Effects of conditioned media from murine lung cancer cells and human tumor cells on cultured myotubes

Guigni, Blas A.; Velden, Jos van der; Kinsey, C. Matthew; Carson, James A.; Toth, Michael J.

doi:10.1152/ajpendo.00310.2019

Cited by 11 publications

(12 citation statements)

References 71 publications

(95 reference statements)

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“…in which the effect of murine and human lung tumour secreted factors on skeletal muscle was investigated. 44 Their report revealed that in fully matured C2C12 myotubes, myotube size and myosin heavy chain content were not affected by tumour‐derived factors. Altogether, these data do not support activation of the proteasome by E3‐ubiquitin ligases and subsequent myofibre atrophy as a direct effect of pancreas tumour‐derived factors.…”

Section: Discussionmentioning

confidence: 98%

“…Although this contrasts with findings of other studies, 8,41,42 our data are in line with a recent study of Guigni et al . in which the effect of murine and human lung tumour secreted factors on skeletal muscle was investigated 44 . Their report revealed that in fully matured C2C12 myotubes, myotube size and myosin heavy chain content were not affected by tumour‐derived factors.…”

Section: Discussionmentioning

confidence: 99%

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Human pancreatic tumour organoid‐derived factors enhance myogenic differentiation

Vaes

Dijk

Farshadi

et al. 2022

J cachexia sarcopenia muscle

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Background Most patients with pancreatic cancer develop cachexia, which is characterized by progressive muscle loss. The mechanisms underlying muscle loss in cancer cachexia remain elusive. Pancreatic tumour organoids are 3D cell culture models that retain key characteristics of the parent tumour. We aimed to investigate the effect of pancreatic tumour organoid-derived factors on processes that determine skeletal muscle mass, including the regulation of muscle protein turnover and myogenesis. Methods Conditioned medium (CM) was collected from human pancreatic cancer cell lines (PK-45H, PANC-1, PK-1, and KLM-1), pancreatic tumour organoid cultures from a severely cachectic (PANCO-9a) and a non-cachectic patient (PANCO-12a), and a normal pancreas organoid culture. Differentiating C2C12 myoblasts and mature C2C12 myotubes were exposed to CM for 24 h or maintained in control medium. In myotubes, NF-kB activation was monitored using a NF-κB luciferase reporter construct, and mRNA expression of E3-ubiquitin ligases and REDD1 was analysed by RT-qPCR. C2C12 myoblast proliferation and differentiation were monitored by live cell imaging and myogenic markers and myosin heavy chain (MyHC) isoforms were assessed by RT-qPCR. Results Whereas CM from PK-1 and KLM-1 cells significantly induced NF-κB activation in C2C12 myotubes (PK-1: 3.1fold, P < 0.001; KLM-1: 2.1-fold, P = 0.01), Atrogin-1/MAFbx and MuRF1 mRNA were only minimally and inconsistently upregulated by the CM of pancreatic cancer cell lines. Similarly, E3-ubiquitin ligases and REDD1 mRNA expression in myotubes were not altered by exposure to pancreatic tumour organoid CM. Compared with the control condition, CM from both PANCO-9a and PANCO-12a tumour organoids increased proliferation of myoblasts, which was accompanied by significant downregulation of the satellite cell marker paired-box 7 (PAX7) (PANCO-9a: À2.1-fold, P < 0.001; PANCO-12a: À2.0-fold, P < 0.001) and myogenic factor 5 (MYF5) (PANCO-9a: À2.1-fold, P < 0.001; PANCO-12a: À1.8-fold, P < 0.001) after 48 h of differentiation. Live cell imaging revealed accelerated alignment and fusion of myoblasts exposed to CM from PANCO-9a and PANCO-12a, which was in line with significantly increased Myomaker mRNA expression levels (PANCO-9a: 2.4-fold, P = 0.001; PANCO-12a: 2.2-fold, P = 0.004). These morphological and transcriptional alterations were accompanied by increased expression of muscle differentiation markers such as MyHC-IIB (PANCO-9a: 2.5-fold, P = 0.04; PANCO-12a: 3.1-fold, P = 0.006). Although the impact of organoid CM on myogenesis was not associated with the cachexia phenotype of the donor patients, it was specific for tumour organoids, as CM of control pancreas organoids did not modulate myogenic fusion. Conclusions These data show that pancreatic tumour organoid-derived factors alter the kinetics of myogenesis, which may eventually contribute to impaired muscle mass maintenance in cancer cachexia.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Human pancreatic tumour organoid‐derived factors enhance myogenic differentiation

