Fibrocytes boost tumor-supportive phenotypic switches in the lung cancer niche via the endothelin system

Abstract

Fibrocytes are bone marrow–derived monocytic cells implicated in wound healing. Here, we identify their role in lung cancer progression/ metastasis. Selective manipulation of fibrocytes in mouse lung tumor models documents the central role of fibrocytes in boosting niche features and enhancing metastasis. Importantly, lung cancer patients show increased number of circulating fibrocytes and marked fibrocyte accumulation in the cancer niche. Using double and triple co-culture systems with human lung cancer cells, fibrocytes, macrophages and endothelial cells, we substantiate the central features of cancer-supporting niche: enhanced cancer cell proliferation and migration, macrophage activation, augmented endothelial cell sprouting and fibrocyte maturation. Upregulation of endothelin and its receptors are noted, and dual endothelin receptor blockade suppresses all cancer-supportive phenotypic alterations via acting on fibrocyte interaction with the cancer niche. We thus provide evidence for a crucial role of fibrocytes in lung cancer progression and metastasis, suggesting targets for treatment strategies.

The β-arrestin1/endothelin axis bolsters ovarian fibroblast-dependent invadosome activity and cancer cell metastatic potential

“…In agreement with previous data [ 26 – 28 , 32 ], ET-1 induces HOFs to acquire features of CAFs, as an increase in platelet-derived growth factor receptor (PDGFR), fibroblast activated protein (FAP), and vimentin expression (Supplementary Fig. 1C ).…”

“…In an orthotopic model of breast cancer, the nanoparticles bearing the ET A/B R antagonist macitentan prevent fibrotic progression by regulating the CAF function [ 27 ]. Notably, ET-1-dependent fibrocyte-associated mechanisms promote lung tumor growth and metastasis, with local upregulation of ET-1 axis members, and bosentan interferes with all phenotypic switches that characterize the lung cancer-supportive niche [ 26 ]. In HG-SOC cells, ET-1 dictates the activation of a p53/YAP/HIF-1α transcriptional apparatus in fibroblasts, enhancing the release of VEGF circuits, regulating the DNA damage response, and the efficacy of PARPi treatment [ 32 ].…”

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“…По некоторым данным, при псориазе демиелинизирующая полиневропатия является результатом иммунологических механизмов воспаления, при котором окислительный стресс является этапом не только микроангиопатии в коже, но и процесса демиелинизации нервных волокон [38][39][40].…”

“…При этом антагонизм к обоим типам рецепторов ЕТ-1 в значительной степени блокирует пролиферативное и промиграционное влияние фиброцитов на клетки рака легкого in vitro и in vivo, т.е. ингибирование рецепторов ЕТ-1 препятствует всем фенотипическим переключениям, которые характеризуют нишу, поддерживающую рак легкого, -усиленной пролиферации и миграции опухолевых клеток, дифференцировке моноцитов в макрофаги с преобладанием М2-типа, миграции эндотелиальных клеток и образованию трубок, ангиогенезу [38].…”

Alterations in the Mammary Gland and Tumor Microenvironment of Formerly Obese Mice

“…In human breast tissue, CD34 + cells have been detected in the extracellular matrix surrounding breast lobules and low grade DCIS but are no longer detected when SMA + myofibroblasts were increased surrounding high grade DCIS and invasive ductal carcinoma [23,24], which is suggestive of differentiating fibrocytes. While recent single cell RNA sequencing studies have identified fibrocytes in lung tumors [25,26], the role of fibrocytes in altering the tumor microenvironment in obesity has not been examined.…”