Metastasis Promoted by Cleaving and Inhibiting Proapoptotic Effect of von Willebrand Factor

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Mochizuki and colleagues from Keio University in Tokyo, the Chemo-Sero-Therapeutic Research Institute in Kumamoto, and RIKEN in Saitama have shown that von Willebrand factor has proapoptotic effects and that a disintegrin and metalloproteinase 28 (ADAM28) promotes metastasis by cleaving and inactivating von Willebrand factor and thus enhancing cancer cell survival in the circulation. These researchers had previously shown that increased tumor and serum levels of ADAM28 correlated with poor prognosis and metastasis in patients with breast and non–small cell lung cancer, and proposed that ADAM28 promotes tumor growth via selective digestion of insulin-like growth factor binding protein 3 and connective tissue growth factor.

In their study of the potential role of ADAM28 in metastasis, screening of a human lung cDNA library for substrates of ADAM28 using a yeast two-hybrid system yielded von Willebrand factor as a candidate binding protein. ADAM28 was found to bind and cleave native von Willebrand factor.

Cells with low ADAM28 expression—breast carcinoma MCF-7, renal carcinoma 769P, and hepatocellular carcinoma HepG2 cells—were susceptible to von Willebrand factor–induced apoptosis. In contrast, cells with high ADAM28 expression—lung carcinoma PC9 and Calu-3, breast carcinoma MDA-MB231, and renal cell carcinoma Caki-2 cells—were resistant to von Willebrand factor–induced apoptosis. Further, von Willebrand factor–induced apoptosis was shown to involve the αVβ3 integrin and activation of a mitochondrial cell death pathway.

In a mouse model of lung metastasis, knockdown of ADAM28 expression in PC-9 and MDA-MB231 cells using short hairpin RNAs (shRNAs) resulted in increased carcinoma cell apoptosis, which occurred mainly in lung blood vessels and was associated with decreased von Willebrand factor degradation in the blood. In vivo imaging showed a significant decrease in lung metastasis at week 3 after injection in ADAM28-shRNA knockdown mice compared with control mice (mean counts of 37 vs 198 × 106 photons/s for PC-9 ADAM28-shRNA, P < .001). Similar inhibition of lung metastasis was observed with ADAM28 knockdown using small interfering RNAs (siRNAs) and with inhibition of ADAM28 activity via an anti-ADAM28 neutralizing antibody.

As summarized by the investigators, “ADAM28 cleaves and inactivates proapoptotic [von Willebrand factor] in carcinoma cells and enhances lung metastasis probably by promoting carcinoma cell survival within the blood vessels.”  ■

Mochizuki S, et al: J Natl Cancer Inst 104:906-922, 2012.

Zucker S, Cao J: J Natl Cancer Inst 104:887-888, 2012.




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