scholarly journals Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia

2021 ◽  
Vol 218 (6) ◽  
Author(s):  
Joseph E. Rupert ◽  
Ashok Narasimhan ◽  
Daenique H.A. Jengelley ◽  
Yanlin Jiang ◽  
Jianguo Liu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Culture ◽  
Weight Loss ◽  
Pancreatic Adenocarcinoma ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Malignant Cells ◽  
Feed Forward ◽  
Orthotopic Xenografts

Most patients with pancreatic adenocarcinoma (PDAC) suffer cachexia; some do not. To model heterogeneity, we used patient-derived orthotopic xenografts. These phenocopied donor weight loss. Furthermore, muscle wasting correlated with mortality and murine IL-6, and human IL-6 associated with the greatest murine cachexia. In cell culture and mice, PDAC cells elicited adipocyte IL-6 expression and IL-6 plus IL-6 receptor (IL6R) in myocytes and blood. PDAC induced adipocyte lipolysis and muscle steatosis, dysmetabolism, and wasting. Depletion of IL-6 from malignant cells halved adipose wasting and abolished myosteatosis, dysmetabolism, and atrophy. In culture, adipocyte lipolysis required soluble (s)IL6R, while IL-6, sIL6R, or palmitate induced myotube atrophy. PDAC cells activated adipocytes to induce myotube wasting and activated myotubes to induce adipocyte lipolysis. Thus, PDAC cachexia results from tissue crosstalk via a feed-forward, IL-6 trans-signaling loop. Malignant cells signal via IL-6 to muscle and fat, muscle to fat via sIL6R, and fat to muscle via lipids and IL-6, all targetable mechanisms for treatment of cachexia.

scholarly journals Pancreatic cancer induces muscle wasting by promoting the release of pancreatic adenocarcinoma upregulated factor

2021 ◽  
Author(s):  
Wonbeak Yoo ◽  
Hyunji Choi ◽  
Young Hoon Son ◽  
Jaemin Lee ◽  
Seongyea Jo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Weight Loss ◽  
Body Weight ◽  
Pancreatic Adenocarcinoma ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Group Analysis ◽  
Body Weight Loss ◽  
C2c12 Myotubes ◽  
Pancreatic Cancer Cells

AbstractCancer cachexia is a highly debilitating condition characterized by weight loss and muscle wasting that contributes significantly to the morbidity and mortality of pancreatic cancer. The factors that induce cachexia in pancreatic cancer are largely unknown. We previously showed that pancreatic adenocarcinoma upregulated factor (PAUF) secreted by pancreatic cancer cells is responsible for tumor growth and metastasis. Here, we analyzed the relation between pancreatic cancer-derived PAUF and cancer cachexia in mice and its clinical significance. Body weight loss and muscle weight loss were significantly higher in mice with Panc-1/PAUF tumors than in those with Panc-1/Mock tumors. Direct administration of rPAUF to muscle recapitulated tumor-induced atrophy, and a PAUF-neutralizing antibody abrogated tumor-induced muscle wasting in Panc-1/PAUF tumor-bearing mice. C2C12 myotubes treated with rPAUF exhibited rapid inactivation of Akt-Foxo3a signaling, resulting in Atrogin1/MAFbx upregulation, myosin heavy chain loss, and muscle atrophy. The neutrophil-to-lymphocyte ratio and body weight loss were significantly higher in pancreatic cancer patients with high PAUF expression than in those with low PAUF expression. Analysis of different pancreatic cancer datasets showed that PAUF expression was significantly higher in the pancreatic cancer group than in the nontumor group. Analysis of The Cancer Genome Atlas data found associations between high PAUF expression or a high DNA copy number and poor overall survival. Our data identified tumor-secreted circulating PAUF as a key factor of cachexia, causing muscle wasting in mice. Neutralizing PAUF may be a useful therapeutic strategy for the treatment of pancreatic cancer-induced cachexia.

