GDF-15 Contributes to Proliferation and Immune Escape of Malignant Gliomas

Roth, Patrick; Junker, Markus; Tritschler, Isabel; Mittelbronn, Michel; Dombrowski, Yvonne; Breit, Samuel N.; Tabatabai, Ghazaleh; Wick, Wolfgang; Weller, Michael; Wischhusen, Jörg

doi:10.1158/1078-0432.ccr-10-0705

Cited by 146 publications

(135 citation statements)

References 42 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…In fact, proliferation of T cells was inhibited by coculture with autologous or allogeneic CICs, but not with FBS tumor cells. CIC-associated factors, such as TGF-b, IL-10, IL-13, galectin, and PDGE2, which can play a negative regulatory role in the induction of tumor reactive T cells, have been described (12)(13)(14) and, notably, shown to be shared with normal stem cells as well (30). The complexity of this issue is demonstrated by the evidence that none of the molecules described above have been found to be specifically expressed or upregulated in CICs that we have isolated in vitro (data not shown), in line with the results that have been previously published by our group for GBM (10).…”

Section: Discussionmentioning

confidence: 99%

“…Cancer-testis Ags have been found to be expressed by mesenchymal stem cells and to regulate the epithelial-to-mesenchymal transition, a process involved in development of metastases; thus these Ags may possibly have a role in the stemness properties of cancer cells and could represent target molecules for immunotherapy (11). Nevertheless, antitumor immunity could be attenuated by tumor-related immunosuppressive mechanisms that have been described in association with CICs isolated from melanoma or GBM (12)(13)(14). These findings suggest that a detailed immunological characterization of CICs isolated from different human tumors is a relevant issue to design new CICtargeted immunotherapeutic interventions.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cancer-Initiating Cells from Colorectal Cancer Patients Escape from T Cell–Mediated Immunosurveillance In Vitro through Membrane-Bound IL-4

Volonté

Tomaso

Spinelli

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

Cancer-initiating cells (CICs) that are responsible for tumor initiation, propagation, and resistance to standard therapies have been isolated from human solid tumors, including colorectal cancer (CRC). The aim of this study was to obtain an immunological profile of CRC-derived CICs and to identify CIC-associated target molecules for T cell immunotherapy. We have isolated cells with CIC properties along with their putative non-CIC autologous counterparts from human primary CRC tissues. These CICs have been shown to display “tumor-initiating/stemness” properties, including the expression of CIC-associated markers (e.g., CD44, CD24, ALDH-1, EpCAM, Lgr5), multipotency, and tumorigenicity following injection in immunodeficient mice. The immune profile of these cells was assessed by phenotype analysis and by in vitro stimulation of PBMCs with CICs as a source of Ags. CICs, compared with non-CIC counterparts, showed weak immunogenicity. This feature correlated with the expression of high levels of immunomodulatory molecules, such as IL-4, and with CIC-mediated inhibitory activity for anti-tumor T cell responses. CIC-associated IL-4 was found to be responsible for this negative function, which requires cell-to-cell contact with T lymphocytes and which is impaired by blocking IL-4 signaling. In addition, the CRC-associated Ag COA-1 was found to be expressed by CICs and to represent, in an autologous setting, a target molecule for anti-tumor T cells. Our study provides relevant information that may contribute to designing new immunotherapy protocols to target CICs in CRC patients.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cancer-Initiating Cells from Colorectal Cancer Patients Escape from T Cell–Mediated Immunosurveillance In Vitro through Membrane-Bound IL-4

Volonté

Tomaso

Spinelli

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Among the 12 genes related to tumor development (upregulated, seven genes including IL-6, IL-8, and CXCL1; downregulated, five genes; Table 1), we decided to focus on the GDF15 gene transcript (GDB accession no. NM_004864) that showed a log2 ratio of ∼ 4.0 in each cell line because TAM-derived GDF15, which is known to be a divergent member of human TGF-β superfamily associated with the growth and invasiveness of various cancers, 19,20 had not yet been reported in the microenvironment of ESCC.…”

