Abstract
Malignant mesothelioma originates from mesothelial cells and is a cancer type that aggressively invades into the surrounding tissue, has poor prognosis and no effective treatment. Gremlin-1 is a cysteine knot protein that functions by inhibiting BMP-pathway activity during development. BMP-independent functions have also been described for gremlin-1. We have previously shown high gremlin-1 expression in mesothelioma tumor tissue. Here, we investigated the functions of gremlin-1 in mesothelioma cell migration and invasive growth. Gremlin-1 promoted mesothelioma cell sprouting and invasion into three dimensional collagen and Matrigel matrices. The expression level of gremlin-1 was linked to changes in the expression of SNAI2, integrins, matrix metalloproteinases (MMP) and TGF-β family signaling - all previously associated with a mesenchymal invasive phenotype. Small molecule inhibitors of MMPs completely blocked mesothelioma cell invasive growth. In addition, inhibitors of TGF-β receptors significantly reduced invasive growth. This was associated with reduced expression of MMP2 but not SNAI2, indicating that gremlin-1 has both TGF-β pathway dependent and independent mechanisms of action. Results of in vivo mesothelioma xenograft experiments indicated that gremlin-1 overexpressing tumors were more vascular and had a tendency to send metastases. This suggests that by inducing a mesenchymal invasive cell phenotype together with enhanced tumor vascularization, gremlin-1 drives mesothelioma invasion and metastasis. These data identify gremlin-1 as a potential therapeutic target in mesothelioma.
Highlights
Malignant mesothelioma is an aggressive cancer that develops from the mesothelial cells of serosal membranes [1]
The expression level of gremlin-1 was linked to changes in the expression of SNAI2, integrins, matrix metalloproteinases (MMP) and transforming growth factor-β (TGF-β) family signaling - all previously associated with a mesenchymal invasive phenotype
In addition to inhibition of bone morphogenetic protein (BMP)-pathway activities, gremlin-1 can function through activation of vascular endothelial growth factor receptor 2 (VEGFR2) signaling and inhibition of migration inhibitory factor (MIF) [8, 22]
Summary
Malignant mesothelioma is an aggressive cancer that develops from the mesothelial cells of serosal membranes [1]. Most often mesothelioma originates from the pleural lining of the lung. Occupational or incidental exposure to asbestos fibers is a known causative factor in mesothelioma and the latency period from exposure to tumor incidence can be long [2]. Mesothelioma prognosis is poor, survival time being usually only 10–14 months after diagnosis [3]. There are three histological subtypes of mesothelioma. Epithelioid mesothelioma is the most common type with prominent papillotubular structures seen in histological micrographs. Sarcomatoid www.impactjournals.com/oncotarget mesothelioma is characterized by spindled cells mimicking fibrosarcoma. Biphasic mesothelioma has areas of both epithelioid and sarcomatoid histology. Mesothelioma shows aggressive local growth and invasion into the chest wall, diaphragm or contralateral lymph nodes [1]. Mesothelioma is highly resistant to conventional cancer therapies
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