Vaes

Dijk

Farshadi

et al. 2022

J cachexia sarcopenia muscle

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“…In vitro models of lung cancer-associated cachexia that use 2D cultures of myotubes and conditioned medium from lung carcinoma cells have been described previously (62)(63)(64). One study using all human cells reported that myotubes showed a lack of atrophy when exposed to cancer cell-conditioned medium (63), perhaps due to the potential issues of a low concentration of tumor-derived factors in conditioned medium and the lack of a temporal change in signal, both of which are accounted for by the low-volume coculture in our microphysiological system. Furthermore, we demonstrated that incorporating drug-resistant tumor tissues in the model contributes to increased elaboration of TNF (Fig.…”

Section: Discussionmentioning

confidence: 99%

Surface-directed engineering of tissue anisotropy in microphysiological models of musculoskeletal tissue

Mondrinos

Alisafaei

et al. 2021

Sci. Adv.

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Here, we present an approach to model and adapt the mechanical regulation of morphogenesis that uses contractile cells as sculptors of engineered tissue anisotropy in vitro. Our method uses heterobifunctional cross-linkers to create mechanical boundary constraints that guide surface-directed sculpting of cell-laden extracellular matrix hydrogel constructs. Using this approach, we engineered linearly aligned tissues with structural and mechanical anisotropy. A multiscale in silico model of the sculpting process was developed to reveal that cell contractility increases as a function of principal stress polarization in anisotropic tissues. We also show that the anisotropic biophysical microenvironment of linearly aligned tissues potentiates soluble factor-mediated tenogenic and myogenic differentiation of mesenchymal stem cells. The application of our method is demonstrated by (i) skeletal muscle arrays to screen therapeutic modulators of acute oxidative injury and (ii) a 3D microphysiological model of lung cancer cachexia to study inflammatory and oxidative muscle injury induced by tumor-derived signals.

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“…Rather, miRNAs, exosomes, proteins, or other small molecules could mediate this crosstalk. This finding importantly contradicts recent reports in other cancer types, where CM from cancer cells did not induce skeletal muscle mitochondrial deficits in vitro67 . This contrast suggests that different cancer types induce skeletal muscle dysfunction via different mechanisms, or perhaps that the small methodological differences between the two laboratories is responsible for the difference in results.…”

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confidence: 94%

Breast cancer associated muscle fatigue: Novel targets to improve survival and quality of life

Wilson¹

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Women diagnosed with breast cancer (BC) currently represent the largest group of cancer survivors in the United States, accounting for over 20% of those living after a cancer diagnosis. Most BC survivors report an unusual degree of fatigue, which can present prior to diagnosis and continue for many years after treatment cessation. Recent studies show that deficits in muscle function predict shorter survival in cancer, perhaps due to the fact that fatigue is known to reduce a patient's tolerance to anticancer therapies. Therefore, improving muscle function in BC patients has the potential to improve both quality of life and survival in the most commonly diagnosed cancer type. At present, few therapies for cancer-related fatigue show clinical efficacy, and the pathogenesis of this condition is largely unknown. This work aimed to identify molecular changes induced in skeletal muscle by BC, using patient samples and by developing novel in vitro and in vivo model systems. We tested the hypothesis that BC induces dysregulation of metabolic pathways regardless of molecular subtype or treatment history. Transcriptomic and proteomic analyses in BC patient muscle samples indicated mitochondrial dysfunction, which was evident across all molecular subtypes of BC and unrelated to patients' treatment histories. In vitro and in vivo experimentation confirmed the ability of BC cells to alter mitochondrial respiration and ATP content in muscle tissue via a secreted factor without the involvement of immune or stromal cell mediators. These data indicate that BC-induced fatigue is related to defects in skeletal muscle mitochondrial function induced directly by BC cells, and that targeting mitochondrial iii function or mitochondrial density in muscle could be a viable therapeutic strategy to improve both survival and quality of life in BC survivors.

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Effects of conditioned media from murine lung cancer cells and human tumor cells on cultured myotubes

Cited by 11 publications

References 71 publications

Human pancreatic tumour organoid‐derived factors enhance myogenic differentiation

Human pancreatic tumour organoid‐derived factors enhance myogenic differentiation

Surface-directed engineering of tissue anisotropy in microphysiological models of musculoskeletal tissue

Breast cancer associated muscle fatigue: Novel targets to improve survival and quality of life

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