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High mobility group box 1 antagonist limits metastatic seeding in the lungs via reduction of cell-cell adhesion
Adi Karsch-Bluman1, Benzion Amoyav1, Nethanel Friedman1
1The Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Abstract:
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.
Insights
Blocking High Mobility Group Box 1 (HMGB1) with Carbenoxolone reduces cancer cell adhesion and lung metastasis. This strategy targets the lung microenvironment to prevent cancer spread, offering a potential prophylactic therapy for metastatic disease.
Area of Science:
- Oncology
- Cell Biology
- Immunology
Background:
- Metastatic spread is a primary cause of cancer mortality, with limited treatment options.
- The lung is a frequent site for metastasis, influenced by tumor cells and the microenvironment.
- Receptor for Advanced Glycation End products (RAGE) and its ligand High Mobility Group Box 1 (HMGB1) are implicated in lung inflammation and metastasis.
Purpose of the Study:
- To investigate the effect of antagonizing HMGB1 on lung metastatic seeding.
- To explore Carbenoxolone, an HMGB1 antagonist, as a potential therapy for metastatic disease.
- To understand the mechanisms by which HMGB1 influences cancer cell adhesion and colonization in the lungs.
Main Methods:
- Utilized murine tumor models to assess primary tumor growth and metastatic progression.
- Tested the efficacy of Carbenoxolone, an HMGB1 antagonist.
- Performed in vitro and in vivo experiments to evaluate cancer cell adhesion and interaction.
- Analyzed the expression of Intercellular Adhesion Molecule 1 (ICAM1).
Main Results:
- Carbenoxolone treatment significantly reduced lung metastasis formation.
- Antagonizing HMGB1 inhibited cancer cell adhesion and colonization in the lungs.
- These effects were mediated by the downregulation of ICAM1.
- Reduced cell-cell interaction was observed both in vitro and in vivo.
Conclusions:
- Blocking HMGB1 with Carbenoxolone is a promising strategy to prevent lung metastasis.
- Carbenoxolone reduces cancer cell adhesion and colonization by downregulating ICAM1.
- This approach holds potential as a prophylactic therapy for limiting metastatic disease in the lungs.