Molecular analysis of xenograft models of human cancer cachexia--possibilities for therapeutic intervention

Approximately 50% of all cancer patients develop cachexia, a paraneoplastic syndrome that is characterized by wasting of adipose tissue and skeletal muscle mass. Cytokines, including TNF-alpha, interleukins-1, -6, and interferon-A are known mediators of the cachectic process. The latter however represent only one of many imbalanced systems in cancer cachexia. The aim of this study was to further delineate the pathogenesis of cachexia by molecular profiling. Human renal cancer xenografts that do and do not induce cachexia in mice were used as disease models. Cachexia-associated gene expression was studied on Human Genome U95 Affymetrix arrays and revealed several new genes such as TNF-alpha ligand superfamily protein, interferon-A treatment inducible protein, and DKFZ5641I1922. The expression of the IL-8 gene was also elevated in cachexia inducing xenografts (CIX). At the protein level, TNF-alpha was found expressed only in CIX, whereas IL-1 and IL-6 were not cachexia specific. Levels of parathyroid hormone-related protein were elevated in CIX and accompanied by hypercalcemia. COX-2 and prostaglandin E2 were also found to be over expressed. By using the COX-2 inhibitors rofecoxib and nimesulide, we were able to delay tumor-mediated wasting in vivo. Overall, our results suggest that cachexia is a multigenetic disease that will require complex combinations of drugs for an effective therapeutic intervention.     

Paraneoplastic syndromes in lung cancer.

Paraneoplastic syndromes are caused by factors produced by cancer cells that often act at a site distant from both the primary site and its metastases. These syndromes are estimated to occur in only 7% to 15% of patients with cancer and are diagnoses of exclusion. If the definition of paraneoplastic syndrome is broadened to include indirect effects of the tumor such as cachexia or the anemia of chronic disease, the incidence is much higher. Lung cancer, particularly small cell lung cancer, is the most common malignancy causing paraneoplastic syndromes. This review focuses on recently published literature on paraneoplastic syndromes associated with lung cancer, including humoral hypercalcemia of malignancy, autoimmune paraneoplastic neurologic syndromes, neuromuscular disorders, and cancer cachexia. It includes advances in both molecular biology and immunology, and in clinical investigation.     

The syndrome of anorexia-cachexia.

Cancer anorexia/cachexia is a major clinical problem, especially in advanced cancer patients. Its pathogenesis is quite complex. Anorexia plays a central role, but cancer cachexia is more complex than pure chronic starvation. One of the key differences is the preferential mobilization of fat and the sparing of skeletal muscle in simple starvation compared with an equal mobilization of fat and skeletal muscle in cancer patients. An increase in basal energy expenditures seems to play a contributory role in many patients. Cytokines, essentially but not exclusively tumor necrosis factor alpha, play an essential role, and the syndrome can be compared with a low-grade chronic inflammatory state. As it is in most fields in medicine, prevention is more efficacious than treatment, and, to avoid the final and dramatic stages of cancer cachexia, adequate nutritional advice and support must be provided sufficiently early. Parenteral nutrition could facilitate the administration of complete doses of chemotherapy or radiotherapy, but no significant survival benefit or decrease in treatment-induced toxicity have ever been demonstrated in prospective randomized trials. The gut should always be used if at all possible. Percutaneous endoscopic gastrostomy is used increasingly in patients who cannot eat but who have functionally intact gastrointestinal tracts, especially in patients with head and neck cancer. Eight randomized, double-blind, placebo-controlled studies have demonstrated that progestational drugs can somewhat stimulate appetite, food intake, and energy level; increase weight in many patients; and often decrease nausea and vomiting severity; however, pharmacologic treatment of cancer cachexia remains disappointing, and more trials with anticytokine drugs should be conducted.     

肿瘤恶液质临床诊断与治疗指南(2020版)

恶液质(cachexia)是一个全球范围的严重疾病,发病率逐年递增,常伴发于多种慢性疾病.其中,肿瘤恶液质(cancer ca-chexia)发病率最高,是各种晚期恶性肿瘤的常见并发症,进展期恶性肿瘤约60％～80％可出现恶液质,约20％肿瘤患者死于恶液质.因此,肿瘤恶液质的准确临床诊断和制定有效干预措施对于晚期恶性肿...     

Cancer cachexia: pathophysiologic aspects and treatment options.

Cancer cachexia is a syndrome characterized with progressive weight loss and abnormal wasting of fat and muscle tissue, and affects 40 to 85% of all terminally ill patients, accounting more than 20% of all cancer deaths. Current treatment for cancer cachexia principally depends on its prevention rather than reversing the present disease state, and the clinical results are far from being satisfactory. Although the exact mechanism and predisposing factors have yet to be clarified in detail, our growing knowledge about the pathophysiology and biochemical changes considering this life threatening condition should help in development of future therapeutic strategies. In the present paper, the current preclinical and clinical features considering the pathophysiology and treatment of cancer related cachexia are reviewed.     