Section: Upregulation Of Gdf15 Expression In Pbmo-derived Macrophagesmentioning

confidence: 99%

“…It has been confirmed that GDF15 activates intracellular signaling cascades such as the PI3K/Akt and MEK/Erk pathways with the induction of the proliferation of cancer cells. 19,21 We thus wondered whether GDF15 would trigger Akt and Erk1/2 phosphorylation on ESCC cell lines in serumfree conditions. We found that Akt and Erk1/2 phosphorylation in the ESCC cell lines was enhanced with 100 ng/ml of rhGDF15 after 10 min (Figure 4b).…”

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

confidence: 99%

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

“…Indeed, GDF is found overexpressed in high-grade glioma cells where it yields an immune-escape function and correlates with poor patient survival. Likewise, GBM cells deprived of GDF become more vulnerable to natural killer cells (Roth et al, 2010). However, other sources suggest that GDF may be secreted by the tumor-infiltrating macrophages instead of the GBM tumor cells (Shnaper et al, 2009).…”

Section: Growth and Differentiation Factor (Gdf)mentioning

confidence: 99%

Overview of Transforming Growth Factor β Superfamily Involvement in Glioblastoma Initiation and Progression

Nana¹,

Yang²,

Lin³

2015

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive of human brain tumors and has a stunning progression with a mean survival of one year from the date of diagnosis. High cell proliferation, angiogenesis and/or necrosis are histopathological features of this cancer, which has no efficient curative therapy. This aggressiveness is associated with particular heterogeneity of the tumor featuring multiple genetic and epigenetic alterations, but also with implications of aberrant signaling driven by growth factors. The transforming growth factor β (TGFβ) superfamily is a large group of structurally related proteins including TGFβ subfamily members Nodal, Activin, Lefty, bone morphogenetic proteins (BMPs) and growth and differentiation factor (GDF). It is involved in important biological functions including morphogenesis, embryonic development, adult stem cell differentiation, immune regulation, wound healing and inflammation. This superfamily is also considered to impact on cancer biology including that of GBM, with various effects depending on the member. The TGFβ subfamily, in particular, is overexpressed in some GBM types which exhibit aggressive phenotypes. This subfamily impairs anti-cancer immune responses in several ways, including immune cells inhibition and major histocompatibility (MHC) class I and II abolishment. It promotes GBM angiogenesis by inducing angiogenic factors such as vascular endothelial growth factor (VEGF), plasminogen activator inhibitor (PAI-I) and insulinlike growth factor-binding protein 7 (IGFBP7), contributes to GBM progression by inducing metalloproteinases (MMPs), "pro-neoplastic" integrins (αvβ3, α5β1) and GBM initiating cells (GICs) as well as inducing a GBMmesenchymal phenotype. Equally, Nodal promotes GICs, induces cancer metabolic switch and supports GBM cell proliferation, but is negatively regulated by Lefty. Activin promotes GBM cell proliferation while GDF yields immune-escape function. On the other hand, BMPs target GICS and induce differentiation and sensitivity to chemotherapy. This multifaceted involvement of this superfamily in GBM necessitates different strategies in anti-cancer therapy. While suppressing the TGFβ subfamily yields advantageous results, enhancing BMPs production is also beneficial.

show abstract

GDF-15 Contributes to Proliferation and Immune Escape of Malignant Gliomas

Cited by 146 publications

References 42 publications

Cancer-Initiating Cells from Colorectal Cancer Patients Escape from T Cell–Mediated Immunosurveillance In Vitro through Membrane-Bound IL-4

Cancer-Initiating Cells from Colorectal Cancer Patients Escape from T Cell–Mediated Immunosurveillance In Vitro through Membrane-Bound IL-4

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

Overview of Transforming Growth Factor β Superfamily Involvement in Glioblastoma Initiation and Progression

Contact Info

Product

Resources

About