High GDF-15 Serum Levels Independently Correlate with Poorer Overall Survival of Patients with Tumor-Free Stage III and Unresectable Stage IV Melanoma

Weide, Benjamin; Schäfer, Tina; Martens, Alexander; Kuzkina, Anastasia; Uder, Laura; Noor, Seema; Garbe, Claus; Harter, Patrick N.; Mittelbronn, Michel; Wischhusen, Jörg

doi:10.1016/j.jid.2016.07.016

Cited by 29 publications

(26 citation statements)

References 33 publications

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“…Growth differentiation factors are known to be associated with many diseases states. For example, GDF15 plays a role in cancer cachexia (Lerner et al, ; Weide et al, ), mitochondrial diseases (Kalko et al, ; Montero et al, ; Yatsuga et al, ), and as a mediator of intensive care unit (ICU)‐acquired muscle weakness (Bloch et al, ). Its expression has even been associated with mortality (Wiklund et al, ).…”

Section: Discussionmentioning

confidence: 99%

mTORC1 underlies age‐related muscle fiber damage and loss by inducing oxidative stress and catabolism

et al. 2019

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Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these age‐related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in TSC1 knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1's activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased GDF15 is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of GDF15 via phosphorylation of STAT3. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and STAT3's phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to age‐related muscle atrophy, and GDF signaling is a proposed mechanism.

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Section: Discussionmentioning

confidence: 99%

mTORC1 underlies age‐related muscle fiber damage and loss by inducing oxidative stress and catabolism

et al. 2019

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“…Although under physiological conditions GDF‐15 is generally regarded to exert anti‐inflammatory and anti‐tumourigenic effects, microarray data reveal that GDF‐15 is a protein with a high level of tumour‐associated expression . Overexpression of GDF‐15 has been confirmed in various types of malignant disease . GDF‐15 is also the only known secreted p53‐regulated cytokine reflecting p53 activation, anticipating a promising role as biomarker.…”

Section: Discussionmentioning

confidence: 99%

“…24 Overexpression of GDF-15 has been confirmed in various types of malignant disease. 9,[11][12][13]16 GDF-15 is also the only known secreted p53regulated cytokine reflecting p53 activation, 10 anticipating a promising role as biomarker. A strong association between circulating levels of GDF-15 and the histopathological grade of malignancy, tumour mass and metastatic progression has been documented for colorectal, pancreatic, prostate and oral squamous cancer in mostly small studies.…”

Section: Gdf-15 In Malignant Diseasementioning

confidence: 99%

“…Hence, GDF‐15 is also implicated in tumour genesis regulating the tumour microenvironment with a potential impact on tumour progression and invasion . Overexpression of GDF‐15 has been reported in tissues of various types of malignant disease as colorectal, oesophageal, pancreatic, prostate, ovarian and endometrial cancers, glioma and melanoma . Additionally, levels of circulating GDF‐15 have been related to histopathological malignant grade and metastatic progression in small studies with the result to consider GDF‐15 a potential biomarker for tumour diagnosis and surveillance …”

Section: Introductionmentioning

confidence: 99%

“…9,10 Overexpression of GDF-15 has been reported in tissues of various types of malignant disease as colorectal, oesophageal, pancreatic, prostate, ovarian and endometrial cancers, glioma and melanoma. [11][12][13][14][15][16] Additionally, levels of circulating GDF-15 have been related to histopathological malignant grade and metastatic progression in small studies 12,15 with the result to consider GDF-15 a potential biomarker for tumour diagnosis and surveillance. 8 From a cardio-oncologic perspective, there are currently no data regarding the relationship between dysregulation of GDF-15 and other cardiac biomarkers in cancer patients available.…”

Section: Introductionmentioning

confidence: 99%

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GDF‐15 in solid vs non‐solid treatment‐naïve malignancies

