Development and characterization of a cancer cachexia model employing a rare human duodenal neuroendocrine carcinoma-originating cell line

Yanagihara, Kazuyoshi; Kubo, Takanori; Iino, Yuki; Mihara, Keichiro; Morimoto, Chie; Seyama, Toshio; Kuwata, Takeshi; Ochiai, Atsushi; Yokozaki, Hiroshi

doi:10.18632/oncotarget.26764

Cited by 6 publications

(4 citation statements)

References 65 publications

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“…Many rodent tumour model studies have focused only on examining body weight and muscle mass. 8,[16][17][18] Although these are important measurements for signs of efficacy, endpoints relating to physical activity and quality of life are critical for building translation to patients, especially, given the lack of success in demonstrating that increases in muscle mass also result in improved function. Rodent tumour models can be leveraged to compare a variety of endpoints related to physical function and activity including skeletal muscle function (force and fatigue independent of behaviour), grip strength, locomotion, and voluntary exercise.…”

Section: Introductionmentioning

confidence: 99%

“…Many rodent tumour model studies have focused only on examining body weight and muscle mass 8,16–18 . Although these are important measurements for signs of efficacy, endpoints relating to physical activity and quality of life are critical for building translation to patients, especially, given the lack of success in demonstrating that increases in muscle mass also result in improved function.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of cachexia in the human fibrosarcoma HT‐1080 mouse tumour model

Bernardo

Joaquim

Garren

et al. 2020

J cachexia sarcopenia muscle

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Background Cancer cachexia is a complex metabolic disease with unmet medical need. Although many rodent models are available, none are identical to the human disease. Therefore, the development of new preclinical models that simulate some of the physiological, biochemical, and clinical characteristics of the human disease is valuable. The HT-1080 human fibrosarcoma tumour cell line was reported to induce cachexia in mice. Therefore, the purpose of this work was to determine how well the HT-1080 tumour model could recapitulate human cachexia and to examine its technical performance. Furthermore, the efficacy of ghrelin receptor activation via anamorelin treatment was evaluated, because it is one of few clinically validated mechanisms. Methods Female severe combined immunodeficient mice were implanted subcutaneously or heterotopically (renal capsule) with HT-1080 tumour cells. The cachectic phenotype was evaluated during tumour development, including body weight, body composition, food intake, muscle function (force and fatigue), grip strength, and physical activity measurements. Heterotopic and subcutaneous tumour histology was also compared. Energy balance was evaluated at standard and thermoneutral housing temperatures in the subcutaneous model. The effect of anamorelin (ghrelin analogue) treatment was also examined. Results The HT-1080 tumour model had excellent technical performance and was reproducible across multiple experimental conditions. Heterotopic and subcutaneous tumour cell implantation resulted in similar cachexia phenotypes independent of housing temperature. Tumour weight and histology was comparable between both routes of administration with minimal inflammation. Subcutaneous HT-1080 tumour-bearing mice presented with weight loss (decreased fat mass and skeletal muscle mass/fibre cross-sectional area), reduced food intake, impaired muscle function (reduced force and grip strength), and decreased spontaneous activity and voluntary wheel running. Key circulating inflammatory biomarkers were produced by the tumour, including growth differentiation factor 15, Activin A, interleukin 6, and TNF alpha. Anamorelin prevented but did not reverse anorexia and weight loss in the subcutaneous model. Conclusions The subcutaneous HT-1080 tumour model displays many of the perturbations of energy balance and physical performance described in human cachexia, consistent with the production of key inflammatory factors. Anamorelin was most effective when administered early in disease progression. The HT-1080 tumour model is valuable for studying potential therapeutic targets for the treatment of cachexia.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of cachexia in the human fibrosarcoma HT‐1080 mouse tumour model

