Distinct cachexia profiles in response to human pancreatic tumours in mouse limb and respiratory muscle

Nosacka, Rachel L.; Delitto, Andrea E.; Delitto, Dan; Patel, Rohan; Judge, Sarah M.; Treviño, José G.; Judge, Andrew R.

doi:10.1002/jcsm.12550

Cited by 26 publications

(40 citation statements)

References 93 publications

(155 reference statements)

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“…In fact, compared to our previous works, significant reductions in mitochondrial efficiency occurred in the diaphragm before the limb muscle [ 24 ], perhaps suggesting that the diaphragm may be more susceptible to mitochondrial aberrations during cachexia development. This would align with research across other models of myopathies, such as in critical care patients [ 13 , 18 , 30 ] as well as works demonstrating differential responses between tissues during cachexia and other inflammatory diseases [ 17 , 31 , 32 , 33 ]. This divergent response may be due to different fiber type compositions, as the prior works were conducted in more mixed muscle fibers (plantaris and gastrocnemius), compared to the highly oxidative diaphragm muscle.…”

Section: Discussionsupporting

confidence: 52%

Mitochondrial Function and Protein Turnover in the Diaphragm are Altered in LLC Tumor Model of Cancer Cachexia

Rosa‐Caldwell

Benson²,

Lee

et al. 2020

IJMS

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It is established that cancer cachexia causes limb muscle atrophy and is strongly associated with morbidity and mortality; less is known about how the development of cachexia impacts the diaphragm. The purpose of this study was to investigate cellular signaling mechanisms related to mitochondrial function, reactive oxygen species (ROS) production, and protein synthesis during the development of cancer cachexia. C57BL/J6 mice developed Lewis Lung Carcinoma for either 0 weeks (Control), 1 week, 2 weeks, 3 weeks, or 4 weeks. At designated time points, diaphragms were harvested and analyzed. Mitochondrial respiratory control ratio was ~50% lower in experimental groups, which was significant by 2 weeks of cancer development, with no difference in mitochondrial content markers COXIV or VDAC. Compared to the controls, ROS was 4-fold elevated in 2-week animals but then was not different at later time points. Only one antioxidant protein, GPX3, was altered by cancer development (~70% lower in experimental groups). Protein synthesis, measured by a fractional synthesis rate, appeared to become progressively lower with the cancer duration, but the mean difference was not significant. The development and progression of cancer cachexia induces marked alterations to mitochondrial function and ROS production in the diaphragm and may contribute to increased cachexia-associated morbidity and mortality.

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Section: Discussionsupporting

confidence: 52%

Mitochondrial Function and Protein Turnover in the Diaphragm are Altered in LLC Tumor Model of Cancer Cachexia

Rosa‐Caldwell

Benson²,

Lee

et al. 2020

IJMS

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“…Thus, the cancer systemic environment has the potential to dysregulate myofiber gene expression and metabolic signaling through alterations to the ECM. Muscle fibrosis and dysregulation of the ECM has been reported in cachectic skeletal muscle from pancreatic cancer patients ( Judge et al, 2018 ; Nosacka et al, 2020 ), and fibrosis can negatively impact myofiber growth and healing from damage ( Bedair et al, 2007 ; Li et al, 2016a ). Muscle inflammatory processes are established modulators of the ECM for healing and wound repair and also critical for muscle remodeling to exercise and overload.…”

Section: Skeletal Muscle Microenvironmentmentioning

confidence: 99%

“…While the proper coordination of fibroblast proliferation and collagen formation is necessary for healthy skeletal muscle repair and remodeling, both reduced or exacerbated fibroblast activity can result in fibrosis and reduced skeletal muscle plasticity and overall functional capacity ( Chapman et al, 2016 ). Fibrosis during the progression of cancer cachexia has received significant attention due to its role in reduced skeletal muscle plasticity and the loss of strength disproportionate to mass ( Judge et al, 2018 ; Ramage and Skipworth, 2018 ); however, evidence of impaired regeneration and increased fibrosis in cachectic skeletal muscle is limited to cancer type and severity of the disease ( Nosacka et al, 2020 ).…”

Section: Skeletal Muscle Microenvironmentmentioning

confidence: 99%

“…Inflammatory signaling can impact several cell types located in the muscle microenvironment leading to altered myofiber protein synthesis ( Gao et al, 2017 ) and mitochondrial quality control ( Gomez-Cabrera et al, 2016 ; Fix et al, 2018 ), which are known drivers of muscle wasting with cancer. Additionally, muscle fibrosis and dysregulation of the ECM, of which immune cells play a central regulatory role, have been reported in cachectic skeletal muscle from pancreatic cancer patients ( Judge et al, 2018 ; Nosacka et al, 2020 ). Therefore, this review explores the growing body of evidence for immune cell modulation of the skeletal muscle microenvironment during cancer-induced muscle wasting.…”