Treatment and underlying mechanisms of pancreatic cancer cachexia (PANCAX study).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. TPS491-TPS491
Author(s):  
Jasleen Khanuja ◽  
Gillian Gresham ◽  
Arsen Osipov ◽  
Richard Tuli ◽  
Andrew Eugene Hendifar
Keyword(s):  
Quality Of Life ◽  
Pancreatic Cancer ◽  
Weight Loss ◽  
Pancreatic Adenocarcinoma ◽  
Cancer Cachexia ◽  
Fecal Microbiome ◽  
Gut Hormone ◽  
The Relationship ◽  
Advanced Pancreatic Adenocarcinoma

TPS491 Background: Advanced pancreatic adenocarcinoma is characterized by progressive weight loss and nutritional deterioration, resulting in a cachexia-anorexia syndrome. This wasting has been linked to poorer survival, alterations in host defenses, and decreased functional ability and quality of life. Gut microbiota alterations affect muscle composition and have been demonstrated in mouse models of cancer cachexia. The relationship between pancreatic cancer cachexia and the composition of the fecal microbiome will be investigated. We propose the first prospective study of peptide-based enteral nutritional support in cachectic advanced pancreatic adenocarcinoma patients undergoing chemotherapy. We aim to establish the feasibility and efficacy of enteral nutrition as measured by changes in weight, lean body mass, and hand-grip strength. We will also explore the relationship between anorexia-cachexia with gut hormone changes and alterations in the fecal micro-biome, which may account for resultant malnutrition and muscle loss. Methods: Eligible patients will have a diagnosis of both pancreatic adenocarcinoma and cachexia, defined as greater than 5% unintentional weight loss within the previous 6 months. Peptamen 1.5 will be administered via a jejunal tube for 12 weeks. Lean body mass, evaluated by DEXA, and weight will be assessed at predefined intervals. Oral food intake will measured by 24 hour food recall and a taste and smells alteration survey. Secondary outcomes including, response to chemotherapy, survival, and quality of life will be studied. Fecal microbiome, serum inflammatory markers, and gut hormone levels will be assessed at pre-defined intervals. We have received funding from NIH/NCATS Grant # UL1TR000124 and opened enrollment in September 2014.

scholarly journals Continued Weight Loss and Sarcopenia Predict Poor Outcomes in Locally Advanced Pancreatic Cancer Treated with Chemoradiation

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 709 ◽  
Author(s):  
Patrick Naumann ◽  
Jonathan Eberlein ◽  
Benjamin Farnia ◽  
Thilo Hackert ◽  
Jürgen Debus ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Pancreatic Cancer ◽  
Weight Loss ◽  
Muscle Mass ◽  
Muscle Wasting ◽  
Statistical Tests ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Skeletal Muscle Index ◽  
Poor Outcomes

Background: Surgical resection offers the best chance of survival in patients with pancreatic cancer, but those with locally advanced disease (LAPC) are usually not surgical candidates. This cohort often receives either neoadjuvant chemotherapy or chemoradiation (CRT), but unintended weight loss coupled with muscle wasting (sarcopenia) can often be observed. Here, we report on the predictive value of changes in weight and muscle mass in 147 consecutive patients with LAPC treated with neoadjuvant CRT. Methods: Clinicopathologic data were obtained via a retrospective chart review. The abdominal skeletal muscle area (SMA) at the third lumbar vertebral body was determined via computer tomographic (CT) scans as a surrogate for the muscle mass and skeletal muscle index (SMI) calculated. Uni- and multi-variable statistical tests were performed to assess for impact on survival. Results: Weight loss (14.5 vs. 20.3 months; p = 0.04) and loss of muscle mass (15.1 vs. 22.2 months; p = 0.007) were associated with poor outcomes. The highest survival was observed in patients who had neither cachectic weight loss nor sarcopenia (27 months), with improved survival seen in those who ultimately received a resection (23 vs. 10 months; p < 0.001). Cox regression revealed that either continued weight loss or continued muscle wasting (SMA reduction) was predictive of poor outcomes, whereas a sarcopenic SMI was not. Conclusions: Loss of weight and lean muscle in patients with LAPC is prognostic when persistent. Therefore, both should be assessed longitudinally and considered before surgery.

scholarly journals JNK signaling contributes to skeletal muscle wasting and protein turnover in pancreatic cancer cachexia

