Pancreatic cancerrelated cachexia: influence on metabolism and correlation to weight loss and pulmonary function

Bachmann, Jeannine; Ketterer, Knut; Marsch, Christiane; Fechtner, Kerstin; Krakowski-Roosen, Holger; Büchler, Markus W.; Friess, Helmut; Martignoni, Marc E.

doi:10.1186/1471-2407-9-255

Cited by 120 publications

(128 citation statements)

References 29 publications

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“…PDAC is also among the deadliest forms of cancer, with a 93% mortality rate in 5 years following diagnosis 33, 34, 35, 36. Current approaches to treating PDAC include cytotoxic chemotherapy, ionizing radiation, and surgical resection 37, 38.…”

Section: Discussionmentioning

confidence: 99%

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

Michaelis

Zhu

Burfeind

et al. 2017

J cachexia sarcopenia muscle

110

161

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BackgroundCachexia is a complex metabolic and behavioural syndrome lacking effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is one of the most important conditions associated with cachexia, with >80% of PDAC patients suffering from the condition. To establish the cardinal features of a murine model of PDAC‐associated cachexia, we characterized the effects of implanting a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D P53R172H Pdx‐Cre+/+ (KPC) mouse.MethodsMale and female C57BL/6 mice were inoculated subcutaneously, intraperitoneally, or orthotopically with KPC tumour cells. We performed rigorous phenotypic, metabolic, and behavioural analysis of animals over the course of tumour development.ResultsAll routes of administration produced rapidly growing tumours histologically consistent with moderate to poorly differentiated PDAC. The phenotype of this model was dependent on route of administration, with orthotopic and intraperitoneal implantation inducing more severe cachexia than subcutaneous implantation. KPC tumour growth decreased food intake, decreased adiposity and lean body mass, and decreased locomotor activity. Muscle catabolism was observed in both skeletal and cardiac muscles, but the dominant catabolic pathway differed between these tissues. The wasting syndrome in this model was accompanied by hypothalamic inflammation, progressively decreasing brown and white adipose tissue uncoupling protein 1 (Ucp1) expression, and increased peripheral inflammation. Haematological and endocrine abnormalities included neutrophil‐dominant leukocytosis and anaemia, and decreased serum testosterone.ConclusionsSyngeneic KPC allografts are a robust model for studying cachexia, which recapitulate key features of the PDAC disease process and induce a wide array of cachexia manifestations. This model is therefore ideally suited for future studies exploring the physiological systems involved in cachexia and for preclinical studies of novel therapies.

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Section: Discussionmentioning

confidence: 99%

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

Michaelis

Zhu

Burfeind

et al. 2017

J cachexia sarcopenia muscle

110

161

View full text Add to dashboard Cite

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“…PC patients with cachexia had more progressed tumor stages and a worse nutritional status. Moreover, patients with cachexia had an impaired lung function and a reduction in fat tissue (Bachmann et al 2009). Patients with PC and cachexia had lived significantly shorter.…”

Section: Cachexia/wasting Syndrome With Central Role In Pancreas Cancmentioning

confidence: 97%

“…The multiple effects of cachexia in PC patients were analyzed, in terms of resection rate, effects on pulmonary function, amount of fat and muscle tissue, as well as changes in laboratory parameters (Bachmann et al 2009). Of 198 patients with PC, 70 % were suffering from weight loss at time of operation, and in 40 % weight loss exceeded 10 % of the stable weight (Bachmann et al 2009). In patients with cachexia, metastases were significantly more frequent (47 vs. 24 %, p \ 0.001), leading to a significantly reduced resection rate.…”

