A new model of cancer cachexia: contribution of the ubiquitin-proteasome pathway

Lazarus, Douglas; Destree, Antonia T.; Mazzola, Laureen M.; McCormack, Teresa A.; Dick, Lawrence R.; Xu, Bi H.; Huang, Jian; Pierce, Jacqueline W.; Read, Margaret; Coggins, Michael B.; Solomon, Vered; Goldberg, Alfred L.; Brand, Stephen; Elliott, Peter J.

doi:10.1152/ajpendo.1999.277.2.e332

Cited by 38 publications

(40 citation statements)

References 42 publications

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“…The higher relative weight could be attributed to edema (accumulation of fluid and inflammatory cells) considering the increased inflammation status. Inconsistent with the literature (27,32,33) we found food intake is decreased in colon-26 tumor-bearing mice. However, decreased food consumption alone is not sufficient to cause skeletal muscle wasting in this model given the fact that the weights of skeletal muscles were comparable in the Pair-fed and No Tumor groups.…”

Section: Discussionsupporting

confidence: 84%

Cardiac alterations in cancer-induced cachexia in mice

et al. 2010

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Abstract. Cachexia is a common syndrome in advanced cancer patients and causes up to 22% of cancer-related deaths. It remains elusive whether cancer cachexia causes heart failure. We investigated the effect of cancer cachexia on heart function and cardiac muscle structure in a mouse model. Male CD2F1 mice were inoculated with either colon-26 adenocarcinoma cells (Tumor group) or vehicle (PBS) (No Tumor group and Pair-fed group). Heart function as measured by fractional shortening in vivo using transthoracic echocardiography was performed on day 14 after tumor or PBS inoculation. At necropsy (day 17), hearts were collected for histology, transmission electron microscopy, RT-PCR and SDS-PAGE analysis. Mice from the Tumor group displayed a significantly reduced fractional shortening compared to mice in the No Tumor and Pair-fed groups. In hearts of the Tumor mice compared to the other groups, there was marked fibrosis and transmission electron microscopy revealed disrupted myocardial ultrastructure. Gene expression of troponin I, a regulator of cardiac muscle contraction, was reduced. Moreover, both mRNA and protein levels of myosin heavy chain (MHC) were altered whereby MHC· (adult isoform) was decreased and MHCß (fetal isoform) was increased indicating reactivation of the fetal gene expression pattern. In conclusion, heart function was diminished in mice with tumorinduced cachexia, and this impaired function was associated with increased fibrosis, disrupted myocardial structure and altered composition of contractile proteins of cardiac muscle.

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Section: Discussionsupporting

confidence: 84%

Cardiac alterations in cancer-induced cachexia in mice

et al. 2010

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“…8B). In the literature, it has been shown that the serum level of IL-6 does not correlate with cachexia in C26 cancer (39,40). The sustained injection of IL-6 alone into mice was not sufficient for inducing cachexia (6,9,41) unless it is at supraphysiological levels (12,42).…”

Section: Discussionmentioning

confidence: 99%

A Key Role for Leukemia Inhibitory Factor in C26 Cancer Cachexia

Seto

Kandarian

Jackman

2015

Journal of Biological Chemistry

108

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Background: Cachexia is the widespread loss of muscle and fat that causes death in many cancers. Results: Secretion of leukemia inhibitory factor (LIF) by C26 cancer cells activates differential gene expression that results in muscle cell atrophy. Conclusion: LIF produced by cancer cells acts on muscle to cause atrophy. Significance: LIF and its signaling pathway are new targets in fighting cancer cachexia.

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“…Upregulation of the ubiquitin proteasome pathway has been established in cancer-induced cachexia (22), but other proteolytic or degradation pathways have not been extensively studied. This study is the first to demonstrate that cancer-induced cachexia in a mouse model is associated with increased expression of MMPs and TIMPs in skeletal and cardiac muscle.…”

Section: Discussionmentioning

confidence: 99%

Metalloproteinase expression is altered in cardiac and skeletal muscle in cancer cachexia

Devine

Bicer

Reiser

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Cardiac and skeletal muscle dysfunction is a recognized effect of cancerinduced cachexia, with alterations in heart function leading to heart failure and negatively impacting patient morbidity. Cachexia is a complex and multifaceted disease state with several potential contributors to cardiac and skeletal muscle dysfunction. Matrix metalloproteinases (MMPs) are a family of enzymes capable of degrading components of the extracellular matrix (ECM). Changes to the ECM cause disruption both in the connections between cells at the basement membrane and in cell-to-cell interactions. In the present study, we used a murine model of C26 adenocarcinoma-induced cancer cachexia to determine changes in MMP gene and protein expression in cardiac and skeletal muscle. We analyzed MMP-2, MMP-3, MMP-9, and MMP-14 as they have been shown to contribute to both cardiac and skeletal muscle ECM changes and, thereby, to pathology in models of heart failure and muscular dystrophy. In our model, cardiac and skeletal muscles showed a significant increase in RNA and protein levels of several MMPs and tissue inhibitors of metalloproteinases. Cardiac muscle showed significant protein increases in MMP-2, MMP-3, MMP-9, and MMP-14, whereas skeletal muscles showed increases in MMP-2, MMP-3, and MMP-14. Furthermore, collagen deposition was increased after C26 adenocarcinoma-induced cancer cachexia as indicated by an increased left ventricular picrosirius red-positive-stained area. Increases in serum hydroxyproline suggest increased collagen turnover, implicating skeletal muscle remodeling. Our findings demonstrate that cancer cachexia-associated matrix remodeling results in cardiac fibrosis and possible skeletal muscle remodeling. With these findings, MMPs represent a possible therapeutic target for the treatment of cancer-induced cachexia.

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A new model of cancer cachexia: contribution of the ubiquitin-proteasome pathway

Cited by 38 publications

References 42 publications

Cardiac alterations in cancer-induced cachexia in mice

Cardiac alterations in cancer-induced cachexia in mice

A Key Role for Leukemia Inhibitory Factor in C26 Cancer Cachexia

Metalloproteinase expression is altered in cardiac and skeletal muscle in cancer cachexia

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