Roles of the TGF-β–VEGF-C Pathway in Fibrosis-Related Lymphangiogenesis

Kinashi, Hiroshi; Ito, Yasuhiko; Sun, Ting; Kuriyama, Takayuki; Takei, Yoshiyuki

doi:10.3390/ijms19092487

Cited by 65 publications

(57 citation statements)

References 134 publications

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“…58 In renal and peritoneal fibrosis processes, TGF-β promotes lymphangiogenesis through the TGF-β/VEGF-C pathway. 59 As previously mentioned, in our study, the activity of CNV in the nAMD group was low, and most of the cases were in chronic state, in which circumstance, elevated VEGF-C may take part in the prolonged fibrotic processes of nAMD.…”

Section: Discussionsupporting

confidence: 57%

CCL1, IL-22, and IL-36β Have Higher Expression Levels in Aqueous Humor of Neovascular Age-Related Macular Degeneration Patients in Comparison to Cataract Patients

Chen

Zheng

et al. 2020

Preprint

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Purpose: To investigate the aqueous humor cytokine expression profile in neovascular age-related macular degeneration (nAMD) patients before and after ranibizumab treatments in comparison to cataract patients. Methods: This prospective study included 20 treatment-naïve nAMD eyes of 20 patients who received three consecutive monthly injections of ranibizumab. Aqueous humor samples were collected before the first (baseline), second (1 month later), and third (2 months later) injections. Controls were 20 age- and gender-matched cataract patients without any other ocular disease. The aqueous concentrations of 28 cytokines were measured using a multiplex bead assay. Central macular thickness (CMT) and maximum retinal thickness (MRT)-3mm were measured by spectral domain optical coherence tomography (SD-OCT). The greatest linear diameter (GLD) was measured by fundus fluorescein angiography (FA). Results: Nine cytokines in aqueous humor, including angiogenin, bone morphogenetic protein-9 (BMP-9), C-C motif chemokine ligand 1 (CCL1), CCL13, interleukin-8 (IL-8), fibroblast growth factor-acidic (FGF-α), IL-22, IL-36β, and vascular endothelial growth factor-C (VEGF-C) were significantly higher in nAMD patients in comparison to cataract patients, whether before or after two consecutive monthly ranibizumab injections. Compared with the nAMD patients’ basal levels, two consecutive monthly ranibizumab injections effectively reduced the aqueous concentration of VEGF-A, improved best corrected visual acuity (BCVA), as well as reduced the values of CMT, MRT-3mm, and GLD. Conclusions: Nine cytokines have higher expression levels in nAMD patients in comparison to cataract patients, whether before or after 2 months of ranibizumab therapy. These cytokines may have correlations with the pathogenesis of nAMD.

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Section: Discussionsupporting

confidence: 57%

CCL1, IL-22, and IL-36β Have Higher Expression Levels in Aqueous Humor of Neovascular Age-Related Macular Degeneration Patients in Comparison to Cataract Patients

Chen

Zheng

et al. 2020

Preprint

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“…However, the function of TGFβ in the formation of the cancer-associated lymphatic system is not well understood. 168 TGFβ and immune-related cells in the TME There are a variety of innate and adaptive immune cells dispersed throughout the TME (Fig. 5c).…”

Section: Functions Of Tgfβ In the Tmementioning

confidence: 99%

Targeting TGFβ signal transduction for cancer therapy

Liu

Ren

Dijke

2021

Sig Transduct Target Ther

224

173

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Transforming growth factor-β (TGFβ) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of adult tissue homeostasis. Dysregulation of TGFβ family signaling can lead to a plethora of developmental disorders and diseases, including cancer, immune dysfunction, and fibrosis. In this review, we focus on TGFβ, a well-characterized family member that has a dichotomous role in cancer progression, acting in early stages as a tumor suppressor and in late stages as a tumor promoter. The functions of TGFβ are not limited to the regulation of proliferation, differentiation, apoptosis, epithelial–mesenchymal transition, and metastasis of cancer cells. Recent reports have related TGFβ to effects on cells that are present in the tumor microenvironment through the stimulation of extracellular matrix deposition, promotion of angiogenesis, and suppression of the anti-tumor immune reaction. The pro-oncogenic roles of TGFβ have attracted considerable attention because their intervention provides a therapeutic approach for cancer patients. However, the critical function of TGFβ in maintaining tissue homeostasis makes targeting TGFβ a challenge. Here, we review the pleiotropic functions of TGFβ in cancer initiation and progression, summarize the recent clinical advancements regarding TGFβ signaling interventions for cancer treatment, and discuss the remaining challenges and opportunities related to targeting this pathway. We provide a perspective on synergistic therapies that combine anti-TGFβ therapy with cytotoxic chemotherapy, targeted therapy, radiotherapy, or immunotherapy.

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“…Signaling via vascular endothelial growth factor (VEGF)-C/D and VEGF receptor (VEGFR)-3 is central to lymphangiogenesis 14,15 . During peritoneal fibrosis, transforming growth factor–β (TGF-β) promotes VEGF-C expression, which leads to lymphangiogenesis 13,16 . Furthermore, blocking lymphangiogenesis with soluble VEGFR-3 improves impaired ultrafiltration in a mouse peritoneal fibrosis model 17 .…”

Section: Introductionmentioning

confidence: 99%

Connective tissue growth factor is correlated with peritoneal lymphangiogenesis

Kinashi

Toda

Sun

et al. 2019

Sci Rep

Self Cite

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Lymphatic absorption in the peritoneal cavity may contribute to ultrafiltration failure in peritoneal dialysis (PD). Lymphatic vessels develop during PD-related peritoneal fibrosis. Connective tissue growth factor (CTGF, also called CCN2) is an important determinant of fibrotic tissue remodeling, but little is known about its possible involvement in lymphangiogenesis. In this study, we investigated the relationship between CTGF and peritoneal lymphangiogenesis. A positive correlation was observed between vascular endothelial growth factor-C (VEGF-C), a major lymphangiogenic growth factor, and the CTGF concentration in human PD effluents. CTGF expression was positively correlated with expression of lymphatic markers and VEGF-C in human peritoneal biopsies. We found a positive correlation between the increase in CTGF and the increase in VEGF-C in cultured human peritoneal mesothelial cells (HPMCs) treated with transforming growth factor-β1 (TGF-β1). The diaphragm is a central player in peritoneal lymphatic absorption. CTGF expression was also correlated with expression of VEGF-C and lymphatics in a rat diaphragmatic fibrosis model induced by chlorhexidine gluconate (CG). Furthermore, CTGF gene deletion reduced VEGF-C expression and peritoneal lymphangiogenesis in the mouse CG model. Inhibition of CTGF also reduced VEGF-C upregulation in HPMCs treated with TGF-β1. Our results suggest a close relationship between CTGF and PD-associated lymphangiogenesis.

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Roles of the TGF-β–VEGF-C Pathway in Fibrosis-Related Lymphangiogenesis

Cited by 65 publications

References 134 publications

CCL1, IL-22, and IL-36β Have Higher Expression Levels in Aqueous Humor of Neovascular Age-Related Macular Degeneration Patients in Comparison to Cataract Patients

CCL1, IL-22, and IL-36β Have Higher Expression Levels in Aqueous Humor of Neovascular Age-Related Macular Degeneration Patients in Comparison to Cataract Patients

Targeting TGFβ signal transduction for cancer therapy

Connective tissue growth factor is correlated with peritoneal lymphangiogenesis

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