From Molecular Insights to Clinical Strategies: Delve into the complexities of cachexia, encompassing cancer cachexia, molecular mechanisms, and evolving therapeutic approaches. Discover the forefront of research aimed at understanding and combating this debilitating condition.
Exosomes are extracellular vesicles that contain cargo such as proteins, lipids, nucleic acids and more. Their function is to alter cell signalling in the cell it releases its cargo into. For example, exosomes have been seen to alter muscle and adipose tissue metabolism. This has led to the thought that they may be involved in cancer cachexia. Inhibiting tumour derived exosome release therefore may improve survival and cancer cachexia in patients. Specifically, tumour derived exosome micro-RNAs have been associated with muscle wasting and tumour presence. Furthermore, they may package inflammatory cytokines. This could play a causal role in cancer cachexia as increase cytokine circulation is thought to precede the loss of appetite in cachexia, holding a causal role in the disease progression.
This review by Pitzer CR et al. aimed to summarise the potential involvement of tumour derived exosomes in cancer cachexia.
Currently, there are many interventions and treatments for cancer cachexia. Early nutritional intervention and care are essential to ensure that sufficient nutritional requirements are met for the patients. This includes oral nutrition where possible, as well as nutrition and exercise therapy. Furthermore, preventive care to minimise loss of skeletal muscle mass is vital. Pharmacological options are also available. These include many options, such as non-steroidal anti-inflammatory drugs, anti-cytokine therapy and eicosapentaenoic acid. Furthermore, steroids are often used for cachexia. However, they have limited effects are limited, so recently, anamorelin hydrochloride, a ligand with a similar action to that of ghrelin, was developed. It is used to treat weight loss by increasing appetite and has been approved for use in cachexia. Anamorelin hydrochloride holds great promise to function as an effective therapeutic drug for cancer cachexia.
This review by Watanabe H & Oshima T aimed to review the current treatments of cancer cachexia, as well as anamorelin hydrochloride, a new and promising treatment.
In this study, TOV21G cancer cachexia mouse models were used to demonstrate impaired muscle function and performance which is seen in cachexia patients. With growth differentiation factor 15, GDF15, neutralization, the mice were seen to exhibit restored muscle function and performance. GDF15 is a stress-responsive cytokine which is secreted by many cells, including tumour cells and damaged cells. GDF15 functions by activating glial cell line-derived neurotrophic factor, GDNF, receptor GFRAL. This is expressed in the hindbrain and leads to reducing food intake and weight loss. This is relevant to cachexia patients, and patients with chronic diseases such as heart failure, as their GDF15 levels are significantly higher than that of healthy people. In this study, the mice were treated with mAB2, an anti-GDF15 antibody. They demonstrated weight gain in terms of fat mass and lean mass, improved muscle function and physical performance. Hence, it is thought that GDF15-related therapy may be effective for patients with cachexia. However, symptoms of cachexia such as fatigue do not appear to be related to GDF15 levels, so further exploration is necessary.
This review by Kim-Muller JY et al. aimed to explore how GDF15 levels are related to weight loss and highlight how GDF15 neutralization could be an option for treating cachexia.
Cachexia is defined as an unintentional loss of 5% or more of body weight, a complication which often negatively affects survival rates. Cachexia is caused by circulating cytokines in the body which are produced by cancer cells and immune cells, causing behavioural and systemic changes. However, how cachexia impacts different tissues is unknown; there is a large amount of information missing, as it is likely there are more tissues in the body affected by cachexia than we know. There are known differences in tissue wasting: in the heart, atrophy is seen after 2 weeks of tumour implantation, but very little wasting in any other tissues at this point. The heart and skeletal muscles are the tissues affected first and foremost. This study also discovered that tissues such as the brain which do not undergo wasting, experience functional derangement due to transcriptional changes such as the upregulation of angiotensin-converting enzyme (ACE). Using lisinopril, a drug which inhibits ACE, muscle force can be improved, even if wasting is not prevented. However, this study was completed on mice with no T lymphocytes - this is a limitation as T cells have been seen to induce or protect from cachexia, so more studies are needed to understand the involvement of T cells in cachexia.
