Figure - available from: Nutrients
This content is subject to copyright.
Conditions which are linked with pancreatic cancer cachexia and their therapeutic management. NSAID: nonsteroidal anti-inflammatory drugs; JAK: Janus kinase; STAT: signal transducer and activator of transcription; IGF: insulin-like growth factor; SARMs: selective androgen receptor modulators.
Source publication
Cachexia is a major characteristic of multiple non-malignant diseases, advanced and metastatic cancers and it is highly prevalent in pancreatic cancer, affecting almost 70-80% of the patients. Cancer cachexia is a multifactorial condition accompanied by compromised appetite and changes in body composition, i.e., loss of fat. It is associated with l...
Citations
... Though there is no definitive and consistent definition of cachexia in cancer patients, cachexia is defined in tumor patients as a weight loss of 10% or more within 6 months. The main physical changes in cachexia are anorexia and malnutrition resulting from changes in gastrointestinal function and loss of appetite as well as massive loss of adipose and muscle tissue [3]. Alterations in metabolism and a systemic inflammatory reaction contribute largely to the wasting of muscle and adipose tissue in pancreatic cancer, which is one of the typical symptoms of cachexia [4]. ...
Cancer cachexia-associated muscle wasting as a multifactorial wasting syndrome, is an important factor affecting the long-term survival rate of tumor patients. Photobiomodulation therapy (PBMT) has emerged as a promising tool to cure and prevent many diseases. However, the effect of PBMT on skeletal muscle atrophy during cancer progression has not been fully demonstrated yet. Here, we found PBMT alleviated the atrophy of myotube diameter induced by cancer cells in vitro, and prevented cancer-associated muscle atrophy in mice bearing tumor. Mechanistically, the alleviation of muscle wasting by PBMT was found to be involved in inhibiting E3 ubiquitin ligases MAFbx and MuRF-1. In addition, transcriptomic analysis using RNA-seq and GSEA revealed that PI3K/AKT pathway might be involved in PBMT-prevented muscle cachexia. Next, we showed the protective effect of PBMT against muscle cachexia was totally blocked by AKT inhibitor in vitro and in vivo. Moreover, PBMT-activated AKT promoted FoxO3a phosphorylation and thus inhibiting the nucleus entry of FoxO3a. Lastly, in cisplatin-treated muscle cachexia model, PBMT had also been shown to ameliorate muscle atrophy through enhancing PI3K/AKT pathway to suppress MAFbx and MuRF-1 expression. These novel findings revealed that PBMT could be a promising therapeutic approach in treating muscle cachexia induced by cancer.
Graphical Abstract
Schematic representation of the signaling pathway for PBM therapy ameliorates cancer cachexia-associated muscle wasting. In cancer cachexia mice, myostatin and activin released by tumor cells act on the corresponding receptor ActRIIB by vascular transportation. Subsequent Smad2/3 are phosphorylated to reduce AKT activity and suppress FoxO3a phosphorylation. Dephosphorylated FoxO3a are translocated into the nucleus and induce the transcription of target genes (MAFbx and MuRF-1) which regulate the ubiquitin–proteasome systems, resulting in muscle wasting. After receiving PBM therapy, PI3K-AKT signaling is activated, and then stimulates protein synthesis by activating mTOR. mTOR activates the P70S6K, leading to protein synthesis. AKT also phosphorylates and inhibits the nucleus entry of FoxO3a, thereby alleviating muscle wasting.
... In ammation, malnutrition, and pancreatic exocrine insu ciency have intricate crosstalk [39], and discrimination among these markers is di cult. As described below, these factors contribute to cancer cachexia [40]. Our result may re ect cancer cachexia. ...
Background
The bidirectional association between pancreatic cancer (PaC) and diabetes mellitus (DM) is well-established. PaC-related DM (PRDM) is characterized by low insulin secretion and insulin resistance.