2020 ◽  
Vol 491 ◽  
pp. 70-77 ◽  
Author(s):  
Scott E. Mulder ◽  
Aneesha Dasgupta ◽  
Ryan J. King ◽  
Jaime Abrego ◽  
Kuldeep S. Attri ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Pancreatic Cancer ◽  
Protein Turnover ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Jnk Signaling ◽  
Skeletal Muscle Wasting

scholarly journals Stage-specific muscle wasting mechanisms in a novel cancer cachexia mouse model for ovarian granulosa cell tumor

2020 ◽  
Author(s):  
Yaqi Zhang ◽  
Jie Zhu ◽  
So-Youn Kim ◽  
Megan M Romero ◽  
Kelly A Even ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Weight Loss ◽  
Granulosa Cell ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Activin A ◽  
Mice Model ◽  
E3 Ligases ◽  
Ovarian Granulosa Cell ◽  
Specific Muscle

AbstractCachexia is a progressive muscle wasting syndrome that increases mortality risk in cancer patients, while there are still no effective treatment due to the complexity of syndrome and the lack of preclinical models. We identified a transgenic mice model with ovarian granulosa cell tumors mimic the progression of cachexia seen in humans, including drastic weight loss, skeletal muscle wasting and increased serum cachexia biomarker activin A and GDF15. Hypercatabolism was detected in skeletal muscle, having upregulation of E3 ligases Atrogin-1 and Murf-1. Our cachexia model exhibited stage-specific muscle wasting mechanisms. At precachexia stage, elevation of activin A activates p38 MAPK. Inhibition of activin A with Follistatin reversed weight loss at precachexia stage. At cachexia stage, energy stress in skeletal muscle activates AMPKα and leads to upregulation of FoxO3. Our results indicate this novel preclinical cancer cachexia model is exploitable for studying pathophysiological mechanisms and testing therapeutic agents of cachexia.

scholarly journals The systemic activin response to pancreatic cancer: Implications for effective cancer cachexia therapy

2018 ◽  
Author(s):  
Xiaoling Zhong ◽  
Marianne Pons ◽  
Christophe Poirier ◽  
Yanlin Jiang ◽  
Jianguo Liu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Weight Loss ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Conditioned Medium ◽  
Tumor Cells ◽  
Stromal Cells ◽  
Cancer Cachexia ◽  
Dominant Negative ◽  
Prolonged Survival ◽  
Ductal Adenocarcinoma

AbstractPancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy with high rates of cachexia. Serum activin correlates with PDAC cachexia and mortality, while activin administration causes cachexia in mice. We studied activin in human tumors and in mice with orthotopic or genetic PDAC. Cachexia severity correlated with activin expression in tumor lines. Activins were expressed in both cancer and tumor stromal cells, but also in organs in murine PDAC cachexia. Tumor cells expressed activin-βA, or Inhba, while organs expressed both activin-βA and activin-βB, or Inhbb. PDAC elicits activin expression; PDAC conditioned medium induced activin and atrophy of myotubes. Treatment with the activin trap, ACVR2B/Fc, reduced cachexia and prolonged survival in mice with activin-low tumors, and reduced cachexia in activin-high tumors, without affecting activin expression in organs. Mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not survival. Overall our results indicate that PDAC induces a systemic activin response, leading to cachexia, and that activin targets might include organs beyond muscle. Targeting of both tumor-derived and host-derived activins could improve cachexia therapy.

Retrospective analysis of prognostic and predictive markers in patients with locally advanced unresectable and metastatic pancreatic adenocarcinoma treated with gemcitabine/nabpaclitaxel: Influence of the presence of stent.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 483-483 ◽  
Author(s):  
Ana Fernandez Montes ◽  
Paula Gonzalez Villarroel ◽  
Manuel Valladares Ayerbes ◽  
Juan Cruz De la Cámara Gómez ◽  
Guillermo Quintero ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Weight Loss ◽  
Pancreatic Adenocarcinoma ◽  
Univariate Analysis ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Biliary Stent ◽  
Neutrophil Lymphocyte Ratio ◽  
Risk Of Death ◽  
Metastatic Pancreatic Adenocarcinoma

