Tumour‐derived transforming growth factor‐β signalling contributes to fibrosis in patients with cancer cachexia

Lima, Joanna Darck Carola Correia; Simoes, Estefanía; Castro, Gabriela Salim de; Morais, Mychel Raony Paiva Teixeira; Matos-Neto, Emídio Marques de; Alves, Michele Joana; Pinto, Nelson Inácio; Figuerêdo, Raquel Galvão; Zorn, Telma Maria Tenório; Felipe-Silva, Aloisio Souza; Tokeshi, Flávio; Otoch, José Pinhata; Alcântara, Paulo Sérgio Martins de; Cabral, Fernanda Janku; Ferro, Emer S.; Laviano, Alessandro; Seelaender, Marília

doi:10.1002/jcsm.12441

Cited by 42 publications

(37 citation statements)

References 77 publications

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“…Although IL-15 acts as a chemoattractant for natural killer (NK) cells, in metastatic colon cancer NK cells infiltrating tumors do not correlate with IL-15 concentration and were fewer, in comparison to the numbers observed in nonmetastatic tumors [66]. Our previous work showed that tumor homogenates from CC patients with colon cancer presents increased protein content for TGF-b and higher presence of angiogenic markers, together with higher deposition of collagen fibers [67], reduced percentage of M2 macrophages and increased content of proinflammatory cytokines, in relation to WSC [7]. Therefore, IL-15 expression seems to be correlated with tumor growth and metastatic potential, being a likely player in inducing increased tumor inflammation observed in cachexia.…”

Section: Discussionmentioning

confidence: 99%

Myokines in treatment-naïve patients with cancer-associated cachexia

et al. 2021

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Cancer-associated cachexia is a complex metabolic syndrome characterized by weight loss and systemic inflammation. Muscle loss and fatty infiltration into muscle are associated with poor prognosis in cancer patients. Skeletal muscle secretes myokines, factors with autocrine, paracrine and/or endocrine action, which may be modified by or play a role in cachexia. This study examined myokine content in the plasma, skeletal muscle and tumor homogenates from treatment-naïve patients with gastric or colorectal stages I-IV cancer with cachexia (CC, N ¼ 62), or not (weight stable cancer, WSC, N ¼ 32). Myostatin, interleukin (IL) 15, follistatin-like protein 1 (FSTL-1), fatty acid binding protein 3 (FABP3), irisin and brain-derived neurotrophic factor (BDNF) protein content in samples was measured with Multiplex technology; body composition and muscle lipid infiltration were evaluated in computed tomography, and quantification of triacylglycerol (TAG) in the skeletal muscle. Cachectic patients presented lower muscle FSTL-1 expression (p ¼ 0.047), higher FABP3 plasma content (p ¼ 0.0301) and higher tumor tissue expression of FABP3 (p ¼ 0.0182), IL-15 (p ¼ 0.007) and irisin (p ¼ 0.0110), compared to WSC. Neither muscle TAG content, nor muscle attenuation were different between weight stable and cachectic patients. Lumbar adipose tissue (AT) index, visceral AT index and subcutaneous AT index were lower in CC (p ¼ 0.0149, p ¼ 0.0455 and p ¼ 0.0087, respectively), who also presented lower muscularity in the cohort (69.2% of patients; p ¼ 0.0301), compared to WSC. The results indicate the myokine profile in skeletal muscle, plasma and tumor is impacted by cachexia. These findings show that myokines eventually affecting muscle wasting may not solely derive from the muscle itself (as the tumor also may

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Section: Discussionmentioning

confidence: 99%

Myokines in treatment-naïve patients with cancer-associated cachexia

et al. 2021

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“…The differences in the profiles of intracellular peptides observed when THOP1 −/− mice were a fed HD could also be related to alterations in the levels of intracellular peptide precursor proteins. Most of the intracellular peptide precursor proteins identified herein were previously shown to be functional in energy metabolism [101][102][103][104][105][106][107][108][109][110]. Several histone marks were identified in a prediabetic mouse model, providing a resource for studying the epigenetic functions of histone modifications in obesity and type 2 diabetes [109].The histone-derived intracellular peptides identified herein have putative post-translational lysine modification sites in their structure (indicated in bold underlined: AQGGVLPNIQAVLLPK and KQVHPDTGISSKAMGIMNS), suggesting a possible role of these peptides in regulating histone modifications in adipose tissue.…”

