Cancer cachexia is a severe and disabling clinical condition that frequently accompanies the development of cancer. The hallmark of cancer cachexia is the loss of muscle mass and function with or without concomitant fat mass loss. Sarcopenia identifies a clinical condition of progressive and generalized loss of muscle mass associated with reduced muscle strength and/or physical performance. The systemic effects of cancer cachexia are the result of circulating factors, such as pro-inflammatory cytokines, responsible for modifying central mechanisms that regulate appetite and energy expenditure and promoting the activation of several transcription factors and mediators directly involved in muscle mass loss such as Growth and Differentiation Factor 15 (GDF-15). GDF-15 is associated with weight loss, decreased muscle mass and strength, and poor survival in cancer patients, serving as a prognostic indicator in cancer patients and as a potential therapeutic target for cancer-related weight loss. Moreover, GDF-15 is able to suppress the transcription of various muscle tissue microRNAs (miRs) resulting in loss of muscle mass and promoting muscle atrophy, especially in lung cancer. Identification and dosage of serum concentrations of circulating miRs and GDF-15 could be useful as potential biomarkers in the diagnosis and prognosis of lung cancer patients and as potential therapeutic targets. Naïve lung cancer patients will be enrolled and divided in sarcopenic and non sarcopenic. Evaluation of skeletal muscle mass will be calculated. Dosage of proinflammatory cytokines and GDF-15 levels will be performed, and muscle specific miRs on serum, saliva and urine samples will be investigated. Overall survival and progression-free survival data will be collected. These results will be useful for subsequent studies aimed at reducing morbidity, mortality and improving the quality of life of cancer patients through specific and personalized nutritional and pharmacological interventions
Cachexia and sarcopenia are clinical entities which negatively impact on the outcomes of cancer patients. Given the limited awareness of these two conditions and the objective difficulties in their diagnosis, both identification and preventative/therapeutic strategies are still scarcely implemented in clinical practice. Moreover, cachexia and sarcopenia define clinical phenotypes which may stem from the complex interplay of several factors, including aging, type and severity of principal underlying disease, type, number and severity of comorbidities, concurrent therapies, inflammation, abnormal substrate metabolism, reduced food intake and impaired physical activity.
It is therefore clear that the multifactorial pathogenesis of cachexia and sarcopenia makes it difficult to develop single intervention-based strategies for their prevention or attenuation and treatment. Rather, it is becoming increasingly clear that novel approaches to these two conditions, independently of being chemical, biological, or physical in origin (nature), should be part of an integrated support program, including a multidimensional approach to cancer. Maintenance of muscle mass and function has major clinical implications, since muscle loss has been clearly identified as an independent predictor of mortality and reduced tolerance to treatments. Sarcopenia is a critical component of frailty, a multifactorial condition inducing loss of autonomy, impinged quality of life and non-resilience in patients. This explains why the ultimate goal in the field of cachexia and sarcopenia is to develop novel agents at least capable for attenuating the progressive loss of muscular function(s). The better understanding of some of the mechanisms involved in the pathogenesis of both cachexia and sarcopenia will progressively allow for the identification of several potential molecular targets for (intervention) therapies. Effectively, it represents a promising field where to convey interest, research and investments in next few years. In this perspective, an extremely intriguing new area of interest for the development of biological therapies is represented by miRs. MiRs regulate gene expression targeting the 3¿ untranslated region of mRNAs, resulting in accelerated degradation of mRNA and/or inhibition of translation. MiRs are involved in several events such as cell proliferation, differentiation and death, DNA repair and oxidative stress response (45). Moreover, miRs have a key regulatory role in protein expression in pathological states, including skeletal muscle atrophy. Once released into the extracellular environment, free or included into extracellular vescicles (EVs), miRs may convey functional information to distant sites. For example, EVs containing miRs-21 have been proposed to be involved in cancer-related muscle wasting.
Research is currently ongoing to understand not only how and to what extent are miRs responsible for physiological and pathological inter-organ signaling, but also whether anti-miRs may represent a potential therapeutic option to counteract muscle loss.
The data obtained with this study will allow an early diagnosis of sarcopenia in cancer patients for which a careful nutritional and metabolic assessment is required to improve nutritional status and reduce the risk of complications during cancer therapies. In addition, the comparison between CT and functional data will allow to accuratelycharactherize sarcopenia in cancer patients. These results will be useful for further interventions aimed at reducing morbidity, mortality and improving the quality of life of lung cancer patients through specific and personalized nutritional and/or pharmacological interventions.
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