This review by Graca FA et al. aimed to summarise how cachexia affects different tissue systems in the body.
The Journal of Cachexia, Sarcopenia and Muscle mainly publishes research on cachexia, sarcopenia and muscle wasting disorders, but also includes papers on cancer, heart failure, ageing and many other conditions. Before November 2022, there were seen to be 775,000 downloads of the articles within the journal, with the top three countries downloading articles being China, the US and Japan. The most downloaded and cited article is entitled, Cachexia as a major underestimated and unmet medical need: facts and numbers.
This review by Frohlich A et al. aimed to review the successes of the Journal of Cachexia, Sarcopenia and Muscle in 2022.
Around half of a healthy personโs body weight is made up of skeletal muscle. This type of muscle is able to demonstrate high levels of plasticity. In muscle homeostasis, as well as repair processes, there are satellite cells and inflammatory cells which play key roles. However, if the recruitment of inflammatory cells is not carefully controlled, muscle atrophy and fibrosis may occur, leading to muscle function impairment. Hence, the inflammation occurring in muscle repair as a double-edged sword. This is because inflammatory mediators play a role in fighting pathogens as well as in the formation of mature myofibres, but may also cause damage to the muscle. For example, inflammation is also associated with cachexia - specifically, there is a correlation between cachexia and high levels of circulating cytokines.
This paper also ends with a summary of approaches to treating muscle wasting disorders, such as cachexia, discussing exercise, nutritional interventions and targeting inflammatory pathways.
This review by Bouredji Z et al. aimed to discuss inflammation in muscle homeostasis and repair, as well as some management approaches to muscle wasting disorders such as cachexia.
Pancreatic ductal adenocarcinoma, PDAC, is one of the most fatal types of solid tumours. It is also linked to a high prevalence of cachexia, with around 80% of PDAC patients exhibiting cachexia. There is one hypothesis, the endocrine organโlike tumour hypothesis, which aims to explain the reasons behind cancer cachexia occurring during pancreatic ductal adenocarcinoma. Some of the reasons include metabolites, epigenetic changes, hormonal disturbance and genetic instability may be behind the development of cancer cachexia. Generally, the belief is held that metabolic disruption is the process behind cachexia development, but it is also believed there is not one single factor that triggers it.
This review by Yu Y et al aimed to synthesise an understanding of cancer cachexia development and the response of cachexia to current available treatments.
For patients with head and neck cancer, malnutrition and frailty are linked with adverse treatment outcomes, higher mortality rates, complications post-surgery and generally lower quality of life. However, the relationship between malnutrition and frailty is not fully known. It is, however, clear that these two conditions often coexist, suggesting they may share similar risk factors. In this study on 197 patients, it was found that the risk of malnutrition is strongly positively associated with frailty. However, some other interesting factors were discovered. Alcohol consumption was shown to present a greater risk of developing malnutrition, but on the other hand, alcohol consumption seems protective for being frail. Overall, these conditions often coexist but do not always fully overlap: screening for both conditions is therefore recommended.
This review by Dewansingh P et al aimed to understand the relationship between the risk of malnutrition and frailty in patients with head and neck cancer.
Cancer cachexia has no simple criteria to distinguish its severity in patients. Diagnostic criteria generally includes observing factors such as weight loss, fatigue, abnormal levels of albumin, reduced food intake and others. However, this study explored the cachexia staging score, a method of diagnosing cancer cachexia severity. This score explores strength, walking, rising from a chair, climbing up stairs and how often the patients fall. This allows clinicians to understand the patientโs muscle function. In this study, the cachexia staging score was testing in patients with advanced cancer who are receiving palliative care, to assess its usefulness in these patients. Here, the cachexia staging score was excellent at predicting life expectancy in the patients with advancing cancer receiving palliative care, and was able to classify patients according to their different stages of cachexia. This review by Ueshima J et al. aimed to assess whether the cachexia staging score could be applied to patients with advanced cancer under palliative care.
