Extracellular vesicles-released parathyroid hormone-related protein from Lewis lung carcinoma induces lipolysis and adipose tissue browning in cancer cachexia

Hu, Wenjun; Xiong, Hairong; Ru, Zeyuan; Zhao, Yan; Zhou, Yali; Xie, Kairu; Xiao, Wen; Zhang, Xiong; Wang, Cheng; Yuan, Chunrong; Shi, Jian; Du, Quansheng; Zhang, Xiaoping; Yang, Hongmei

doi:10.1038/s41419-020-03382-0

Cited by 34 publications

(42 citation statements)

References 44 publications

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“…Circulating PTHrP, a paraneoplastic factor that induces hypercalcaemia, has been shown to indirectly increase HSL phosphorylation, which is required for HSL enzymatic lipase activity, through protein kinase A. 18 , 36 , 37 PTHrP is also reportedly associated with browning via increased UCP‐1 protein 17 in AT in rodent models, making its impact on thermogenesis and lipolysis difficult to differentiate. Other groups have reported that cancer patients with detectable circulating PTHrP levels have higher relative REE 17 and reduced body fat 19 than those with undetectable PTHrP.…”

Section: Discussionmentioning

confidence: 99%

Whole‐body and adipose tissue metabolic phenotype in cancer patients

Anderson

Lee

et al. 2022

J cachexia sarcopenia muscle

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Background Altered adipose tissue (AT) metabolism in cancer‐associated weight loss via inflammation, lipolysis, and white adipose tissue (WAT) browning is primarily implicated from rodent models; their contribution to AT wasting in cancer patients is unclear. Methods Energy expenditure (EE), plasma, and abdominal subcutaneous WAT were obtained from men (aged 65 ± 8 years) with cancer, with (CWL, n = 27) or without (CWS, n = 47) weight loss, and weight‐stable non‐cancer patients (CON, n = 26). Clinical images were assessed for adipose and muscle area while plasma and WAT were assessed for inflammatory, lipolytic, and browning markers. Results CWL displayed smaller subcutaneous AT (SAT; P = 0.05) and visceral AT (VAT; P = 0.034) than CWS, and displayed higher circulating interleukin (IL)‐6 (P = 0.01) and WAT transcript levels of IL‐6 (P = 0.029), IL‐1β (P = 0.042), adipose triglyceride lipase (P = 0.026), and browning markers (Dio2, P = 0.03; PGC‐1a, P = 0.016) than CWS and CON. There was no difference across groups in absolute REE (P = 0.061), %predicted REE (P = 0.18), circulating free fatty acids (FFA, P = 0.13) or parathyroid hormone‐related peptide (PTHrP; P = 0.88), or WAT protein expression of inflammation (IL‐6, P = 0.51; IL‐1β, P = 0.29; monocyte chemoattractant protein‐1, P = 0.23) or WAT protein or gene expression of browning (uncoupling protein‐1, UCP‐1; P = 0.13, UCP‐1, P = 0.14). In patients with cancer, FFA was moderately correlated with WAT hormone‐sensitive lipase transcript (r = 0.38, P = 0.018, n = 39); circulating cytokines were not correlated with expression of WAT inflammatory markers and circulating PTHrP was not correlated with expression of WAT browning markers. In multivariate regression using cancer patients only, body mass index (BMI) directly predicted SAT (N = 25, R2 = 0.72, P < 0.001), VAT (N = 28, R2 = 0.64, P < 0.001), and absolute REE (N = 22, R2 = 0.43, P = 0.001), while BMI and WAT UCP‐1 protein were indirectly associated with %predicted REE (N = 22, R2 = 0.45, P = 0.02), and FFA was indirectly associated with RQ (N = 22, R2 = 0.52, P < 0.001). Conclusions Cancer‐related weight loss was associated with elevated circulating IL‐6 and elevations in some WAT inflammatory, lipolytic and browning marker transcripts. BMI, not weight loss, was associated with increased energy expenditure. The contribution of inflammation and lipolysis, and lack thereof for WAT browning, will need to be clarified in other tumour types to increase generalizability. Future studies should consider variability in fat mass when exploring the relationship between cancer and adipose metabolism and should observe the trajectory of lipolysis and energy expenditure over time to establish the clinical significance of these associations and to inform more mechanistic interpretation of causation.