Cancer Cachexia: From Molecular Mechanisms to Patient's Care

Cancer cachexia is a disabling syndrome because of the complex interactions between the tumor, host metabolism, and proinflammatory cytokines that increases patients' morbidity and mortality. Considering the recent new definition and classification of cachexia, we aimed to review cancer cachexia from its underlying mechanisms to the clinical approach. Cancer cachexia is featured by a disruption in energy balance, metabolic changes, a decrease in fat mass, depletion of skeletal muscle mass, and perturbations in proinflammatory cytokines. Diagnostic effort should be focused on the recognition of precachexia to prevent or delay changes in body composition and nutritional complications secondary to cancer. From the point of disease diagnosis, every cancer patient needs continuous monitoring to receive effective, tailored nutritional and metabolic support. To date, practical guidelines to counteract cancer-related muscle wasting are lacking, mainly because of the multifactorial pathogenesis of the syndrome. A single therapy may not be effective; only a multimodal approach involving different treatment combinations is more likely to be successful in the prevention and treatment of cancer cachexia.     

Chronic Exendin-4 Treatment Prevents the Development of Cancer Cachexia Symptoms in Male Rats Bearing the Yoshida Sarcoma

Cancer cachexia is the syndrome of weight loss, loss of appetite, and wasting of skeletal muscle and adipose tissue experienced by many individuals with cancer. Currently, few effective treatment and prevention strategies are available for these patients, due in part to a poor understanding of the mechanisms contributing to cachexia. Insulin resistance has been associated with cancer cachexia in epidemiological, human, and animal research. The present experiment was designed to examine the ability of Exendin-4, a GLP-1 agonist and insulin sensitizing agent, to prevent the development of cachexia symptoms in male Sprague Dawley rats bearing the Yoshida sarcoma. Following tumor implantation or sham surgery, rats were treated daily with saline or Exendin-4 (3 μg/kg body weight/day) and were monitored for tumor growth and cachexia symptoms for 21–23 days. As a result of large variability in treatment effects, data were analyzed separately for animals with large and small tumors. Exendin-4 treatment reduced tumor growth and prevented the development of cancer cachexia symptoms in animals with small, but not large, tumors. In addition, insulin levels were preserved in Exendin-4-treated tumor-bearing animals. The results of this experiment demonstrate a novel preventative therapy for cancer cachexia and a novel use of Exendin-4. Further research is necessary to determine the mechanisms through which Exendin-4 exerts these potent effects.     

Management of paraneoplastic syndromes in lung cancer

Opinion statement Paraneoplastic syndromes are common complications of lung cancer. Although most frequently associated with advanced disease, paraneoplastic syndromes may also occur at early stages. Occasionally, the paraneoplastic syndrome may be the presenting symptom of lung cancer. For most paraneoplastic syndromes, the best treatment is to treat the underlying malignancy. However, in many cases, treatment of moderate efficacy or urgent therapy is required. Specific recommendations for the management of the most common paraneoplastic syndromes, including cachexia, hypercalcemia, and hyponatremia, are provided.     

Update on Management of Cancer-Related Cachexia

Cachexia is a metabolic syndrome driven by inflammation and characterized by loss of muscle with or without loss of fat mass. In cancer cachexia, the tumor burden and host response induce increased inflammation, decreased anabolic tone, and suppressed appetite leading to the clinical presentation of reduced body weight and quality of life (QOL). There is no approved treatment for cancer cachexia, and commonly used nutritional and anti-inflammatory strategies alone have proven ineffective for management of symptoms. Several other pharmacological agents are currently in development and have shown promise as a clinical strategy in early-phase trials. Recently, it has been proposed that multimodal strategies, with an anabolic focus, initiated early in the disease/treatment progression may provide the most therapeutic potential for symptom management. Here we review the data from recent clinical trials in cancer cachexia including pharmacological, exercise, and nutritional interventions.     

