ArticleOncotarget2017
An autocrine/paracrine circuit of growth differentiation factor (GDF) 15 has a role for maintenance of breast cancer stem-like cells.
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 58 citations in OpenAlex.
- GDF15 promotes 5-Fluorouracil and Oxaliplatin resistance by promoting stem cell-like phenotype in colorectal cancer.British journal of cancer · 2026Article
- Baseline Plasma Growth-differentiation Factor 15 and Recovery of Physical Function Following Total Knee Replacement in the Study of Physical Resilience and Aging.The journals of gerontology. Series A, Biological sciences and medical sciences · 2026Article
- Hypoxia-induced secretory autophagy in cancer-associated fibroblasts promotes ECM remodelling through serglycin secretion in oral squamous cell carcinoma.Clinical and translational medicine · 2025Article
- The Multifaceted Role of Growth Differentiation Factor 15 (GDF15): A Narrative Review from Cancer Cachexia to Target Therapy.Biomedicines · 2025Review
- Silencing Calumenin Expression via Artificial MicroRNA, a Potential Breakthrough for Inhibiting Proliferation, Halting Migration, and Triggering Apoptosis in Breast Cancer Cells.Advanced pharmaceutical bulletin · 2025Article
- Mapping growth differentiation factor-15 (GDF15)-mediated signaling pathways in cancer: insights into its role across different cancer types.Discover oncology · 2025Article
- Senescence of endothelial cells promotes phenotypic changes in adventitial fibroblasts: possible implications for vascular aging.Molecular and cellular biochemistry · 2025Article
- Hepatocyte-specific GDF15 overexpression improves high-fat diet-induced obesity and hepatic steatosis in mice via hepatic FGF21 induction.Scientific reports · 2024Article
- GALNT14 in association with GDF-15 promotes stemness and drug resistance through β-catenin signalling pathway in breast cancer.Molecular biology reports · 2024Article
- Tumor microenvironment of cancer stem cells: Perspectives on cancer stem cell targeting.Genes & diseases · 2024Review
- Overexpression of Growth Differentiation Factor 15 in Glioblastoma Stem Cells Promotes Their Radioresistance.Cancers · 2023Article
- Article
- Identification of a novel ER-NFĸB-driven stem-like cell population associated with relapse of ER+ breast tumors.Breast cancer research : BCR · 2022Article
- Clinical usefulness and acceleratory effect of macrophage inhibitory cytokine-1 on biliary tract cancer: an experimental biomarker analysis.Cancer cell international · 2022Article
- FOXM1 mediates GDF-15 dependent stemness and intrinsic drug resistance in breast cancer.Molecular biology reports · 2022Article
- Pathophysiological role of growth differentiation factor 15 (GDF15) in obesity, cancer, and cachexia.Cytokine & growth factor reviews · 2022Review
- Systemic Immune Dysregulation in Early Breast Cancer Is Associated With Decreased Plasma Levels of Both Soluble Co-Inhibitory and Co-Stimulatory Immune Checkpoint Molecules.Frontiers in immunology · 2022Article
- Case Report: Small intestinal metastatic breast cancer: A case report and literature review.Frontiers in oncology · 2022Article
- Bone morphogenetic proteins, activins, and growth and differentiation factors in tumor immunology and immunotherapy resistance.Frontiers in immunology · 2022Review
- Review
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cancer stem cells are thought to be responsible for tumor growth, recurrence, and resistance to conventional cancer therapy. However, it is still unclear how they are maintained in tumor tissues. Here, we show that the growth differentiation factor 15 (GDF15), a member of the TGFβ family, may maintain cancer stem-like cells in breast cancer tissues by inducing its own expression in an autocrine/paracrine manner. We found that GDF15, but not TGFβ, increased tumor sphere formation in several breast cancer cell lines and patient-derived primary breast cancer cells. As expected, TGFβ strongly stimulated the phosphorylation of Smad2. GDF15 also stimulated the phosphorylation of Smad2, but the GDF15-induced tumor sphere forming efficiency was not significantly affected by treatment with SB431542, an inhibitor of the TGFβ signaling. Although TGFβ transiently activated ERK1/2, GDF15 induced prolonged activation of ERK1/2. Treatment with U0126, an inhibitor of the MEK-ERK1/2 signaling, greatly inhibited the GDF15-induced tumor sphere formation. Moreover, cytokine array experiments revealed that GDF15, but not TGFβ, is able to induce its own expression; furthermore, it appears to form an autocrine/paracrine circuit to continuously produce GDF15. In addition, we found heterogeneous expression levels of GDF15 among cancer cells and in human breast cancer tissues using immunohistochemistry. This may reflect a heterogeneous cancer cell population, including cancer stem-like cells and other cancer cells. Our findings suggest that GDF15 induces tumor sphere formation through GDF15-ERK1/2-GDF15 circuits, leading to maintenance of GDF15high cancer stem-like cells. Targeting GDF15 to break these circuits should contribute to the eradication of tumors.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.