Section: Discussionmentioning

confidence: 99%

The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity

et al. 2020

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Thimet oligopeptidase (EC 3.4.24.15; EP24.15; THOP1) is a potential therapeutic target, as it plays key biological functions in processing biologically functional peptides. The structural conformation of THOP1 provides a unique restriction regarding substrate size, in that it only hydrolyzes peptides (optimally, those ranging from eight to 12 amino acids) and not proteins. The proteasome activity of hydrolyzing proteins releases a large number of intracellular peptides, providing THOP1 substrates within cells. The present study aimed to investigate the possible function of THOP1 in the development of diet-induced obesity (DIO) and insulin resistance by utilizing a murine model of hyperlipidic DIO with both C57BL6 wild-type (WT) and THOP1 null (THOP1−/−) mice. After 24 weeks of being fed a hyperlipidic diet (HD), THOP1−/− and WT mice ingested similar chow and calories; however, the THOP1−/− mice gained 75% less body weight and showed neither insulin resistance nor non-alcoholic fatty liver steatosis when compared to WT mice. THOP1−/− mice had increased adrenergic-stimulated adipose tissue lipolysis as well as a balanced level of expression of genes and microRNAs associated with energy metabolism, adipogenesis, or inflammation. Altogether, these differences converge to a healthy phenotype of THOP1−/− fed a HD. The molecular mechanism that links THOP1 to energy metabolism is suggested herein to involve intracellular peptides, of which the relative levels were identified to change in the adipose tissue of WT and THOP1−/− mice. Intracellular peptides were observed by molecular modeling to interact with both pre-miR-143 and pre-miR-222, suggesting a possible novel regulatory mechanism for gene expression. Therefore, we successfully demonstrated the previously anticipated relevance of THOP1 in energy metabolism regulation. It was suggested that intracellular peptides were responsible for mediating the phenotypic differences that are described herein by a yet unknown mechanism of action.

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“…The excessive accumulation of extracellular matrix is attributable to the pathological recruitment of fibroblasts to injured sites and their transformation to α-SMA-expressing myofibroblasts (6,26). Although the regulatory mechanisms underlying fibroblast activation are not completely understood, numerous studies have demonstrated that TGF-β1 serves as the main effector (40)(41)(42). The present study indicated that ATG treatment significantly decreased the expression of α-SMA and TGF-β1 in BLM-induced fibrotic skin, suggesting that the antifibrotic effect of ATG was associated with suppression of TGF-β1-mediated ECM gene transcription and fibroblast activation.…”

Section: Discussionmentioning

confidence: 99%

Arctigenin suppresses fibroblast activity and extracellular matrix deposition in hypertrophic scarring by reducing inflammation and oxidative stress

Jiang

Deng

et al. 2020

Mol Med Rep

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Hypertrophic scars (HSs) are a progressive fibroproliferation disorder caused by abnormal tissue repair after deep skin injury, and are characterized by continuous activation of fibroblasts and excessive deposition of extracellular matrix. Arctigenin (ATG), a phytomedicine derived from certain plants, displays antifibrotic effects in certain diseases, such as oral submucous fibrosis and peritoneal fibrosis. In the present study, to determine the antifibrotic potential of ATG in HS, a bleomycin (BLM)-induced skin fibrosis murine model was established. C57BL/6 mice were randomly divided into Control group, BLM group and BLM+ATG group. At 1 day post-bleomycin induction, the BLM+ATG group was intraperitoneally injected with 3 mg/kg/day ATG for 28 consecutive days. Pathological changes in the skin tissues were observed by hematoxylin and eosin staining. Collagen content was determined using a Sircol Collagen assay kit. Immunofluorescence staining was performed to detect the expression of TGF-β1 and α-SMA. The expression changes of various factors were detected by reverse transcription-quantitative PCR, western blotting and ELISA. Compared with the BLM group, ATG treatment significantly alleviated skin fibrosis by reducing dermal thickness, collagen content and expression levels of extracellular matrix-related genes (collagen type I α1 chain, collagen type i α2 chain, connective tissue growth factor and plasminogen activator inhibitor-1) in BLM-induced fibrotic skin. ATG also inhibited the transformation of fibroblasts into myofibroblasts in vivo and decreased the expression of TGF-β1 in BLM-induced fibrotic skin. Furthermore, the contents of proinflammatory cytokines, including IL-1β, il-4, IL-6, TNF-α and monocyte chemoattractant protein-1, were significantly decreased in the BLM+ATG group compared with the BLM group. Redox imbalance and oxidative stress were also reversed by ATG in BLM-induced fibrotic skin, as demonstrated by the upregulation of antioxidants (glutathione and superoxide dismutase) and downregulation of oxidants (malondialdehyde) in the BLM+ATG group compared with the BLM group. Moreover, the results indicated that the antioxidant effect of ATG may occur via activation of the nuclear factor erythroid-2-related factor 2/heme oxygenase-1 signaling pathway. Collectively, the present study indicated that ATG could ameliorate skin fibrosis in a murine model of HS, which was partly mediated by reducing inflammation and oxidative stress. Therefore, ATG may serve as a therapeutic agent for HSs.

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Tumour‐derived transforming growth factor‐β signalling contributes to fibrosis in patients with cancer cachexia

Cited by 42 publications

References 77 publications

Myokines in treatment-naïve patients with cancer-associated cachexia

Myokines in treatment-naïve patients with cancer-associated cachexia

The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity

Arctigenin suppresses fibroblast activity and extracellular matrix deposition in hypertrophic scarring by reducing inflammation and oxidative stress

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