Mechanisms of cancer cachexia

It is currently hypothesized that the mechanisms of cancer cachexia involve the host's production of inflammatory cytokines, which in turn orchestrate a series of complex interrelated steps that ultimately lead to a chronic state of wasting, malnourishment, and death (see Fig. 1). The metabolic changes seen in the tumor-bearing host are similar, but not identical, to those seen in sepsis and inflammation and appear to result from a generalized response of the host to the stimulus of invasion--the tumor. Although there are likely to be several humoral factors, of either host or tumor origin (see Fig. 1), involved in cancer cachexia, recombinant DNA methodology has provided sufficient amounts of only a few cytokines to enable careful investigation of their cachectic potential. TNF/cachectin has been most extensively studied and appears to play a clear role, because administration of low-dose continuous or escalating doses simulates changes associated with cancer cachexia. In addition, these cachectic changes have been blocked by a specific antisera. IL-1, IL-6, and interferon-gamma all have potential as mediators of cancer cachexia and more work is clearly indicated. It is possible that, given our current understanding of the mechanisms of cancer cachexia, it can be theorized that TNF, which causes many of the manifestations of cancer cachexia, and IL-1 are released by macrophages in response to tumor (see Fig. 1). Interferon-gamma appears to potentiate these effects and may also be necessary for the complete syndrome of cancer cachexia. IL-6 probably is released as another mediator, principally mediating the acute phase response seen in cancer cachexia. Other factors are certain to be involved. Further study into the mechanisms and possible treatment of cancer cachexia is needed, because a large proportion of cancer patients who are incurable by current therapies continue to suffer from this lethal wasting diathesis. Furthermore, specific strategies to reverse the cachectic changes associated with cancer will likely improve antitumor treatment.     

Update on anorexia and cachexia

Declining physical, emotional, and social function as a result of anorexia and cachexia are considerable contributors to discomfort for cancer patients and their families, and they impair the patient's ability to express optimal physical and psychosocial potential as long as possible. This decline no longer has to be accepted as an indispensable sequel to advanced cancer, just as pain is no longer considered to be unavoidable. A routine screening for anorexia and cachexia and associated symptoms is necessary, as is a careful, comprehensive assessment, because the condition is not always obvious. Decisions about anorexia and cachexia treatment are guided by prioritizing the different, concurrent physical, psychosocial, and existential problems and by considering the natural course of the cancer and the effects of antineoplastic therapies. Reversible causes for anorexia and cachexia need to be identified and treated, if appropriate. Nutritional interventions are often indicated; patients with a predominant starvation component and without inflammation may profit the most. New pharmacologic therapies for primary anorexia and cachexia syndrome are expected to enter clinical practice soon; however, until then, treatment with corticosteroids, progestins, or prokinetics may be indicated for some patients. To understand a multicausal syndrome, multimodal and interdisciplinary therapy is required. Specialist palliative care services can be helpful to provide, hand-in-hand with the disease specialists [172], assessment and management of psychophysical symptoms and sociospiritual needs of patients during the course of the illness and at the end of life [173]. Research efforts aim to better characterize subgroups of patients suffering from secondary causes of anorexia and cachexia and to elucidate the mechanisms involved in the primary anorexia and cachexia syndrome. Increasingly individualized treatments are expected with combination treatments that involve different mechanisms including nutrition.     

Pancreatic cancer cachexia: three dimensions of a complex syndrome

Cancer cachexia is a multifactorial syndrome that is characterised by a loss of skeletal muscle mass, is commonly associated with adipose tissue wasting and malaise, and responds poorly to therapeutic interventions. Although cachexia can affect patients who are severely ill with various malignant or non-malignant conditions, it is particularly common among patients with pancreatic cancer. Pancreatic cancer often leads to the development of cachexia through a combination of distinct factors, which, together, explain its high prevalence and clinical importance in this disease: systemic factors, including metabolic changes and pathogenic signals related to the tumour biology of pancreatic adenocarcinoma; factors resulting from the disruption of the digestive and endocrine functions of the pancreas; and factors related to the close anatomical and functional connection of the pancreas with the gut. In this review, we conceptualise the various insights into the mechanisms underlying pancreatic cancer cachexia according to these three dimensions to expose its particular complexity and the challenges that face clinicians in trying to devise therapeutic interventions.Subject terms: Cancer metabolism, Gastrointestinal cancer     

癌性恶病质的药物治疗进展

癌性恶病质是复杂的临床综合征,伴随体重下降、慢性炎症、新陈代谢紊乱、厌食、肌肉消耗、生活质量下降等。癌性恶病质治疗棘手,缺乏有效的治疗手段,目前许多新药的临床前及临床实验正在进行中。本文针对癌性恶病质药物治疗的现状及研究进展作一综述。     

Grundlagen der Kachexie bei Tumorpatienten

Background

The cancer cachexia syndrome is the most common paraneoplastic syndrome affecting approximately half of the patients with a malignant tumor.

Objective

Presentation of the pathophysiological processes in cancer cachexia and the clinical consequences.

Material and methods

Selective literature search in PubMed with inclusion of the current guidelines.