Cancer cachexia can be mainly categorised with the occurrence of muscle loss, malnutrition and systemic inflammation. Its prognosis can be assessed through the cachexia index, but the use of this index is limited due to it being a complicated procedure with high testing costs. This study explored using a hand grip strength-based cachexia index, testing it with 14, 682 cancer patients. A low hand grip strength index score was found to be associated with high systemic inflammation, high levels of malnutrition and co-morbidities, implying that this index may be associated with disease progression. Overall, using the hand grip strength index for cachexia reflects the muscular and inflammatory conditions of cachexia in one assessment, rather than using multiple such as serum albumin testing, in a simple, non-invasive measure. Furthermore, there is a potential that hand grip strength can provide information about the prognosis of other malignancies.
This review by Xie H et al. aimed to compare the hand grip strength-based cachexia index to the original cachexia index to understand its benefits.
Colorectal cancer (CRC) incidence has been shown to increase with age, an association which is clinically significant in the context of global ageing populations. Frailty, defined as increased vulnerability to stressors like surgery, is a marker associated with poor outcomes in patients with CRC. Sarcopenia, characterised by an age- and disease-related loss in muscle function and mass, has been identified as a major contributor to frailty. Patients with cancer also commonly experience cancer cachexia, i.e., loss of fat and muscle mass. This syndrome has also been associated with poorer survival rates for cancer patients. As such, both sarcopenia and cachexia constitute potentially modifiable risk factors of negative surgical outcomes.
This study aimed to examine the prevalence of preoperative sarcopenia and cachexia in a group of older (โฅ65 years) vulnerable patients undergoing resection for localized CRC.
Amino acid metabolism is hugely altered in tumours. Cancer cells use amino acids for energy production, which supports cell proliferation. In this sense, their amino acid dependency provides a metabolic vulnerability for treatment. Research has been aimed at starving cancerous cells of amino acids to improve cancer treatment outcomes. However, supplementing amino acids has also shown benefits both in vivo and in vitro. Further research into amino acid supplementation is needed, as deprivation exacerbates cancer cachexia, a risk best avoided in cancer treatment. Supplementing branched-chain amino acids has been proved as beneficial in hepatocellular carcinoma, and an essential amino acid rich diet has demonstrated decreased tumour growth in mice. Understanding more about amino acid metabolism in cancer may provide more efficient, personalised treatments for cancer patients.
This review by Ragni M et al. aimed to discuss amino acid deprivation and supplementation in reducing tumour growth, underscoring the complexity of the metabolic pathways involved.
Colorectal cancer is the second leading cause of cancer death in the world. However, incidence rates and mortality can both be significantly reduced through adhering to healthy lifestyle recommendations. In this study, 82 people were included, where their nutritional profile was evaluated to assess their risk of colorectal cancer. This is because obesity is one of the biggest risk factors for colorectal cancer, and when associated with sarcopenia, there are usually worse health outcomes. This study has therefore highlighted the need for understanding muscle composition in obese individuals when screening for cancer, as this may affect outcomes. Furthermore, this study underscores the necessity to aim for health lifestyles through weight control and physical exercise, to decrease incidence and mortality of diseases such as colorectal cancer.
This review by Santos M et al. aimed to evaluate nutritional profiles for those screening for colorectal cancer, to aid a better understanding of the risk factors behind this cancer.
In this study, 102 Japanese patients with gastrointestinal or non-small cell lung cancer with cancer cachexia were used to test anamorelin. Anamorelin is a selective ghrelin receptor agonist and is taken orally. This drug is generally known to increase appetite and was hypothesised to help with improving cancer cachexia as well as increasing the patientsโ low body mass index. It was found that improvements in their body weight were durable for up to 24 weeks, and overall, the patients reported a better appetite and overall well-being. The drug was also generally well tolerated, with around 37% of patients experiencing adverse side effects. Most commonly, these included symptoms such as glycosylated haemoglobin increase, peripheral oedema and constipation.
This review by Naito T et al. aimed to understand the benefits of anamorelin in cancer cachexia patients with improving their low body mass index.
Weight loss is clearly related to cancer, yet there is very little data concerning when and at what stage weight loss should be considered a sign of a need to diagnose cancer. In this study of 43,302 patients, it was found that there was a linear increase in the chance of being diagnosed with cancer compared to the amount of weight lost. This finding was independent of any co-factors, such as age, sex, original weight or co-morbidities. Therefore, it is clear that the percentage of weight lost must be focused on, rather than a guideline with an arbitrary cut-off point for a cancer diagnosis. It could be possible to trigger an alert for patients who lose certain percentages of weight over specified periods of time.
