Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia

Rupert, Joseph E.; Narasimhan, Ashok; Jengelley, Daenique H.; Jiang, Yanlin; Liu, Jianguo; Au, Ernie D.; Silverman, Libbie M; Sandusky, George E.; Bonetto, Andrea; Cao, Sha; Lu, Xiaoyu; O’Connell, Thomas M.; Liu, Yunlong; Koniaris, Leonidas G.; Zimmers, Teresa A.

doi:10.1084/jem.20190450

Cited by 106 publications

(102 citation statements)

References 89 publications

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“…Notably, the overexpression of IL-1α and IL-6 in these models also reduced overall survival and led to more aggressive tumour progression 22 , 23 . In a different approach, mice into which pancreatic tumour cells lacking IL-6 expression had been injected showed reduced loss of fat tissue and protection against muscle atrophy 25 . Further analysis of adipose tissue and muscles, both in vivo and in vitro, revealed a catabolic feedforward loop of IL-6 signalling between the tumour, the adipose tissue and the muscles 25 .…”

Section: Cytokines and Cachexiamentioning

confidence: 99%

The interplay of immunology and cachexia in infection and cancer

2021

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Diverse inflammatory diseases, infections and malignancies are associated with wasting syndromes. In many of these conditions, the standards for diagnosis and treatment are lacking due to our limited understanding of the causative molecular mechanisms. Here, we discuss the complex immunological context of cachexia, a systemic catabolic syndrome that depletes both fat and muscle mass with profound consequences for patient prognosis. We highlight the main cytokine and immune cell-driven pathways that have been linked to weight loss and tissue wasting in the context of cancer-associated and infection-associated cachexia. Moreover, we discuss the potential immunometabolic consequences of cachexia on the basis of newly identified pathways and explore the multilayered area of immunometabolic crosstalk both upstream and downstream of tissue catabolism. Collectively, this Review highlights the intricate relationship of the immune system with cachexia in the context of malignant and infectious diseases.

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Section: Cytokines and Cachexiamentioning

confidence: 99%

The interplay of immunology and cachexia in infection and cancer

2021

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“…Cancer-induced IL-6, leukemia inhibitory factor, etc. are also associated with adipose wasting [55][56][57].…”

Section: Mechanism For Cachexiamentioning

confidence: 99%

Cancer Cachexia: Its Mechanism and Clinical Significance

Nishikawa

Goto

Fukunishi

et al. 2021

IJMS

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The term “cachexia” is derived from the Greek words kakos (bad) and hexis (habit). Cachexia is a malnutrition associated with chronic diseases such as cancer, chronic heart failure, chronic renal failure, and autoimmune diseases, and is characterized by decreased skeletal muscle mass. Cancer cachexia is quite common in patients with advanced cancer. Weight loss is also a characteristic symptom of cancer cachexia, along with decreased skeletal muscle mass. As nutritional supplementation alone cannot improve cachexia, cytokines and tumor-derived substances have been attracting attention as its relevant factors. Cancer cachexia can be also associated with reduced chemotherapeutic effects, increased side effects and treatment interruptions, and even poorer survival. In 2011, a consensus definition of cachexia has been proposed, and the number of relevant research reports has increased significantly. However, the pathogenesis of cachexia is not fully understood, and there are currently few regulatory-approved standard treatments for cachexia. The main reason for this is that multiple etiologies are involved in the development of cachexia. In this review, we will outline the current status of cachexia, the mechanisms of which have been elucidated in recent years, especially from the perspective of advanced cancer.

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“…Multi-organ systemic inflammation occurs in both the tumor and the cachectic muscle, with signals/factors from one site affecting other sites, and with multiple deregulated signaling pathways involved [ 35 , 36 ]. Pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-8, interferon-γ (IFN-γ), monocyte chemoattractant protein-1 (MCP-1), and other catabolic factors (activin and myostatin) are released into circulation by the tumor [ 37 ].…”

Section: Pdac-associated Cachexiamentioning

confidence: 99%

Section: Pdac-associated Cachexiamentioning

confidence: 99%

“…TNF-α is a major mediator of muscle catabolism associated with poor nutritional status in PDAC patients [22,38]. IL-6, overexpressed in PDAC, correlates with cachexia, chemotherapy response, and survival [22,35,38]. Both TNF-α and IL-6 can activate the transcription factor nuclear factor kappa-light-chain-enhancer of B cells (NF-κB), known to inhibit differentiation of SKM [22,39].…”

Section: Pdac-associated Cachexiamentioning

confidence: 99%

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Ketogenic Diets in Pancreatic Cancer and Associated Cachexia: Cellular Mechanisms and Clinical Perspectives

Cortez

Mackenzie

2021

Nutrients

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and extremely therapy-resistant cancer. It is estimated that up to 80% of PDAC patients present with cachexia, a multifactorial disorder characterized by the involuntary and ongoing wasting of skeletal muscle that affects therapeutic response and survival. During the last decade, there has been an increased interest in exploring dietary interventions to complement the treatment of PDAC and associated cachexia. Ketogenic diets (KDs) have gained attention for their anti-tumor potential. Characterized by a very low carbohydrate, moderate protein, and high fat composition, this diet mimics the metabolic changes that occur in fasting. Numerous studies report that a KD reduces tumor growth and can act as an adjuvant therapy in various cancers, including pancreatic cancer. However, research on the effect and mechanisms of action of KDs on PDAC-associated cachexia is limited. In this narrative review, we summarize the evidence of the impact of KDs in PDAC treatment and cachexia mitigation. Furthermore, we discuss key cellular mechanisms that explain KDs’ potential anti-tumor and anti-cachexia effects, focusing primarily on reprogramming of cell metabolism, epigenome, and the gut microbiome. Finally, we provide a perspective on future research needed to advance KDs into clinical use.

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Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia

Cited by 106 publications

References 89 publications

The interplay of immunology and cachexia in infection and cancer

The interplay of immunology and cachexia in infection and cancer

Cancer Cachexia: Its Mechanism and Clinical Significance

Ketogenic Diets in Pancreatic Cancer and Associated Cachexia: Cellular Mechanisms and Clinical Perspectives

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