Results

Characteristic of cancer cachexia is a systemic inflammation syndrome. Tumor-specific and proinflammatory mediators lead to loss of appetite, systemic inflammation, metabolic and hormonal changes. Systemic inflammation has effects on protein, carbohydrate and lipid metabolism of the liver and peripheral organs. Frequently, insulin resistance and impaired glucose tolerance are also present. The consequences are a diminished food intake, lower nutrient utilization and loss of muscle tissue, with or without loss of fat mass. In addition, cancer therapy even with newer targeted anticancer agents, may speed up muscle breakdown and promote the development of cancer cachexia.

Conclusion

Cancer cachexia leads to a progressive reduction of performance, to fatigue and a loss of independence. In the multimodal therapy of cancer cachexia syndrome in cancer patients nutritional therapeutic measures represent an important component in order to improve the clinical course of patients.

     

癌症恶病质的诊断及药物治疗进展

癌症恶病质是恶性肿瘤的常见并发症,是由多因素引起的一系列虚弱症状为临床表现的综合征。全文就癌症恶病质的定义、诊断规范化及药物治疗研究进展进行综述。     

Adiponectin, ghrelin, and leptin in cancer cachexia in breast and colon cancer patients

BACKGROUND: The hormone ghrelin and the adipocytokines leptin and adiponectin participate in body weight regulation. In response to weight loss, ghrelin and adiponectin levels increase and leptin decreases. Cancer cachexia is a complex metabolic state, characterized by loss of muscle mass and adipose tissue together with anorexia. The authors hypothesized that responses of these hormones may be attenuated in cancer cachexia. METHODS: Fasting plasma ghrelin, adiponectin, and leptin levels, as well as weight loss, were determined in 40 cancer patients: 18 of them suffered from cancer-induced cachexia, and 22 served as a comparison group. Hormone levels were measured before administration of cancer therapy. RESULTS: A similar distribution of age, gender, and diagnosis was observed in both study groups, but the cachectic patients had higher rates of metastatic disease and lower albumin levels. No significant correlation was observed between plasma adiponectin levels and weight loss. Mean plasma ghrelin levels were higher among cachectic compared with noncachectic patients. Notably, the association between ghrelin levels and weight loss was only modest, and in a third of the cachectic patients, ghrelin levels were equal to or lower than those in the noncachectic group. Plasma leptin levels showed gender-dependent associations, and significantly lower levels were found among cachectic women but not among cachectic men. CONCLUSIONS: Results suggested a gender-dependent attenuation of expected physiologic responses to weight loss among cancer cachexia patients. Thus, impaired response of adiponectin, ghrelin, and leptin may play a role in the pathogenesis of cancer cachexia syndrome.     

癌性恶病质内科治疗进展

癌症恶病质是晚期肿瘤患者常见综合征,是肿瘤组织与机体相互作用的结果,肿瘤组织产生炎性细胞因子及特定因子作用于机体,而机体应激产生全身急性反应及神经内分泌反应,如此相互作用导致恶病质.同时,患者的年龄、体力活动水平和肌肉蛋白的异常代谢也被认为与癌性恶病质发生相关.目前,临床治疗癌性恶病质的策略主要针对改善患者的厌食症状,随着对发病机制深入了解,一些具有明确靶点的药物研究成为热点.     

Myosin heavy chain is not selectively decreased in murine cancer cachexia

Cachexia is a severe muscle-wasting syndrome associated with several chronic diseases such as cancer and AIDS. Muscle mass loss significantly decreases prognosis and survival. The mechanisms of muscle atrophy and the specific proteins targeted for degradation have been intensely studied and are potential therapeutic targets. Published reports that myosin heavy chain (MyHC), the most abundant protein by mass in skeletal muscle, is selectively targeted for degradation in cancer cachexia remain controversial. Here we show that the results of previous studies showing a selective decrease in MyHC are likely an artifact resulting from muscle lysis methods which do not solubilize myosin out of myofibrils. We show that MyHC decreases in parallel with other myofibrillar proteins in cachectic skeletal muscle, which has mechanistic and therapeutic implications. These findings should lead to mechanistic insight into the stoichiometry of sarcomeric disassembly and degradation during cancer cachexia.     

Carnitine administration reduces cytokine levels, improves food intake, and ameliorates body composition in tumor-bearing rats

Increased cytokine expression contributes to the pathogenesis of cancer anorexia?cachexia syndrome. Carnitine may reduce inflammation in chronic diseases. We tested the effects of L-propionylcarnitine (PC group) or saline (C group) on food intake (FI), body composition, and inflammatory status of MCA-sarcoma-bearing rats. On tumor appearance, rats were randomly assigned to daily i.p. injection of L-propionylcarnitine (250 mg/kgBW/d; n = 8) or saline (equal volume; n = 8). FI and fat-free mass wasting improved in PC rats only (p < .01 vs. controls). Cytokines? levels decreased in PC rats vs. controls (p < .02). Results suggest that carnitine may ameliorate cancer anorexia?cachexia, via reduction of the inflammatory status.