Molecular Pathways: Cachexia Signaling—A Targeted Approach to Cancer Treatment

Miyamoto, Yuji; Hanna, Diana L.; Zhang, Wu; Baba, Hideo; Lenz, Heinz Josef

doi:10.1158/1078-0432.ccr-16-0495

Cited by 91 publications

(82 citation statements)

References 55 publications

(55 reference statements)

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“…4), gives the opportunity for developing more comprehensive diagnostic instruments and therapy strategies (52) aimed at improving quality of life and overall survival. To sum up, the present application of a combined proteomics, metabolomics and lipidomics approach clearly connected widespread fragment knowledge of melanoma biology (53), helping us to build a simple, clear and comprehensive model for systemic tumor-promoting activities. Currently, we are establishing clinical studies with appropriate statistical power for the evaluation of the here presented model.…”

Section: Discussionmentioning

confidence: 84%

“…Complete remissions may be now translated into long-term improved overall survival (51). By putting the tumor disease in a holistic communicative context, thereby considering tumor mediated functional changes at distant organ sites (52), we may better meet the diagnostic and therapeutic requirements of late stage tumor diseases with their typical syndromes, B-symptoms (weight loss and night sweats), or cachexia and fatigue (53).…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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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“…Inflammation which occurs in the tumor microenvironment is believed to be a major driver of anorexia and catabolic events which include muscle proteolysis and adipose tissue lipolysis. There is increasing information regarding molecular mediators of cachexia (15). Pro-inflammatory cytokines including TNF-α, IL-1, and IL-6 are associated with skeletal muscle breakdown in cachexia (15)(16)(17).…”

mentioning

confidence: 99%

“…There is increasing information regarding molecular mediators of cachexia (15). Pro-inflammatory cytokines including TNF-α, IL-1, and IL-6 are associated with skeletal muscle breakdown in cachexia (15)(16)(17). Muscle mass also depends upon the balance between regulators of myogenesis, with IGF-I promoting myogenesis and with myostatin and activin inhibiting myogenesis (15).…”

mentioning

confidence: 99%

“…Pro-inflammatory cytokines including TNF-α, IL-1, and IL-6 are associated with skeletal muscle breakdown in cachexia (15)(16)(17). Muscle mass also depends upon the balance between regulators of myogenesis, with IGF-I promoting myogenesis and with myostatin and activin inhibiting myogenesis (15). Comparing serum levels of these proteins in patients who gained weight versus those who lost weight during antineoplastic therapy might provide insights regarding the mechanisms of cachexia.…”

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confidence: 99%

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Practical and theoretical implications of weight gain in advanced non-small cell lung cancer patients

et al. 2017

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Differentially expressed alternatively spliced genes in skeletal muscle from cancer patients with cachexia

Narasimhan

Greiner

Bathe

et al. 2017

J cachexia sarcopenia muscle

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BackgroundAlternative splicing (AS) is a post‐transcriptional gene regulatory mechanism that contributes to proteome diversity. Aberrant splicing mechanisms contribute to various cancers and muscle‐related conditions such as Duchenne muscular dystrophy. However, dysregulation of AS in cancer cachexia (CC) remains unexplored. Our objectives were (i) to profile alternatively spliced genes (ASGs) on a genome‐wide scale and (ii) to identify differentially expressed alternatively spliced genes (DASGs) associated with CC.MethodsRectus abdominis muscle biopsies obtained from cancer patients were stratified into cachectic cases (n = 21, classified based on International consensus diagnostic framework for CC) and non‐cachectic controls (n = 19, weight stable cancer patients). Human transcriptome array 2.0 was used for profiling ASGs using the total RNA isolated from muscle biopsies. Representative DASG signatures were validated using semi‐quantitative RT–PCR.ResultsWe identified 8960 ASGs, of which 922 DASGs (772 up‐regulated and 150 down‐regulated) were identified at ≥1.4 fold‐change and P < 0.05. Representative DASGs validated by semi‐quantitative RT–PCR confirmed the primary findings from the human transcriptome arrays. Identified DASGs were associated with myogenesis, adipogenesis, protein ubiquitination, and inflammation. Up to 10% of the DASGs exhibited cassette exon (exon included or skipped) as a predominant form of AS event. We also observed other forms of AS events such as intron retention, alternate promoters.ConclusionsOverall, we have, for the first time, conducted global profiling of muscle tissue to identify DASGs associated with CC. The mechanistic roles of the identified DASGs in CC pathophysiology using model systems is warranted, as well as replication of findings in independent cohorts.

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Molecular Pathways: Cachexia Signaling—A Targeted Approach to Cancer Treatment

Cited by 91 publications

References 55 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

Practical and theoretical implications of weight gain in advanced non-small cell lung cancer patients

Differentially expressed alternatively spliced genes in skeletal muscle from cancer patients with cachexia

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