483 Background: Placement of a biliary stent is a standard measure for patients (pts) with pancreatic cancer. We evaluated prognostic/predictive factors that could predict the benefit of gemcitabine/nabpaclitaxel in pts with locally advanced unresectable and metastatic pancreatic adenocarcinoma and whether the presence of a biliary stent reduced the treatment efficacy Methods: We retrospectively analyzed 39 pts with locally advanced and metastatic pancreatic cancer treated with gemcitabine/nabpaclitaxel. Data included lactate dehydrogenase (LDH) level, alkaline phosphatase, neutrophil/lymphocyte ratio (NLR), performance status (PS), weight loss, presence of stent, analgesics use and CA 19.9 level. The correlation with response rate, progression-free survival (PFS) and overall survival (OS) was analyzed. Objective toxicities were assessed. Results: 30 pts (77%) had metastatic disease and 9 (23%) locally advanced pancreatic cancer. 46% had liver metastases and 41% lung metastases. Mean age of pts: 62 years (62% male). 20% had PS:0, 67% PS:1 and 13% PS:2. Stents were placed in 30% of pts, 69% had weight loss and 64% used analgesics at diagnosis. At the time of analysis 14 pts had died (25 alive). 56% had progressed, 3% were lost to follow-up and 41% had not progressed. A total of 54% disease stabilizations, 21% partial responses and 18% progressions were achieved (deaths: 7%). 43% required dose reduction. The main toxicity was hematologic (grade 1 anemia). Median PFS: 6 months (95%CI 4.4-7.6). Median OS: 15 months (95%CI 10.4-19.6). There was a statistically significant relationship between LDH level, NLR and PS and OS: LDH level higher than 363 increased the risk of death, NLR above 3.1 increased 1.8 times the risk of death and mean OS of pts with ECOG:0,1 was greater than that of pts with ECOG:2. No relationship between the presence of stent and PFS or OS was found, as well as with any of the other variables. Conclusions: The presence of stent did not reduce the efficacy of gemcitabine/nabpaclitaxel. Univariate analysis showed PS as a prognostic factor while multivariate showed LDH and NLR.

scholarly journals Identification of Potential Serum Protein Biomarkers and Pathways for Pancreatic Cancer Cachexia Using an Aptamer-Based Discovery Platform

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3787
Author(s):  
Ashok Narasimhan ◽  
Safi Shahda ◽  
Joshua K. Kays ◽  
Susan M. Perkins ◽  
Lijun Cheng ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Weight Loss ◽  
Plasma Proteins ◽  
Cancer Cachexia ◽  
Ductal Adenocarcinoma ◽  
Cancer Stage ◽  
Protein Biomarkers ◽  
Skeletal Muscle Index ◽  
Novel Proteins ◽  
Upstream Regulator

Patients with pancreatic ductal adenocarcinoma (PDAC) suffer debilitating and deadly weight loss, known as cachexia. Development of therapies requires biomarkers to diagnose, and monitor cachexia; however, no such markers are in use. Via Somascan, we measured ~1300 plasma proteins in 30 patients with PDAC vs. 11 controls. We found 60 proteins specific to local PDAC, 46 to metastatic, and 67 to presence of >5% cancer weight loss (FC ≥ |1.5|, p ≤ 0.05). Six were common for cancer stage (Up: GDF15, TIMP1, IL1RL1; Down: CCL22, APP, CLEC1B). Four were common for local/cachexia (C1R, PRKCG, ELANE, SOST: all oppositely regulated) and four for metastatic/cachexia (SERPINA6, PDGFRA, PRSS2, PRSS1: all consistently changed), suggesting that stage and cachexia status might be molecularly separable. We found 71 proteins that correlated with cachexia severity via weight loss grade, weight loss, skeletal muscle index and radiodensity (r ≥ |0.50|, p ≤ 0.05), including some known cachexia mediators/markers (LEP, MSTN, ALB) as well as novel proteins (e.g., LYVE1, C7, F2). Pathway, correlation, and upstream regulator analyses identified known (e.g., IL6, proteosome, mitochondrial dysfunction) and novel (e.g., Wnt signaling, NK cells) mechanisms. Overall, this study affords a basis for validation and provides insights into the processes underpinning cancer cachexia.

