Local and Systemic Protumorigenic Effects of Cancer-Associated Fibroblast-Derived GDF15

Bruzzese, Francesca; Hägglöf, Christina; Leone, Alessandra; Sjöberg, Elin; Roca, Maria Serena; Kiflemariam, Sara; Sjöblom, Tobias; Hammarsten, Peter; Egevad, Lars; Bergh, Anders; Budillon, Alfredo; Augsten, Martin

doi:10.1158/0008-5472.can-13-2259

Cited by 103 publications

(85 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study too, the GDF15-positive cells in the ESCC tissues were mostly confined to the cytoplasm of ESCC cells, whereas GDF15 immunoreactions were detected in other stromal cells such as erythrocytes and macrophages. Although GDF15 expression has been reported in bone marrow stromal cells in multiple myeloma and cancer-associated fibroblasts in prostate cancer, 45,46 this may be the first report of GDF15 expression in TAMs. The serum GDF15 concentration has been reported to be closely associated with the depth of invasion, lymph node metastasis, and overall survival of ESCC patients.…”

Section: Gdf15 Increased the Growth Of The Escc Cell Lines By Triggermentioning

confidence: 76%

GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways

Urakawa

Utsunomiya

Nishio

et al. 2015

Laboratory Investigation

View full text Add to dashboard Cite

Tumor-associated macrophages (TAMs) are known to be involved in the progression, angiogenesis, and motility of various cancers. We previously reported the association between an increased number of infiltrating TAMs with tumor progression and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To study the roles of TAMs in ESCC, we first exposed peripheral blood monocyte (PBMo)-derived macrophages from healthy volunteers to conditioned media of TE series human ESCC cell line (TECM) and confirmed the induction of the expression of the M2 macrophage marker CD204 and the protumorigenic factors interleukin (IL)-10, VEGFA, and MMPs. Next, we compared gene expression profiles between PBModerived macrophages stimulated with or without TECM by cDNA microarray and focused on growth differentiation factor 15 (GDF15) among the highly expressed genes including IL-6, IL-8, and CXCL1. Our immunohistochemical study of 70 surgically resected ESCCs revealed that GDF15 was present not only in cancer cells but also in macrophages. The high expression of GDF15 in the ESCCs was significantly correlated with several more malignant phenotypes including vessel invasion, lymph node metastasis, and clinical stages. Patients with high GDF15 expression showed significantly poorer disease-free survival (P = 0.011) and overall survival (P = 0.041). We also found that recombinant human GDF15 promotes cell proliferation and the phosphorylation of both Akt and Erk1/2 in ESCC cell lines in vitro. These results indicate that GDF15 is secreted by both TAMs and cancer cells in the tumor microenvironment and is associated with aberrant growth and a poor prognosis in human ESCC.

show abstract

Section: Gdf15 Increased the Growth Of The Escc Cell Lines By Triggermentioning

confidence: 76%

GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways

Urakawa

Utsunomiya

Nishio

et al. 2015

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…The following reasons could possibly be responsible for the close association between increased tumor-infiltrating podoplanin + fibroblasts and worse outcome of patients presented in this study: Fibroblasts in the TME are able to promote tumor cell invasion, proliferation and survival through releasing growth factors, cytokines [39] and extracellular matrix-degrading proteases such as matrix metalloproteinases (MMPs) (e.g. MMP1) [40].…”

Section: Discussionmentioning

confidence: 97%

Tumor-Infiltrating Podoplanin+ Fibroblasts Predict Worse Outcome in Solid Tumors

Wang

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Tumor-infiltrating fibroblasts are a heterogeneous population, and different subpopulations play differential roles in tumor microenvironment. However, the prognostic role of podoplanin⁺ fibroblasts in human solid tumors still remains controversial. Therefore, we performed the meta-analysis to better understand the role of this subpopulation in prognosis prediction for patients with solid tumor. Methods: We searched PubMed and EBSCO to identify the studies evaluating the association of intratumoral podoplanin⁺ fibroblast density detected by immunohistochemical method and overall survival (OS) and/or disease-free survival (DFS) in patients with solid tumor, then computed extracted data into hazard ratios for OS, DFS and clinicopathological features with STATA 12.0. Results: A total of 4883 patients from 29 published studies were incorporated into this meta-analysis. We found that podoplanin⁺ fibroblast infiltration significantly decreased OS and DFS in all types of solid tumors. In stratified analyses, podoplanin⁺ fibroblast infiltration was significantly associated with worse OS in cholangiocarcinoma, breast, lung and pancreatic cancer. And these cells were inversely associated with DFS in breast, lung and pancreatic cancer. In addition, high density of these cells significantly correlated with unfavorable clinicopathological features such as lymph node metastasis, TNM stage, lymphatic and vascular invasion of solid tumor. Conclusion: Podoplanin⁺ fibroblast infiltration leads to worse clinical outcome in solid tumors, implicating that it is a valuable prognostic biomarker and targeting it may have a potential for effective treatment.

show abstract

“…Many studies also consider that GDF15 is a contributor to the development and progression of some malignant tumors [20, 21, 36–38], although several documents have reported that retinoid-related molecule or anti-inflammatory drug can induce tumor cell apoptosis via GDF15 [39–41]. Bruzzese F 20 points out that the pro- and anti-tumor activities of GDF15 are highly dependent on the cellular and microenvironmental context.…”

Section: Discussionmentioning

confidence: 99%

C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation

Zhao

Qiu

et al. 2018

Oncogene

View full text Add to dashboard Cite

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and multiple evidence has confirmed that C5a production is elevated in NSCLC microenvironment. Although NSCLC cell proliferation induced by C5a has been reported, the involved mechanism has not been elucidated. In this study, we examined the proliferation-related genes (i.e., KLF5, GCN5, and GDF15) and C5a receptor (C5aR) expression in tumor tissues as well as C5a concentration in plasma of NSCLC patients, and then determined the roles of KLF5, GCN5, and GDF15 in C5a-triggered NSCLC cell proliferation and the related mechanism both in vitro and in vivo. Our results found that the expression of KLF5, GCN5, GDF15, C5aR, and C5a was significantly upregulated in NSCLC patients. Mechanistic exploration in vitro revealed that C5a could facilitate A549 cell proliferation through increasing KLF5, GCN5, and GDF15 expression. Besides, KLF5 and GCN5 could form a complex, binding to GDF15 promoter in a KLF5-dependent manner and leading to GDF15 gene transcription. More importantly, GCN5-mediated KLF5 acetylation contributing to GDF15 gene transcription and cell proliferation upon C5a stimulation, the region (−103 to +58 nt) of GDF15 promoter which KLF5 could bind to, and two new KLF5 lysine sites (K335 and K391) acetylated by GCN5 were identified for the first time. Furthermore, our experiment in vivo demonstrated that the growth of xenograft tumors in BALB/c nude mice was greatly suppressed by the silence of KLF5, GCN5, or GDF15. Collectively, these findings disclose that C5a-driven KLF5–GCN5–GDF15 axis had a critical role in NSCLC proliferation and might serve as targets for NSCLC therapy.

show abstract

Local and Systemic Protumorigenic Effects of Cancer-Associated Fibroblast-Derived GDF15

Cited by 103 publications

References 44 publications

GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways

GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways

Tumor-Infiltrating Podoplanin+ Fibroblasts Predict Worse Outcome in Solid Tumors

C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation

Contact Info

Product

Resources

About