Aims
To investigate the diabetic state and PRDM, and assess whether these markers have predictive value for survival in patients with PaC.
Methods
We retrospectively examined the clinical factors, glucagon stimulation test results, and homeostasis model assessment of insulin resistance (HOMA-IR) scores in patients with PaC. PRDM was defined as if fasting blood glucose was ≥ 126 mg/dL or if hemoglobin A1c (HbA1c) was ≥ 6.5%. We reviewed new-onset PRDM without diabetes treatment history. Increments in C-peptide levels after glucagon stimulation (ΔC-peptide) was examined. Kaplan–Meier curves and log-rank tests were used for data analysis.
Results
The ΔC-peptide value was ≥ 1 ng/ml in 77.3% of the patients with PaC, of which 13.8% demonstrated a HOMA-IR score > 2.5 and 42.2% of them showed PRDM. The presence of PRDM was significantly shorter overall survival (OS). Patients with ΔC-peptide < 1ng/ml did not show significantly shorter OS than those with ≥ 1 ng/ml (median, 546 [95%CI, 373–900] vs. 567 [514–772] days, p = 0.59). The group with HOMA-IR ≥ 2.5 also did not show a significantly shorter median OS than the group with HOMA-IR < 2.5 (median, 371 [528–710] vs. 571 [221–954] days, p = 0.068)
Conclusions
The ΔC-peptide values and HOMA-IR score were not significant predictors of survival although PRDM could be related with prognosis.
... Cachexia is a multifactorial syndrome defined by non--volitional weight loss, sarcopenia, anorexia, fatigue, weakness, loss of appetite, taste alterations, and early satiety [45]. It has been shown to affect approximately 50% of oncological patients and be driven by reduced food intake and specific alterations in metabolism caused by host-tumor interactions [46]. Insufficient food intake is a significant driver of weight loss, while metabolic changes and reduced activity contribute to the loss of muscle mass, called sarcopenia [47]. ...
... Yet, pancreatic cancerrelated comorbidities also contribute to the poor patient survival. Cachexia, a multisystemic syndrome causing anorexia and muscle catabolism, occurs in approximately 80 % of pancreatic cancer patients and is considered a major cause of PDAC mortality (Poulia et al., 2020). Furthermore, it is hypothesized that a bidirectional link between cancer and the central nervous system exists, that induces psychiatric comorbidities such as depression and anxiety, thereby further reducing the quality-of-life of cancer patients (Santos and Pyter, 2018). ...
... Cancer anorexia-cachexia syndrome (CAS) occurs in up to 70-80% of lung, gastric, and pancreatic cancer patients [1,2]. CAS is a complex multifactorial syndrome with ongoing skeletal muscle loss despite nutritional intervention, and the patient may or may not present with fat mass loss [3]. ...
Background: Cancer anorexia-cachexia syndrome (CAS) is a multifactorial condition that is highly prevalent in advanced cancer patients and associated with significant reduction in functional performance, reduction in quality of life, and increased mortality. Currently, no medications are approved for this indication. Recently, the American Society of Clinical Oncology (ASCO) released a rapid recommendation suggesting that low-dose olanzapine once daily may be used to treat cancer cachexia. Many questions still exist on how to use olanzapine for this indication in clinical practice. The objective of this review is to identify existing knowledge on the use of olanzapine for CAS. Methods: A comprehensive search was conducted to identify the primary literature that involved olanzapine for anorexia and cachexia in cancer patients between 2000 and 2023. Results: Seven articles were identified and are discussed here, including two randomized double-blinded placebo-controlled studies, one randomized comparative study, two prospective open-label studies, one retrospective chart review, and one case report. Conclusions: Low dose olanzapine (2.5–5 mg once daily) may be useful in the treatment of CAS for increasing appetite, reducing nausea and vomiting, and promoting weight gain. Further large-scale multi-center randomized placebo-controlled studies will be needed to investigate the impact of olanzapine on weight change in CAS patients.