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Section: Discussionmentioning

confidence: 99%

Whole‐body and adipose tissue metabolic phenotype in cancer patients

Anderson

Lee

et al. 2022

J cachexia sarcopenia muscle

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“…99 Interestingly, it was shown that LLC tumors are able to release extracellular vesicles (EVs) containing PTHrP, and this event induces lipolysis in 3T3-L1 adipocytes in vitro. 100 In in vivo conditions, the same EVs-containing PTHrP were found to be important drivers of fat loss and WAT browning in LLC bearers. 100 Altogether, these observations support PTHrP as a new target to counteract muscle, WAT, and bone loss during cancer cachexia.…”

Section: Osteokines In Muscle-bone Crosstalkmentioning

confidence: 96%

“…100 In in vivo conditions, the same EVs-containing PTHrP were found to be important drivers of fat loss and WAT browning in LLC bearers. 100 Altogether, these observations support PTHrP as a new target to counteract muscle, WAT, and bone loss during cancer cachexia.…”

Section: Osteokines In Muscle-bone Crosstalkmentioning

confidence: 96%

Role of myokines and osteokines in cancer cachexia

Bonewald

Bonetto

2021

Exp Biol Med (Maywood)

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Cancer-induced muscle wasting, i.e. cachexia, is associated with different types of cancer such as pancreatic, colorectal, lung, liver, gastric and esophageal. Cachexia affects prognosis and survival in cancer, and it is estimated that it will be the ultimate cause of death for up to 30% of cancer patients. Musculoskeletal alterations are known hallmarks of cancer cachexia, with skeletal muscle atrophy and weakness as the most studied. Recent evidence has shed light on the presence of bone loss in cachectic patients, even in the absence of bone-metastatic disease. In particular, we and others have shown that muscle and bone communicate by exchanging paracrine and endocrine factors, known as myokines and osteokines. This review will focus on describing the role of the most studied myokines, such as myostatin, irisin, the muscle metabolite β-aminoisobutyric acid, BAIBA, and IL-6, and osteokines, including TGF-β, osteocalcin, sclerostin, RANKL, PTHrP, FGF23, and the lipid mediator, PGE2 during cancer-induced cachexia. The interplay of muscle and bone factors, together with tumor-derived soluble factors, characterizes a complex clinical scenario in which musculoskeletal alterations are amongst the most debilitating features. Understanding and targeting the “secretome” of cachectic patients will likely represent a promising strategy to preserve bone and muscle during cancer cachexia thereby enhancing recovery.

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“…84–86 Table 2 summarizes the mechanism of cachexia. 13,14,34,87–124 The broad picture of CC is summarized in Figure 1.…”

Section: Imbalance Of Anabolism and Catabolism: Insight Into The Mole...mentioning

confidence: 99%

“…151–154 Mechanistic studies conducted by Zhang et al 155 showed that EV-derived HSP70 and HSP90 activate Toll-like receptor 4 (TLR4) and p38–MAPK pathways resulting in CC, and that this is prevented by either neutralizing or silencing HSP70 and HSP90 in LLC cells. Recently, Hu et al 106 demonstrated that LLC cell-derived EVs induce lipolysis both in vitro and in vivo by delivering the parathyroid hormone–related protein (PTHrP) which interacts with its receptor parathyroid hormone receptor (PTHR) to exert downstream effects. Similar observations were made by Yang et al 156 in 2019 in pancreatic tumor xenograft models.…”

Section: Imbalance Of Anabolism and Catabolism: Insight Into The Mole...mentioning

confidence: 99%

Tumor cell anabolism and host tissue catabolism-energetic inefficiency during cancer cachexia

Hegde

Daimary

Girisa

et al. 2022

Exp Biol Med (Maywood)

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Cancer-associated cachexia (CC) is a pathological condition characterized by sarcopenia, adipose tissue depletion, and progressive weight loss. CC is driven by multiple factors such as anorexia, excessive catabolism, elevated energy expenditure by growing tumor mass, and inflammatory mediators released by cancer cells and surrounding tissues. In addition, endocrine system, systemic metabolism, and central nervous system (CNS) perturbations in combination with cachexia mediators elicit exponential elevation in catabolism and reduced anabolism in skeletal muscle, adipose tissue, and cardiac muscle. At the molecular level, mechanisms of CC include inflammation, reduced protein synthesis, and lipogenesis, elevated proteolysis and lipolysis along with aggravated toxicity and complications of chemotherapy. Furthermore, CC is remarkably associated with intolerance to anti-neoplastic therapy, poor prognosis, and increased mortality with no established standard therapy. In this context, we discuss the spatio-temporal changes occurring in the various stages of CC and highlight the imbalance of host metabolism. We provide how multiple factors such as proteasomal pathways, inflammatory mediators, lipid and protein catabolism, glucocorticoids, and in-depth mechanisms of interplay between inflammatory molecules and CNS can trigger and amplify the cachectic processes. Finally, we highlight current diagnostic approaches and promising therapeutic interventions for CC.

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Extracellular vesicles-released parathyroid hormone-related protein from Lewis lung carcinoma induces lipolysis and adipose tissue browning in cancer cachexia

Cited by 34 publications

References 44 publications

Whole‐body and adipose tissue metabolic phenotype in cancer patients

Whole‐body and adipose tissue metabolic phenotype in cancer patients

Role of myokines and osteokines in cancer cachexia

Tumor cell anabolism and host tissue catabolism-energetic inefficiency during cancer cachexia

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