High mobility group box 1 antagonist limits metastatic seeding in the lungs via reduction of cell–cell adhesion
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Adi Karsch-Bluman1, Benzion Amoyav1, Nethanel Friedman1, Hila Shoval1, Ouri Schwob1, Ezra Ella2, Ori Wald2,3, Ofra Benny1
1The Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
2The Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
3Division of General Thoracic Surgery, Michael E. DeBakey Department of General Surgery, Baylor College of Medicine, Houston, TX, USA
Ofra Benny, email: email@example.com
Keywords: HMGB1, ICAM1, LLC, Carbenoxolone, metastasis
Received: January 31, 2017 Accepted: March 06, 2017 Published: March 14, 2017
Metastatic spread is the leading cause for cancer-related mortality, with the lungs being a major site for metastatic seeding. Available therapies for patients with metastatic disease are extremely limited. Therefore, there is a desperate need for new strategies to prevent or limit metastatic dissemination and treat existing metastases. The metastatic cascade is highly complex and is affected by multiple factors related to both tumor cells themselves and the microenvironment in the future site of metastasis. We hypothesized that modifying the lung microenvironment by blocking central ubiquitous signals may affect metastatic seeding in the lungs. Given the high basal levels of the Receptor for Advanced Glycation End products (RAGE) in the pulmonary tissue, and its pro-inflammatory properties, we investigated the consequences of interfering with its ligand; High Mobility Group Box 1 (HMGB1). To this end, we tested the effect of Carbenoxolone, an HMGB1 antagonist, on primary tumor growth and metastatic progression in several murine tumor models. We show that antagonizing HMGB1 prevents the adhesion and colonization of cancer cells in the lungs through the reduction of their adhesion and cell–cell interaction both in vitro and in vivo. We demonstrated that these activities are mediated by downregulation of the adhesion molecule Intercellular Adhesion Molecule 1 (ICAM1) and ultimately result in reduced metastatic burden. Carbenoxolone decreases significantly lung metastases formation and can be used potentially as prophylactic therapy for metastatic diseases.
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