This review by Nicholson B et al aimed to understand the diagnostic value of weight loss in relationship to cancer.
Cancer is often associated with cachexia, a wasting syndrome which is multifactorial and cannot be resolved with simple nutritional aid. It causes loss of muscle mass and is the cause of death for almost a third of cancer patients. However, cachexia is very complex. This muscle-wasting disorder has many underlying mechanisms, whether cancer-induced or chemotherapy induced. Heighted protein catabolism and reduced anabolism, as well as disrupted energy metabolism, are associated with cachexia, but the mechanisms underlying these changes are not fully known. Inflammation and oxidative stress are believed to be important within the mechanisms.
This review by Huot J et al. aimed to evaluate the mechanisms underlying cancer cachexia, particularly discussing the role of oxidative stress.
Cachexia has been defined as a loss of lean tissue mass, involving a weight loss greater than 5% of body weight in 12โmonths or less in the presence of chronic illness or as a body mass index (BMI) lower than 20โkg/m2. In addition, usually three of the following five criteria are required: decreased muscle strength, fatigue, anorexia, low fat-free mass index, increase of inflammation markers such as C-reactive protein or interleukin (IL)-6 as well as anaemia or low serum albumin.
Cachexia can occur in most major diseases including infections, cancer, heart disease, chronic kidney disease, chronic obstructive pulmonary disease, and stroke.
REFERENCES
Evans WJ, Morley JE, Argiles J, Bales C, Baracos V, Guttridge D, et al. Cachexia: a new definition. Clin Nutr 2008;27:793โ799
Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, MacDonald N, Mantovani G, Davis M, Muscaritoli M, Ottery F, Radbruch L, Ravasco P, Walsh D, Wilcock A, Kaasa S, Baracos VE. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 2011;12:489โ495.
Subscribe to the SCWD Newsletter
Stay Informed with the Latest Updates and Exclusive Insights!
Manage Cookie Consent
To provide the best experiences, we use technologies like cookies to store and/or access device information. Consenting to these technologies will allow us to process data such as browsing behavior or unique IDs on this site. Not consenting or withdrawing consent, may adversely affect certain features and functions.
Functional
Always active
The technical storage or access is strictly necessary for the legitimate purpose of enabling the use of a specific service explicitly requested by the subscriber or user, or for the sole purpose of carrying out the transmission of a communication over an electronic communications network.
Preferences
The technical storage or access is necessary for the legitimate purpose of storing preferences that are not requested by the subscriber or user.
Statistics
The technical storage or access that is used exclusively for statistical purposes.The technical storage or access that is used exclusively for anonymous statistical purposes. Without a subpoena, voluntary compliance on the part of your Internet Service Provider, or additional records from a third party, information stored or retrieved for this purpose alone cannot usually be used to identify you.
Marketing
The technical storage or access is required to create user profiles to send advertising, or to track the user on a website or across several websites for similar marketing purposes.
To provide the best experiences, we use technologies like cookies to store and/or access device information. Consenting to these technologies will allow us to process data such as browsing behavior or unique IDs on this site. Not consenting or withdrawing consent, may adversely affect certain features and functions.
Functional
Always active
The technical storage or access is strictly necessary for the legitimate purpose of enabling the use of a specific service explicitly requested by the subscriber or user, or for the sole purpose of carrying out the transmission of a communication over an electronic communications network.
Preferences
The technical storage or access is necessary for the legitimate purpose of storing preferences that are not requested by the subscriber or user.
Statistics
The technical storage or access that is used exclusively for statistical purposes.The technical storage or access that is used exclusively for anonymous statistical purposes. Without a subpoena, voluntary compliance on the part of your Internet Service Provider, or additional records from a third party, information stored or retrieved for this purpose alone cannot usually be used to identify you.
Marketing
The technical storage or access is required to create user profiles to send advertising, or to track the user on a website or across several websites for similar marketing purposes.