... Muscle catabolism is accelerated by the cytokines produced during and after surgery, leading to a decrease in muscle content after surgery [44]. Cytokines associated with inflammatory reactions could possibly cause the adverse feedback action of leptin on the hypothalamus, causing a loss of appetite [45]. Furthermore, patients who underwent PDAC lose the largest percentage of BW until discharge from the department compared to those with gastric cancer and colorectal cancer [46]; however, according to another previous report considering operative methods, BW change 12 months after surgery in the PD group was significantly lower than that found in the total gastrectomy and distal gastrectomy groups [47]. ...
Background
Few reports have performed a prognostic analysis based on bioelectrical impedance analysis in patients with radical resection of pancreatic ductal adenocarcinoma (PDAC), and its usefulness in prognostic analysis remains unclear. This study aimed to evaluate body composition changes in patients undergoing radical resection for PDAC and analyze its impact on prognosis.
Methods
The medical records of radical resection for patients with PDAC were retrospectively reviewed, and the parameters of body composition, including body weight, skeletal muscle mass, body fat mass (BFM), and extracellular water-total body water ratio, from preoperatively to 12 months postoperatively, for each surgical procedure were measured based on direct segmental multifrequency bioelectrical impedance analysis with an InBody 770 (InBody Inc., Tokyo, Japan) device. The clinicopathological and prognostic factors were analyzed.
Results
Among 79 patients who underwent radical resection for PDAC, 36 (46%), 7 (8%), and 36 (46%) underwent pancreatoduodenectomy, total pancreatectomy, and distal pancreatectomy, respectively. The multivariate overall survival analysis demonstrated that BFM loss percentage at 1 month postoperatively ≧14% (p = 0.021), lymph node metastasis (p = 0.014), and non-adjuvant chemotherapy (p < 0.001) were independent poor prognostic factors. Multivariate analysis revealed that preoperative BFM < 12 kg and preoperative albumin < 3.5 g/dL were independently associated with BFM loss percentage at 1 month postoperatively ≧14% (p = 0.021 and p = 0.047, respectively).
Conclusions
Loss of BFM in the early postoperative period may have a poor prognosis in radical resection of PDAC.
... However, because the main aim of this study is to assess the correlation between modalities, this could have had little effect on the results. Second, individuals diagnosed with cancer have a different metabolism than individuals without cancer, and there can be a slight difference in the body composition between these two types of individuals [29]. Disease-specific analysis should be performed in further studies. ...
... Hepatic gluconeogenesis is also affected by inflammatory cytokines, such as TNF-α, IL-6 and IL-1. Production of inflammatory proteins, such as acute-phase proteins, in the liver also requires muscle deterioration as a source of amino acids in cancer cachexia (11,53). In the present study, treatment with BC suppressed IL-6 and TNF-α serum levels, which may inhibit hepatic gluconeogenesis. ...
Cancer cachexia is a metabolic disease involving multiple organs, which is accompanied by the depletion of muscle tissue and is associated with ~20% of cancer-related deaths. Muscle wasting is a critical factor in cancer cachexia. β-carotene (BC) has been shown to increase muscle mass and hypertrophy in healthy mice. However, its effects on muscle tissue dysregulation in cancer cachexia have yet to be studied. In the present study, 5-week-old male C57BL/6J mice were injected with 1×10⁶ Lewis lung carcinoma (LLC) cells to induce cancer cachexia; then the mice were administered BC (4 or 8 mg/kg) for 22 days to assess its effects on muscle atrophy in the gastrocnemius muscles. The effects of BC on inflammatory cytokines, myogenesis and muscle atrophy were evaluated using C2C12 myotubes treated with LLC-conditioned media. BC supplementation significantly suppressed tumor growth, inflammatory cytokines, and hepatic gluconeogenesis in the LLC-induced cancer cachexia mouse model, while also improving muscle weight and grip strength. These effects are considered to be mediated by the PI3K/Akt pathway and through regulation of muscle atrophy. Moreover, BC treatment was associated with the recovery of LLC-conditioned media-induced muscle differentiation deficits and muscle atrophy in C2C12 myotubes. These findings indicate BC as a potential novel therapeutic agent for cancer cachexia.
