HSPB1 Inhibits the Endothelial-to-Mesenchymal Transition to Suppress Pulmonary Fibrosis and Lung Tumorigenesis

Abstract

The endothelial-to-mesenchymal transition (EndMT) contributes to cancer, fibrosis, and other pathologic processes. However, the underlying mechanisms are poorly understood. Endothelial HSP1 (HSPB1) protects against cellular stress and has been implicated in cancer progression and pulmonary fibrosis. In this study, we investigated the role of HSPB1 in mediating the EndMT during the development of pulmonary fibrosis and lung cancer. HSPB1 silencing in human pulmonary endothelial cells accelerated emergence of the fibrotic phenotype after treatment with TGFb or other cytokines linked to pulmonary fibrosis, suggesting that HSPB1 maintains endothelial cell identity. In mice, endothelial-specific overexpression of HSPB1 was sufficient to inhibit pulmonary fibrosis by blocking the EndMT. Conversely, HSPB1 depletion in a mouse model of lung tumorigenesis induced the EndMT. In clinical specimens of non-small cell lung cancer, HSPB1 expression was absent from tumor endothelial cells undergoing the EndMT. Our results showed that HSPB1 regulated the EndMT in lung fibrosis and cancer, suggesting that HSPB1-targeted therapeutic strategies may be applicable for treating an array of fibrotic diseases. Cancer Res; 76(5); 1019-30. Ó2016 AACR.

TGF-β Family Signaling in Tumor Suppression and Cancer Progression

“…In this context, TGF-b1 promotes cardiac fibrosis by inducing EndMT in adult coronary endothelial cells, whereas BMP-7 reverses this effect. In the lung, EndMT occurs in bleomycin-induced fibrosis (Hashimoto et al 2010;Choi et al 2016), thus providing a source of myofibroblasts. Similarly, EndMT is pivotal in the accumulation of mesenchymal-like cells in obstructive pulmonary vascular lesions that cause pulmonary hypertension (Ranchoux et al 2015).…”

Fine‐tuning vascular fate during endothelial–mesenchymal transition

“…In a different study where epicardial‐lineage cells were generated from human pluripotent stem cells, addition of bFGF enhanced TGFβ‐stimulated expression of mesenchymal markers including SMA and vimentin, although bFGF‐induced proliferation and expression of the EMT transcription factor SNAI1 was counteracted by TGFβ . During tooth development, bFGF induces EMT in tooth root enamel epithelial cells (Hertwig's epithelial root sheath cells) to form cementoblast‐like cells that are responsible for cementum formation, whereas TGFβ stimulates the same cells to transition to periodontal ligament fibroblast‐like cells . Here, the cooperative action of TGFβ and bFGF is also dependent, at least in part, on the coordinated modulation of the MEK/ERK pathway .…”

“…During tooth development, bFGF induces EMT in tooth root enamel epithelial cells (Hertwig's epithelial root sheath cells) to form cementoblast‐like cells that are responsible for cementum formation, whereas TGFβ stimulates the same cells to transition to periodontal ligament fibroblast‐like cells . Here, the cooperative action of TGFβ and bFGF is also dependent, at least in part, on the coordinated modulation of the MEK/ERK pathway .…”

“…Isolated epicardial cells in response to the combination treatment of bFGF and TGFβ increased motility and proliferation, and penetrated the underlying matrix, which is a characteristic of EMT. In a different study where epicardial-lineage cells were generated from human pluripotent stem cells, addition of bFGF enhanced TGFβ-stimulated expression of mesenchymal markers including SMA and vimentin, although bFGF-induced proliferation and expression cementoblast-like cells that are responsible for cementum formation, whereas TGFβ stimulates the same cells to transition to periodontal ligament fibroblast-like cells [107]. Here, the cooperative action of TGFβ and bFGF is also dependent, at least in part, on the coordinated modulation of the MEK/ERK pathway [41,107].…”

Identification of radiation‐induced EndMT inhibitors through cell‐based phenomic screening

“…The most common cytokines that activate EndMT are the transforming growth factor‐β super family of proteins. Other signaling pathways have also been recently reported; these include Wnt/β‐catenin , Notch , HSPB1 , and various receptor tyrosine kinases . GSK3‐β, a target of CHIR‐99021, is known to regulate tumor migration and invasion by controlling EMT.…”