Cancer-associated fibroblasts promote venous thrombosis through podoplanin/CLEC-2 interaction in podoplanin-negative lung cancer mouse model

Shirai, Toshiaki; Tsukiji, Nagaharu; Sasaki, Takeshi; Oishi, Saori; Yokomori, Ryohei; Takano, Katsuhiro; Suzuki‐Inoue, Katsue

doi:10.1016/j.jtha.2023.07.005

Cited by 10 publications

(5 citation statements)

References 48 publications

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“…The results showed that HSP47 is low in tumor cells of the primary tumors, although some non-cancer cells show high levels of HSP47, especially in cancer-associated fibroblasts (CAFs) ( Figures S1 D and S1F), which is consistent with previous reports. 15 , 16 However, the level of HSP47 is significantly upregulated in tumor cells in BrMs compared to the primary tumors ( Figures S1 E and S1G). Importantly, tumor cell is the most abundant cell type expressing HSP47 in BrMs.…”

Section: Resultsmentioning

confidence: 96%

Targeting the HSP47-collagen axis inhibits brain metastasis by reversing M2 microglial polarization and restoring anti-tumor immunity

Wang,

Li,

Zhan

et al. 2024

Cell Reports Medicine

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Section: Resultsmentioning

confidence: 96%

Targeting the HSP47-collagen axis inhibits brain metastasis by reversing M2 microglial polarization and restoring anti-tumor immunity

Wang,

Li,

Zhan

et al. 2024

Cell Reports Medicine

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“…Podoplanin is a well-known CAF marker similar to FAP [22]. Using a mouse model, Shirai et al [23] reported that extracellular vesicles derived from CAFs promote venous thrombus formation via podoplanin-dependent platelet aggregation. In the present study, podoplanin-positive cells were not observed in the aspirated thrombi.…”

Section: Discussionmentioning

confidence: 99%

Expression of fibroblast activation protein-α in human deep venous thrombus

Oguri,

Gi,

Nakamura

et al. 2024

Preprint

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BackgroundFibroblast activation protein-α (FAP), a type-II transmembrane serine protease, is expressed during wound healing, in cancer-associated fibroblasts, and in chronic fibrosing diseases. However, its expression in deep vein thrombus (DVT) remains unclear. Therefore, in this study, we investigated FAP expression and localization in DVT.MethodsFirst, we pathologically accessed aspirated thrombi of patients with DVT (n=14), classifying thrombotic areas as follows; fresh, cellular lysis, endothelialization, fibroblastic reaction. Endothelialization and fibroblastic reaction were defined as organizing reactions. We immunohistochemically examined FAP-expressed areas and expressed cells. Second, we analyzed FAP expression in cultured dermal fibroblasts.ResultsAll the aspirated thrombi showed a mixture of at least three of the four thrombotic areas. Specifically, 83 % of aspirated thrombi showed fresh and organizing reactions within each thrombus. Immunohistochemical expression of FAP was restricted in organizing area. Further, FAP expression in the thrombi was mainly found in vimentin-positive or α-smooth muscle actin-positive fibroblasts in double immunofluorescence. Some CD163-positive macrophages also showed FAP expression. FAP mRNA and protein levels significantly increased in cultured fibroblasts with low- proliferative activity under 0.1% fetal bovine serum (FBS) than that in fibroblasts under 10% FBS. Fibroblasts cultured in 10% FBS showed a significant decrease in FAP mRNA levels following supplementation with hemin, but not with thrombin.ConclusionsThe heterogeneous composition of the venous thrombi suggests the existence of a multistep thrombus formation process in human DVT. Further, fibroblasts or myofibroblasts may express FAP in organizing process in DVT. FAP expression may increase in fibroblasts with low-proliferative activity.

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“…Acting as a tumor suppressor gene by repressing the expression of vasohibin-1 (VASH1), EZH2, in turn, stimulated the proliferation of ECs. Conversely, inhibition of the VEGF/EZH2 axis led to upregulation of VASH1, which decreased tumor-associated angiogenesis [96] .…”

Section: Caf Interaction With Vascular Structuresmentioning

confidence: 99%

The tumor microenvironment in hepatocarcinoma: dissecting the functions of cancer-associated fibroblasts

Cadamuro,

Nuozzi,

Simioni

et al. 2023

Hepatoma Res

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Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, deriving from the neoplastic transformation of hepatocytes, most often forced to long-lasting regeneration by the cirrhotic background. HCC is an extremely aggressive tumor with still limited effective treatments, and is characterized by the presence of a very complex and multifaceted tumor microenvironment (TME). Among the variety of cell types populating the TME of HCC, cancer-associated fibroblasts (CAFs) are the most prevalent. CAFs are a specific population of fibroblasts in a persistent state of activation, with a high level of heterogeneity, partly dependent on a wide range of cell origin, which are endowed with a repertoire of functions, profoundly modulating the biology of the tumor. Given the close relationship of HCC with cirrhosis, CAFs are paradigmatic of the role played by activated fibroblasts in promoting the evolution of a chronic, non-resolving, fibro-inflammatory condition towards a neoplastic disease and its aggressive phenotype. In this review, we will discuss the most recent findings regarding the interplay of CAFs with the tumoral epithelial compartment, with the multiple cell elements of the TME (macrophages, neutrophils, myeloid-derived suppressor cells, vascular cells), and with the extracellular matrix. Finally, we will address the translational value of CAF manipulation in HCC to unveil possible ameliorations for the treatment of a still worrisome disease.

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Cancer-associated fibroblasts promote venous thrombosis through podoplanin/CLEC-2 interaction in podoplanin-negative lung cancer mouse model

Cited by 10 publications

References 48 publications

Targeting the HSP47-collagen axis inhibits brain metastasis by reversing M2 microglial polarization and restoring anti-tumor immunity

Targeting the HSP47-collagen axis inhibits brain metastasis by reversing M2 microglial polarization and restoring anti-tumor immunity

Expression of fibroblast activation protein-α in human deep venous thrombus

The tumor microenvironment in hepatocarcinoma: dissecting the functions of cancer-associated fibroblasts

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