PTH/PTHrP Receptor Mediates Cachexia in Models of Kidney Failure and Cancer

Kir, Serkan; Komaba, Hirotaka; Garcia, Ana P.; Economopoulos, Konstantinos P.; Liu, Wei; Lanske, Beate; Hodin, Richard A.; Spiegelman, Bruce M.

doi:10.1016/j.cmet.2015.11.003

Cited by 241 publications

(274 citation statements)

References 34 publications

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“…PAF-R are mainly expressed by mesenchymal cells, which may explain the implication of adipose, muscle, liver, and heart tissue, as well as gut barrier and brain dysfunctions in cachexia, supporting our proposed model (31,32,(62)(63)(64). Also, the described crosstalk between wasting of fat tissue and skeletal muscle is compatible with the proposed mechanism (65)(66)(67).…”

Section: Discussionsupporting

confidence: 71%

Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma

Muqaku

Eisinger

Meier

et al. 2017

Molecular & Cellular Proteomics

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Pathophysiologies of cancer-associated syndromes such as cachexia are poorly understood and no routine biomarkers have been established, yet. Using shotgun proteomics, known marker molecules including PMEL, CRP, SAA, and CSPG4 were found deregulated in patients with metastatic melanoma. Targeted analysis of 58 selected proteins with multiple reaction monitoring was applied for independent data verification. In three patients, two of which suffered from cachexia, a tissue damage signature was determined, consisting of nine proteins, PLTP, CD14, TIMP1, S10A8, S10A9, GP1BA, PTPRJ, CD44, and C4A, as well as increased levels of glycine and asparagine, and decreased levels of polyunsaturated phosphatidylcholine concentrations, as determined by targeted metabolomics. Remarkably, these molecules are known to be involved in key processes of cancer cachexia. Based on these results, we propose a model how metastatic melanoma may lead to reprogramming of organ functions via formation of platelet activating factors from long-chain polyunsaturated phosphatidylcholines under oxidative conditions and via systemic induction of intracellular calcium mobilization. Calcium mobilization in platelets was demonstrated to alter levels of several of these marker molecules. Additionally, platelets from melanoma patients proved to be in a rather exhausted state, and platelet-derived eicosanoids implicated in tumor growth were found massively increased in blood from three melanoma patients. Platelets were thus identified Serum is the most important diagnostic sample type because of its minimal invasive access, a relatively high stability and its comprehensive representation of the physiological state of an individual. The latest technological development of mass spectrometric instruments, such as high resolution orbitrap instruments, improved substantially the quality and reliability of serum proteomics data (1). Shotgun proteomics analysis using the orbitrap technology is mainly applied for protein screening purposes (2). This method allows performing untargeted analyses, applicable for hypothesis-generating clinical applications. Targeted proteomics using triple-quadrupole mass spectrometric instruments, represents a complementary approach which is applied for protein quantification, hypotheses verification and validation (3). Enormous efforts have been invested in the last decades focusing on serum biomarker discovery (4). However, mass spectrometrybased proteomics analyses hardly managed to cope with biological variation. As a consequence, almost no clinically validated biomarker has emerged from these investigations yet, and a lot of questions about pathophysiological mechanisms remain unanswered.Using mass spectrometry-based proteomics, we have previously investigated melanoma and neighboring stroma cells, focusing on the identification of biomarkers associated with intrinsic and extrinsic drug resistance (5). In the present article, we followed the question how metastatic melanoma may reprogram distant organ functions, and how these...

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Section: Discussionsupporting

confidence: 71%

Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma

Muqaku

Eisinger

Meier

et al. 2017

Molecular & Cellular Proteomics

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“…It is plausible that anabolic therapies designed to improve bone mass might act to increase fatty acid utilization in the skeleton. As an example, parathyroid hormone has recently been demonstrated to increase the metabolic activity of adipose tissue (60). The role of this hormone in osteoblast metabolism has largely been restricted to its affect on glycolysis (19), even though cAMP signaling, a major effector of PTH, promotes fatty acid utilization (61,62).…”

Section: Discussionmentioning

confidence: 99%

Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner

Kim¹,

Li²,

Zoch³

et al. 2017

JCI Insight

101

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“…Notably, browning is not restricted to one experimental model and is not associated with one specific cancer type, since it was documented in complementary model systems, including genetically engineered mouse models (GEMMs), carcinogen-induced cancers, syngeneic transplants of murine cancer cells, and xenogeneic transplants of human cancer tissue (Petruzzelli et al 2014). Recently, browning of WAT has been shown to take part in the pathogenesis of hypermetabolism commonly observed in other morbid conditions, like post-burn injury, severe adrenergic stress, and kidney failure (Kir et al 2015;Patsouris et al 2015;Sidossis et al 2015). Treatment of mice with a synthetic thyroid hormone receptor agonist induces adaptive thermogenesis in subcutaneous WAT, thus suggesting a role for WAT browning also in hyperthyroidism (Lin et al 2015).…”

Section: Role Of Lipids Burning Fat and White Adipose Tissue (Wat)mentioning

confidence: 99%

Mechanisms of metabolic dysfunction in cancer-associated cachexia

2016

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Metabolic dysfunction contributes to the clinical deterioration observed in advanced cancer patients and is characterized by weight loss, skeletal muscle wasting, and atrophy of the adipose tissue. This systemic syndrome, termed cancer-associated cachexia (CAC), is a major cause of morbidity and mortality. While once attributed solely to decreased food intake, the present description of cancer cachexia is a disorder of multiorgan energy imbalance. Here we review the molecules and pathways responsible for metabolic dysfunction in CAC and the ideas that led to the current understanding.

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PTH/PTHrP Receptor Mediates Cachexia in Models of Kidney Failure and Cancer

Cited by 241 publications

References 34 publications

Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma

Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma

Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner

Mechanisms of metabolic dysfunction in cancer-associated cachexia

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