Section: Cachexia/wasting Syndrome With Central Role In Pancreas Cancmentioning

confidence: 99%

A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme

Elmacı

Altinöz²

2016

Biochem Genet

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Pancreatic cancer (PC) and glioblastoma multiforme (GBM) are among the human cancers with worst prognosis which require an urgent need for efficient therapies. Here, we propose to apply to treat both malignancies with a triple combination of drugs, which are already in use for different indications. Recent studies demonstrated a considerable link between risk of PC and diabetes. In experimental models, anti-diabetogenic agents suppress growth of PC, including metformin (M), pioglitazone (P) and lithium (L). L is used in psychiatric practice, yet also bears anti-diabetic potential and selectively inhibits glycogen synthase kinase-3 beta (GSK-3β). M, a biguanide class anti-diabetic agent shows anticancer activity via activating AMP-activated protein kinase (AMPK). Glitazones bind to PPAR-γ and inhibit NF-κB, triggering cell proliferation, apoptosis resistance and synthesis of inflammatory cytokines in cancer cells. Inhibition of inflammatory cytokines could simultaneously decrease tumor growth and alleviate cancer cachexia, having a major role in PC mortality. Furthermore, mutual synergistic interactions exist between PPAR-γ and GSK-3β, between AMPK and GSK-3β and between AMPK and PPAR-γ. In GBM, M blocks angiogenesis and migration in experimental models. Very noteworthy, among GBM patients with type 2 diabetes, usage of M significantly correlates with better survival while reverse is true for sulfonylureas. In experimental models, P synergies with ligands of RAR, RXR and statins in reducing growth of GBM. Further, usage of P was found to be lesser in anaplastic astrocytoma and GBM patients, indicating a protective effect of P against high-grade gliomas. L is accumulated in GBM cells faster and higher than in neuroblastoma cells, and its levels further increase with chronic exposure. Recent studies revealed anti-invasive potential of L in GBM cell lines. Here, we propose that a triple-agent regime including drugs already in clinical usage may provide a metabolic adjuvant therapy for PC and GBM.

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“…Among these patients, 30% eventually die from cachexia-related complications [2,151]. As a multifactorial condition, pancreatic cancer cachexia is complex disease that is associated with anorexia and excessive catabolism mediated by mechanical factors, pro-inlammatory cytokines, neuropeptides, hormones, and tumor-derived factors.…”

Section: Resultsmentioning

confidence: 99%

Pancreatic Cancer Cachexia: Current Concepts and Clinical Management

Guan¹,

Shinde²,

Hendifar³

2017

Frailty and Sarcopenia - Onset, Development and Clinical Challenges

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There has been great progress over the last decade in understanding the pathophysiology of cachexia associated with pancreatic cancer. However, there is a large need to ind better therapeutic options to successfully manage this complex and challenging condition. Patients with pancreatic cancer have some of the highest prevalence and often the most severe degrees of cachexia, which is described as a multifactorial metabolic syndrome that is associated with unintended weight loss of adipose tissue and skeletal muscle in the seting of anorexia. This chapter will review the current concepts surrounding pancreatic cancer cachexia, its clinical diagnosis, pathophysiology, and its known and proposed therapeutics. A multimodal approach utilizing nutritional support and pharmaceutical therapies is proposed to lead to the most successful management of pancreatic cancer cachexia.Keywords: pancreatic cancer, cachexia, anorexia, metabolic syndrome, catabolism IntroductionIn western countries, pancreatic cancer represents the fourth leading cause of cancer-related death [1]. Among the many complications associated with this disease, cachexia marked by progressive weight loss represents one of the most distressing features related to pancreatic cancer. Cachexia is a multidimensional wasting syndrome that is characterized by unintended loss of both adipose tissue and lean body mass (LBM) that cannot be fully reversed through conventional nutritional support. It is a complex metabolic disorder frequently described in pancreatic cancer and represents a signiicant physical and psychological burden in approximately 80% of pancreatic cancer patients during the disease progression [2]. The complications © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. associated with cachexia, which include immobility, impaired immunity, and severe respiratory muscle impairment leading to cardiopulmonary failure, result in death in up to one-third of pancreatic cancer patients [3]. Cachectic patients are observed to have lower physical function, decreased tolerance to chemotherapy and radiation treatment, and generally worse prognosis than those with stable weight. Poorer outcomes after pancreaticoduodenectomy have also been observed in patients with preoperative signs of cachexia [4].While research over the past decade has provided new insights regarding the pathogenesis of pancreatic cancer cachexia, the mechanistic pathology of this condition is still not entirely understood. In this chapter, we will provide a review of the current concepts, potential therapeutic targets, and management of this signiicant clinical condition. Classiication and progression of cancer cachexiaCachexia has been established to be a common adverse efect of cancer. An international consensus in 2011 deined cachexia as a ...

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Pancreatic cancerrelated cachexia: influence on metabolism and correlation to weight loss and pulmonary function

Cited by 120 publications

References 29 publications

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme

Pancreatic Cancer Cachexia: Current Concepts and Clinical Management

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