Arfsten

Cho

Freitag

et al. 2019

Eur J Clin Investigation

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AimGDF‐15 is an established cardiovascular risk marker but is equally implicated in tumour biology. Elevated levels of GDF‐15 have indeed been observed in distinct tumour entities. This study aimed to explore the relation of GDF‐15 to other cardiac biomarkers and the general association of GDF‐15 on prognosis in an unselected cohort of treatment‐naïve cancer patients.MethodsWe prospectively enrolled 555 consecutive patients at time of diagnosis of malignant disease prior receiving anticancer therapy. Plasma GDF‐15 concentrations were determined alongside other cardiac and routine laboratory markers. All‐cause mortality was defined as primary endpoint.ResultsGDF‐15 levels were 338 ng/L (IQR:205‐534) for the total cohort, and values were comparable for different tumour entities except breast cancer. Metastatic disease was characterized by higher plasma GDF‐15 [435 ng/L (IQR:279‐614) vs 266 ng/L (IQR:175‐427), P < .001]. GDF‐15 correlated positively with inflammatory status reflected by CRP, SAA and IL‐6 [r = .31, P < .001, r = .23, P < .001 and r = .14, P = .002] and cardiac biomarkers as NT‐proBNP, hsTnT, MR‐proADM and CT‐proET‐1 [r = .46; r = .46; r = .59 and r = .50; P < .001 for all]. GDF‐15 was significantly associated with all‐cause mortality after multivariate adjustment [adj.HR for ln(GDF‐15) 1.78, 95%CI:1.47‐2.16, P < .001]. There was a significant interaction between solid and haematological malignancies with loss of association of GDF‐15 with outcome in myelodysplastic and myeloproliferative disease.ConclusionsElevated plasma GDF‐15 is associated with progressing disease severity and poor prognosis in solid tumours of treatment‐naïve cancer patients. GDF‐15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF‐15 represents a promising target for our pathophysiologic understanding in cardio‐oncology linking conditions of both cardiac and neoplastic disease.

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The metastatic microenvironment: Melanoma–microglia cross‐talk promotes the malignant phenotype of melanoma cells

Izraely

Ben-Menachem

Sagi‐Assif

et al. 2018

Intl Journal of Cancer

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Melanoma has the highest propensity to metastasize to the brain compared to other cancers, as brain metastases are found frequently high in patients who have prolonged survival with visceral metastasis. Once disseminated in the brain, melanoma cells communicate with brain resident cells that include astrocytes and microglia. Microglia cells are the resident macrophages of the brain and are the main immunological cells in the CNS involved in neuroinflammation. Data on the interactions between brain metastatic melanoma cells and microglia and on the role of microglia-mediated neuroinflammation in facilitating melanoma brain metastasis are lacking. To elucidate the role of microglia in melanoma brain metastasis progression, we examined the bidirectional interactions between microglia and melanoma cells in the tumor microenvironment. We identified the molecular and functional modifications occurring in brain-metastasizing melanoma cells and microglia cells after the treatment of each cell type with supernatants of the counter cell type. Both cells induced alteration in gene expression programs, cell signaling, and cytokine secretion in the counter cell type. Moreover, melanoma cells exerted significant morphological changes on microglia cells, enhanced proliferation, induced matrix metalloproteinase-2 (MMP-2) activation, and cell migration. Microglia cells induced phenotypic changes in melanoma cells increasing their malignant phenotype: increased melanoma proliferation, MMP-2 activity, cell migration, brain endothelial penetration, and tumor cells ability to grow as spheroids in 3D cultures. Our work provides a novel insight into the bidirectional interactions between melanoma and micoglia cells, suggesting the contribution of microglia to melanoma brain metastasis formation.

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High GDF-15 Serum Levels Independently Correlate with Poorer Overall Survival of Patients with Tumor-Free Stage III and Unresectable Stage IV Melanoma

Cited by 29 publications

References 33 publications

mTORC1 underlies age‐related muscle fiber damage and loss by inducing oxidative stress and catabolism

mTORC1 underlies age‐related muscle fiber damage and loss by inducing oxidative stress and catabolism

GDF‐15 in solid vs non‐solid treatment‐naïve malignancies

The metastatic microenvironment: Melanoma–microglia cross‐talk promotes the malignant phenotype of melanoma cells

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