamics and therapeutic response in breast cancer bone metastasis. Nat Med. 2009; 15(8):960-6. DOI: 10.1038/nm.1943. View

Koblinski J, Ahram M, Sloane B . Unraveling the role of proteases in cancer. Clin Chim Acta. 2000; 291(2):113-35. DOI: 10.1016/s0009-8981(99)00224-7. View

10.

Yang S, Miah A, Pabari A, Winslet M . Growth Factors and their receptors in cancer metastases. Front Biosci (Landmark Ed). 2011; 16(2):531-8. DOI: 10.2741/3703. View

11.

Vigneswaran N, Wu J, Nagaraj N, James R, Zeeuwen P, Zacharias W . Silencing of cystatin M in metastatic oral cancer cell line MDA-686Ln by siRNA increases cysteine proteinases and legumain activities, cell proliferation and in vitro invasion. Life Sci. 2005; 78(8):898-907. DOI: 10.1016/j.lfs.2005.05.096. View

12.

Ross D, Scherf U, Eisen M, Perou C, Rees C, Spellman P . Systematic variation in gene expression patterns in human cancer cell lines. Nat Genet. 2000; 24(3):227-35. DOI: 10.1038/73432. View

13.

Serganova I, Moroz E, Vider J, Gogiberidze G, Moroz M, Pillarsetty N . Multimodality imaging of TGFbeta signaling in breast cancer metastases. FASEB J. 2009; 23(8):2662-72. PMC: 2717767. DOI: 10.1096/fj.08-126920. View

14.

Langley R, Fidler I . The seed and soil hypothesis revisited--the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer. 2011; 128(11):2527-35. PMC: 3075088. DOI: 10.1002/ijc.26031. View

15.

Hess K, Varadhachary G, Taylor S, Wei W, Raber M, Lenzi R . Metastatic patterns in adenocarcinoma. Cancer. 2006; 106(7):1624-33. DOI: 10.1002/cncr.21778. View

16.

Zhang X, Wang Q, Gerald W, Hudis C, Norton L, Smid M . Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell. 2009; 16(1):67-78. PMC: 2749247. DOI: 10.1016/j.ccr.2009.05.017. View

17.

Rocco M, Malorni L, Cozzolino R, Palmieri G, Rozzo C, Manca A . Proteomic profiling of human melanoma metastatic cell line secretomes. J Proteome Res. 2011; 10(10):4703-14. DOI: 10.1021/pr200511f. View

18.

Yoon K, Phelps D, Bush R, Remack J, Billups C, Khoury J . ICAM-2 expression mediates a membrane-actin link, confers a nonmetastatic phenotype and reflects favorable tumor stage or histology in neuroblastoma. PLoS One. 2008; 3(11):e3629. PMC: 2575377. DOI: 10.1371/journal.pone.0003629. View

19.

Keppler D . Towards novel anti-cancer strategies based on cystatin function. Cancer Lett. 2005; 235(2):159-76. DOI: 10.1016/j.canlet.2005.04.001. View

20.

Bendtsen J, Nielsen H, von Heijne G, Brunak S . Improved prediction of signal peptides: SignalP 3.0. J Mol Biol. 2004; 340(4):783-95. DOI: 10.1016/j.jmb.2004.05.028. View