Bernardo

Joaquim

Garren

et al. 2020

J cachexia sarcopenia muscle

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“…Such combined models allow for assessment of multiple factors. For example, the first duodenal NEC cell line (TCC-NECT-2, 2018) induced cachexia in a PDX mouse model by an unknown mechanism, which invites further study that may have been missed if it had only been used in vitro [ 64 , 71 ]. Increasing accessibility of 3D culture techniques such as spheroids or organoids may also contribute to improved ability to recapitulate NEN characteristics.…”

Section: Resultsmentioning

confidence: 99%

Preclinical Models of Neuroendocrine Neoplasia

Sedlack

Saleh-Anaraki

Kumar

et al. 2022

Cancers

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Neuroendocrine neoplasia (NENs) are a complex and heterogeneous group of cancers that can arise from neuroendocrine tissues throughout the body and differentiate them from other tumors. Their low incidence and high diversity make many of them orphan conditions characterized by a low incidence and few dedicated clinical trials. Study of the molecular and genetic nature of these diseases is limited in comparison to more common cancers and more dependent on preclinical models, including both in vitro models (such as cell lines and 3D models) and in vivo models (such as patient derived xenografts (PDXs) and genetically-engineered mouse models (GEMMs)). While preclinical models do not fully recapitulate the nature of these cancers in patients, they are useful tools in investigation of the basic biology and early-stage investigation for evaluation of treatments for these cancers. We review available preclinical models for each type of NEN and discuss their history as well as their current use and translation.

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“…This new and novel model for CAW addresses several needs in the field such as: (1) immunocompetence (i.e., a syngeneic model), (2) exhibits both heightened catabolism and suppressed regeneration, (3) exhibits both lean and fat mass loss, (4) exhibits an inflammatory microenvironment, (5) is flexible in timing and severity, and (6) arises in the tumor organ of origin. To the last point, recent studies have highlighted the importance of tumor location on both [27][28][29]. Our model is an easy and effective method to induce tumor formation in the lungs and concomitant CAW, using lung adenocarcinoma cells.…”

Section: Discussionmentioning

confidence: 98%

A novel transplantable model of lung cancer-associated tissue loss and disrupted muscle regeneration

2020

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Background: Cancer-associated muscle wasting (CAW), a symptom of cancer cachexia, is associated with approximately 20% of lung cancer deaths and remains poorly characterized on a mechanistic level. Current animal models for lung cancer-associated cachexia are limited in that they (1) primarily employ flank transplantation methods, (2) have short survival times not reflective of the patient condition, and (3) are typically performed in young mice not representative of mean patient age. This study investigates a new model for lung cancerassociated cachexia that can address these issues and also implicates muscle regeneration as a contributor to CAW. Methods: We used tail vein injection as a method to introduce tumor cells that seed primarily in the lungs of mice. Body composition of tumor-bearing mice was longitudinally tracked using NMR-based, echo magnetic resonance imaging (echoMRI). These data were combined with histological and molecular assessments of skeletal muscle to provide a complete analysis of muscle wasting.Results: In this new lung CAW model, we observed (1) progressive loss in whole body weight, (2) progressive loss of lean and fat mass, (3) a circulating cytokine/inflammatory profile similar to that seen in other models of CAW, (4) histological changes associated with muscle wasting, and (5) molecular changes in muscle that implicate suppression of muscle repair/regeneration. Finally, we show that survival can be extended without lessening CAW by titrating injected cell number.Conclusions: Overall, this study describes a new model of CAW that could be useful for further studies of lung cancer-associated wasting and accompanying changes in the regenerative capacity of muscle. Additionally, this model addresses many recent concerns with existing models such as immunocompetence, tumor location, and survival time.

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Development and characterization of a cancer cachexia model employing a rare human duodenal neuroendocrine carcinoma-originating cell line

Cited by 6 publications

References 65 publications

Characterization of cachexia in the human fibrosarcoma HT‐1080 mouse tumour model

Characterization of cachexia in the human fibrosarcoma HT‐1080 mouse tumour model

Preclinical Models of Neuroendocrine Neoplasia

A novel transplantable model of lung cancer-associated tissue loss and disrupted muscle regeneration

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