A phase I study of nanoliposomal irinotecan and 5-fluorouracil/folinic acid in combination with interleukin-1-alpha antagonist for advanced pancreatic cancer patients with cachexia (OnFX).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS780-TPS780 ◽  
Author(s):  
Katelyn Mae Atkins ◽  
Jun Gong ◽  
Mourad Tighiouart ◽  
Samuel J. Klempner ◽  
Richard Tuli ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Weight Loss ◽  
Phase I ◽  
Folinic Acid ◽  
Pancreatic Adenocarcinoma ◽  
Lean Body Mass ◽  
Phase I Study ◽  
Interleukin 1 ◽  
Nanoliposomal Irinotecan ◽  
Advanced Pancreatic Adenocarcinoma

TPS780 Background: Patients with pancreatic cancer have the highest rate of weight loss among all advanced cancers. Of which, the majority develop cachexia, characterized by progressive and involuntary loss of weight and skeletal muscle mass. In preclinical studies, interleukin-1-alpha (IL-1α) antagonism has been found to neutralize tumor angiogenesis and onco-inflammation. Early phase single-agent studies in cancer cachexia have demonstrated increased lean body mass and decreased fatigue, pain, and appetite loss. The present study aims to establish the safety of an IL-1α antagonist (Bermekimab) in combination with nanoliposomal irinotecan (Nal-Iri) and 5-fluorouracil (5FU)/folinic acid (FA) in patients with advanced pancreatic adenocarcinoma and cachexia who have failed gemcitabine-based chemotherapy. Methods: This is a single arm, single center, phase I study. The primary objective is to assess the maximum tolerated dose (MTD) of Bermekimab in combination with Nal-Iri and 5FU/FA. MTD is defined as the dose such that the probability of dose-limiting toxicities at MTD is θ = 0.33. The first cohort of up to 3 patients will receive 7.5 mg/kg Bermekimab, 50 mg/m2 nanoliposomal irinotecan, 2000 mg/m2 5FU, and 400 mg/m2 FA and the subsequent doses will be determined by the escalation with overdose control (EWOC) algorithm. Treatment is administered on days 1 and 15 of each 28-day cycle. Key inclusion criteria include: advanced or locally advanced pancreatic adenocarcinoma that has progressed through or intolerant of gemcitabine-based chemotherapy, cachexia defined as > 5% unexplained weight loss 6 months prior to screening or as documented by physician, ECOG PS 0-2 or KPS ≥ 60%, and normal organ and marrow function. Secondary objectives are to assess weight, lean body mass, inflammatory cytokines, overall survival, progression free survival, patient quality of life, and functional status. Since January 2019, 23 patients have been screened and 21 enrolled. Clinical trial information: NCT03207724.

Rethinking Nutritional Support for Persons with Cancer Cachexia

2003 ◽  
Vol 5 (1) ◽  
pp. 3-17 ◽  
Author(s):  
Donna O. McCarthy
Keyword(s):  
Weight Loss ◽  
Arachidonic Acid ◽  
Nutritional Support ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Calorie Intake ◽  
Inflammatory Condition ◽  
Proinflammatory Mediators ◽  
Chronic Inflammatory Condition

Cancer cachexia is a poorly understood syndrome of anorexia, weight loss, and muscle wasting that negatively impacts quality of life and survival in cancer patients. Research has clearly implicated proinflammatory cytokines in the biology of cancer cachexia. More recent research implicates products of arachidonic acid and suggests that cachexia may be a chronic inflammatory condition rather than a nutritional aberration. To date, nutritional support to slow weight loss has focused primarily on increasing calorie intake. Alternatively, many foods contain factors that can modulate the synthesis or activity of proinflammatory mediators, especially the synthesis of prostaglandin E2 from arachidonic acid. These factors and foods are sometimes called nutraceuticals, and research is needed to evaluate their efficacy in combating cancer cachexia.

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