Section: Introductionmentioning

confidence: 99%

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The Impact of Immune Cells on the Skeletal Muscle Microenvironment During Cancer Cachexia

2020

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Progressive weight loss combined with skeletal muscle atrophy, termed cachexia, is a common comorbidity associated with cancer that results in adverse consequences for the patient related to decreased chemotherapy responsiveness and increased mortality. Cachexia’s complexity has provided a barrier for developing successful therapies to prevent or treat the condition, since a large number of systemic disruptions that can regulate muscle mass are often present. Furthermore, considerable effort has focused on investigating how tumor derived factors and inflammatory mediators directly signal skeletal muscle to disrupt protein turnover regulation. Currently, there is developing appreciation for understanding how cancer alters skeletal muscle’s complex microenvironment and the tightly regulated interactions between multiple cell types. Skeletal muscle microenvironment interactions have established functions in muscle response to regeneration from injury, growth, aging, overload-induced hypertrophy, and exercise. This review explores the growing body of evidence for immune cell modulation of the skeletal muscle microenvironment during cancer-induced muscle wasting. Emphasis is placed on the regulatory network that integrates physiological responses between immune cells with other muscle cell types including satellite cells, fibroblast cells, and endothelial cells to regulate myofiber size and plasticity. The overall goal of this review is to provide an understanding of how different cell types that constitute the muscle microenvironment and their signaling mediators contribute to cancer and chemotherapy-induced muscle wasting.

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“…For example, associations between CAR or NLR and PDAC OS were supported by highly suggestive evidence. PDAC can be a deeline in its advanced stage, even at a local advanced stage, which can cause cachexia of patients leading to high mortality (74). Systemic inflammation response (SIR) seems to play an important role in cachexia, such as weight loss and functional decline (75,76).…”

Section: Comparison With Other Studies and Possible Explanationsmentioning

confidence: 99%

Prognostic Biomarkers for Pancreatic Ductal Adenocarcinoma: An Umbrella Review

et al. 2020

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Background: Pancreatic ductal adenocarcinoma (PDAC) leads to the majority of cancer-related deaths due to its morbidity with similar mortality. Lack of effective prognostic biomarkers are the main reason for belated post-operative intervention of recurrence which causes high mortality. Numerous systematic reviews and meta-analyses have explored the prognostic value of biomarkers in PDAC so far. In this article, we performed an umbrella review analyzing these studies to provide an overview of associations between prognostic biomarkers and PDAC survival outcome and synthesized these results to guide better clinical practice. Methods: Systematic reviews and meta-analyses investigating the associations between PDAC survival outcomes and prognostic biomarkers were acquired via the PubMed and Embase databases from inception till February 1, 2020. Associations supported by nominally statistically significant results were classified into strong, highly suggestive, suggestive, and weak based on several critical factors such as the statistical significance of summary estimates, the number of events, the estimate of the largest study included, interstudy heterogeneity, small-study effects, 95% predictive interval (PI), excess significance bias, and the results of credibility ceiling sensitivity analyses. Results: We included 41 meta-analyses containing 63 associations between PDAC survival outcomes and prognostic biomarkers. Although, none was supported by strong evidence among these associations, an association between C-reactive protein to albumin ratio (CAR) and PDAC overall survival (OS) and an association between neutrophil-lymphocyte ratio (NLR) and PDAC OS were supported by highly suggestive evidence. Otherwise, the association between lactate dehydrogenase (LDH) and PDAC OS was supported by suggestive evidence. The remaining 60 associations were supported by weak or not suggestive evidence. Conclusion: Associations between CAR or NLR and PDAC OS were supported by highly suggestive evidence. And the association between LDH and PDAC OS was Wang et al. Prognostic Biomarkers for Pancreatic Cancer supported by suggestive evidence. Although the methodological quality of the included systematic reviews and meta-analyses which were evaluated by AMSTAR2.0 is generally poor, the identification of the relatively robust prognostic biomarkers of PDAC may guide better post-operative intervention and follow-up to prolong patients' survival.

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Distinct cachexia profiles in response to human pancreatic tumours in mouse limb and respiratory muscle

Cited by 26 publications

References 93 publications

Mitochondrial Function and Protein Turnover in the Diaphragm are Altered in LLC Tumor Model of Cancer Cachexia

Mitochondrial Function and Protein Turnover in the Diaphragm are Altered in LLC Tumor Model of Cancer Cachexia

The Impact of Immune Cells on the Skeletal Muscle Microenvironment During Cancer Cachexia

Prognostic Biomarkers for Pancreatic Ductal Adenocarcinoma: An Umbrella Review

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