... The impairment in energy metabolism contributes significantly to the onset and development of cachexia, as shown in previous studies [3,[25][26][27]. Cachexia has been shown to be associated with impaired energy metabolism in a variety of cancers, including pancreatic cancer [28], breast cancer [29], ovarian cancer [30], and kidney cancer [31]. However, due to the different metabolic characteristics of cancer patients at different stages of cachexia, the efficiency of energy metabolism may be different in cancer patients [32]. ...
Cancer cachexia (CAC) is a debilitating condition that often arises from noncachexia cancer (NCAC), with distinct metabolic characteristics and medical treatments. However, the metabolic changes and underlying molecular mechanisms during cachexia progression remain poorly understood. Understanding the progression of CAC is crucial for developing diagnostic approaches to distinguish between CAC and NCAC stages, facilitating appropriate treatment for cancer patients. In this study, we establish a mouse model of colon CAC and categorize the mice into three groups: CAC, NCAC and normal control (NOR). By performing nuclear magnetic resonance (NMR)-based metabolomic profiling on mouse sera, we elucidate the metabolic properties of these groups. Our findings unveil significant differences in the metabolic profiles among the CAC, NCAC and NOR groups, highlighting significant impairments in energy metabolism and amino acid metabolism during cachexia progression. Additionally, we observe the elevated serum levels of lysine and acetate during the transition from the NCAC to CAC stages. Using multivariate ROC analysis, we identify lysine and acetate as potential biomarkers for distinguishing between CAC and NCAC stages. These biomarkers hold promise for the diagnosis of CAC from noncachexia cancer. Our study provides novel insights into the metabolic mechanisms underlying cachexia progression and offers valuable avenues for the diagnosis and treatment of CAC in clinical settings.
... Patients with pancreatic cancer often suffer from body composition derangement, such as sarcopenia, which is a serious syndrome characterised by progressive muscle loss and functional decline. Sarcopenia is significantly correlated with post-operative chemotherapy intolerance, pancreatic fistula, early post-operative recurrence, prolonged hospital stay, and short survival (21,22) . The prevalence of sarcopenia in patients with pancreatic cancer ranges between 21·3% and 86·3% (23) . ...
Pancreatic cancer is the most common medical condition that requires pancreatic resection. Over the last three decades, significant improvements have been made in the conditions and procedures related to pancreatic surgery, resulting in mortality rates lower than 5%. However, it is important to note that the morbidity around pancreatic surgery remains relatively high, with a percentage range of 30-60%. Preoperative malnutrition is considered to be an independent risk factor for postoperative complications in pancreatic surgery, such as impaired wound healing, higher infection rates, prolonged hospital stay, hospital readmission, poor prognosis, and increased morbidity and mortality. Regarding the postoperative period, it is crucial to provide the best possible management of gastrointestinal dysfunction and to handle the consequences of alterations in food digestion and nutrient absorption for those undergoing pancreatic surgery. The European Society for Clinical Nutrition and Metabolism (ESPEN) suggests that early oral feeding should be the preferred way to initiate nourishing surgical patients as it is associated with lower rates of complications. However, there is ongoing debate about the optimal postoperative feeding approach. Several studies have shown that enteral nutrition is associated with a shorter time to recovery, superior clinical outcomes, and biomarkers. On the other hand, recent data suggest that nutritional goals are better achieved with parenteral feeding, either exclusively or as a supplement. The current review highlights recommendations from existing evidence, including nutritional screening and assessment, and pre/postoperative nutrition support fundamentals to improve patient outcomes. Key areas for improvement and opportunities to enhance guideline implementation are also highlighted.
