High mobility group box 1 antagonist limits metastatic seeding in the lungs via reduction of cell-cell adhesion

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.

RAGE-specific single chain Fv for PET imaging of pancreatic cancer

“…RAGE is most highly expressed in lung tissue and expression there may limit the ability of PET imaging for lesions located in the lung. Carbenoxolone, an HMGB1 antagonist, limit metastatic seeding in the lungs [ 44 ], mediated by downregulation of the adhesion molecule Intercellular Adhesion Molecule 1 (ICAM1). Our recent work demonstrates that RAGE ablation in murine models of accelerated pancreatic carcinogenesis with specific ablation of HMGB1 expression in the emergent malignant cells can be obviated by knocking out global RAGE expression but not TLR9 [ 45 ].…”

The role of high‐mobility group protein box 1 in lung cancer

“…Carbenoxolone is a glycyrrhetinic acid derivative with a steroid‐like structure, similar to substances found in the root of the licorice plant. As an antagonist of HMGB1, carbenoxolone could counteract the effect of HMGB1, thereby preventing the adhesion and colonization of cancer cells in the lungs through the reduction of their adhesion and cell‐cell interaction both in vivo and in vitro . However, further investigation should be done to evaluate these therapies and their possible roles in clinical practice.…”

Delineating the HMGB1 and HMGB2 interactome in prostate and ovary epithelial cells and its relationship with cancer

“…Strikingly, in addition to proteins regulating gene expression, we also identified tight junction proteins TJP1 and TJP2 among HMGB1 interacting proteins. This is remarkable in light of HMGB1’s role in metastasis [ 14 , 28 ] and points to potential players cooperating with HMGB1 to promote metastasis.…”

“…HMGB proteins are also involved in sensitizing cells to platinum compounds used in the chemotherapy of prostate and ovary cancer [ 12 , 13 ]. Antagonists against HMGB1 have therapeutic use in lung cancer [ 14 , 15 ] and restore sensitivity towards platinated compounds used in chemotherapy [ 16 ].…”