Elevated TIMP-1 expression is associated with a prometastatic phenotype, disease relapse, and poor survival in neuroblastoma
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Pritha Paul1,4,*, Eric J. Rellinger1,4,*, Jingbo Qiao1,4, Sora Lee1,4, Natasha Volny1,4, Chandrasekhar Padmanabhan1, Carmelle V. Romain1,4, Bret Mobley3, Hernan Correa3 and Dai H. Chung1,2,4
1Section of Surgical Sciences, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
2Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
3Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
4Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
*These authors have contributed equally to this work
Dai H. Chung, email: [email protected]
Keywords: TIMP-1, neuroblastoma, metastasis, liver, LM2
Abbreviations: TIMP, tissue inhibitor of metalloproteinases
Received: August 16, 2016 Accepted: May 04, 2017 Published: July 28, 2017
Approximately two-thirds of patients with neuroblastoma are found to have metastatic disease at time of diagnosis with frequent skeletal, lymph node, central nervous system, and liver involvement. Using a serial in vivo splenic injection model, we have isolated an aggressive subclone (BE(2)-C/LM2) from MYCN-amplified neuroblastomas that demonstrate an enhanced propensity to develop metastatic liver lesions. BE(2)-C/LM2 subclone cells demonstrate increased adherent, soft agar colony and tumorsphere growth in vitro. Components of the tumor microenvironment regulate cancer progression, via networks of cytokines and growth factors. Cytokine array analysis identified increased TIMP-1 in the plasma of mice injected with BE(2)-C/LM2 subclone cells, leading us to hypothesize that TIMP-1 may play a role in our observed prometastatic phenotype. Immunoblotting and ELISA demonstrated enhanced endogenous TIMP-1 expression in our isolated neuroblastoma subclone. Silencing endogenous TIMP-1 successfully blocked in vitro proliferation, soft agar colony formation and tumorsphere formation by BE(2)-C/LM2 cells. Stable RNA interference of endogenous TIMP-1 failed to reverse the prometastatic phenotype of our BE(2)-C/LM2 subclone in our liver metastasis model, suggesting that endogenous TIMP-1 levels may not be an essential component of this in vivo behavior. Notably, tissue microarray analysis and Kaplan-Meier by gene expression demonstrates that elevated TIMP-1 expression is correlated with increased disease relapse and mortality in patients with neuroblastoma. Taken together, our study identifies TIMP-1 as a novel soluble factor that is associated with a prometastatic phenotype in our in vivo model and adverse outcomes in patients with neuroblastoma.
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