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N. Friedman
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-082 - High Mobility Group Box 1 Antagonist Limits Metastatic Seeding in the Lungs via Reduction of Cell-Cel Adhesion (ID 7346)
09:30 - 09:30 | Author(s): N. Friedman
- Abstract
Background:
Metastatic spread is the leading cause for cancer-related mortality, with 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. The metastatic cascade is highly complex and is affected by multiple factors related to 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).
Method:
We performed a panel of cell based assays aimed at identifying the effect of Carbenoxolone on specific steps of tumor growth and metastases. We chose Lewis Lung Carcinoma (LLC) murine cell line because of its highly metastatic potential and the possibility to evaluate both primary and secondary growth in the relevant microenvironment of the lung. To understand which metastatic step is most affected by Carbenoxolone, we applied varying in vitro assays: proliferation, migration, invasion, anoikis, adhesion, cell anchorage and colony formation. To study both tumor progression and spread of metastasis, we performed four different in vivo models. In vivo models applied were two primary tumor models: subcutaneous and orthotopic, and two metastatic-relevant models: cell pulmonary colonization and tumor resection model for spontaneous cancer cell spread.
Result:Model Relevant processes in cancer formation Dosage Duration Results Subcutaneous Lung Model Proliferation 50 mg/kg every other day 17 days No significant difference Orthotropic Lung Model Proliferation 10 mg/kg every day 17 days No significant difference Tail Vein Injection – Lung Tumor Cell colonization Anoikis, Adhesion, Colonization 40 mg/kg every other day 25 days significantly lower number of lesions on lungs (p=0.006) Tumor Resection Lung Metastasis Model Adhesion, Anoikis, Colonization,Intravasation, Migration 50 mg/kg every other day 38 days significantly lower number of lesions on lungs (p=0.002)
Conclusion:
Carbenoxolone hinders adhesion and colonization of cancer cells in the lungs by antagonizing HMGB1 and consequently the downregulation of the ICAM1 and lowering cell-cell adhesion. This ultimately results in reduced metastatic burden. Carbenoxolone decreases significantly lung metastases formation and can be used potentially as prophylactic therapy for metastatic diseases.
