Early Neutrophilia Marked by Aerobic Glycolysis Sustains Host Metabolism and Delays Cancer Cachexia

Petruzzelli, Michele; Ferrer, Miriam; Schuijs, Martijn J.; Kleeman, Sam O.; Mourikis, Nicholas; Hall, Zoe; Perera, David; Raghunathan, Shwethaa; Vacca, Michèle; Gaude, Edoardo; Lukey, Michael J.; Jodrell, Duncan I.; Frezza, Christian; Wagner, Erwin F.; Venkitaraman, Ashok R.; Halim, Timotheus Y.F.; Janowitz, Tobias

doi:10.3390/cancers14040963

Cited by 11 publications

(16 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the C26 model, Balb/c or CD2F1 mice undergo body weight loss and muscle wasting, mainly through increased levels of circulating Interleukin-6 (IL-6), with premature death by 14–30 days from cell inoculation, according to the individual cell clones ( Aulino et al, 2010 ; Talbert et al, 2014 ; Bonetto et al, 2016 ; Petruzzelli et al, 2022 ). Due to the high velocity and penetrance of cachexia induction in C26-bearing mice, this model is suitable for studies on cachexia per se .…”

Section: Cancer Cachexia Preclinical Modelsmentioning

confidence: 99%

“…Accordingly, other studies reported similar results in lung and gastric cancer patients ( Jagoe et al, 2002 ; Smith et al, 2011 ). Although pre-clinical models are distant from human scenario, the observation that inflammation and other derangements precede muscle wasting has been recapitulated in C26-bearing mice ( Petruzzelli et al, 2022 ), in which spleen enlargement and adipose tissue loss occur before skeletal muscle atrophy. Similarly, splenomegaly precedes of at least 2 months muscle wasting in APC Min/+ mice ( You et al, 2006 ).…”

Section: Skeletal Muscle: a Main Target But Not The First Affected Ti...mentioning

confidence: 99%

“…A study reported a reduced number of macrophages and neutrophils in cachectic muscles of C26-bearing mice ( Inaba et al, 2018 ). Conversely, a recent article reported that neutrophilia appears to be an early systemic event upon tumor growth and, notably, the number of neutrophils is also increased in lung and liver at early timepoint ( Petruzzelli et al, 2022 ). The authors suggested that the systemic neutrophilia might originate from the spleen as increased spleen size and high number of splenic neutrophils progenitors were observed prior to the onset of the cachectic phenotype.…”

Section: Immune System: Friend and Foementioning

confidence: 99%

“…The authors suggested that the systemic neutrophilia might originate from the spleen as increased spleen size and high number of splenic neutrophils progenitors were observed prior to the onset of the cachectic phenotype. Beside neutrophils number, their metabolism was affected in tumor-bearing mice with an overall increase in metabolism and dependence on glycolysis ( Petruzzelli et al, 2022 ). Targeting of neutrophilia or aerobic glycolysis worsens the cachectic phenotype and the survival, indicating that neutrophilia might represent an adaptative response to preserve the systemic metabolic homeostasis during cancer progression ( Petruzzelli et al, 2022 ).…”

Section: Immune System: Friend and Foementioning

confidence: 99%

“…Beside neutrophils number, their metabolism was affected in tumor-bearing mice with an overall increase in metabolism and dependence on glycolysis ( Petruzzelli et al, 2022 ). Targeting of neutrophilia or aerobic glycolysis worsens the cachectic phenotype and the survival, indicating that neutrophilia might represent an adaptative response to preserve the systemic metabolic homeostasis during cancer progression ( Petruzzelli et al, 2022 ). In addition, another study reported an early infiltration of neutrophils into regions of the brain that influence feeding behavior and/or energy metabolism, such as the hypothalamus, which contributes to anorexia and muscle atrophy in a mouse model of pancreatic ductal adenocarcinoma ( Burfeind et al, 2020 ).…”

Section: Immune System: Friend and Foementioning

confidence: 99%

See 4 more Smart Citations

Cancer cachexia as a multiorgan failure: Reconstruction of the crime scene

Ferrara

Samaden

Ruggieri

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Cachexia is a devastating syndrome associated with the end-stage of several diseases, including cancer, and characterized by body weight loss and severe muscle and adipose tissue wasting. Although different cancer types are affected to diverse extents by cachexia, about 80% of all cancer patients experience this comorbidity, which highly reduces quality of life and response to therapy, and worsens prognosis, accounting for more than 25% of all cancer deaths. Cachexia represents an urgent medical need because, despite several molecular mechanisms have been identified, no effective therapy is currently available for this devastating syndrome. Most studies focus on skeletal muscle, which is indeed the main affected and clinically relevant organ, but cancer cachexia is characterized by a multiorgan failure. In this review, we focus on the current knowledge on the multiple tissues affected by cachexia and on the biomarkers with the attempt to define a chronological pathway, which might be useful for the early identification of patients who will undergo cachexia. Indeed, it is likely that the inefficiency of current therapies might be attributed, at least in part, to their administration in patients at the late stages of cachexia.

show abstract

Section: Cancer Cachexia Preclinical Modelsmentioning

confidence: 99%

Section: Skeletal Muscle: a Main Target But Not The First Affected Ti...mentioning

confidence: 99%

Section: Immune System: Friend and Foementioning

confidence: 99%

Section: Immune System: Friend and Foementioning

confidence: 99%

Section: Immune System: Friend and Foementioning

confidence: 99%

See 3 more Smart Citations

Cancer cachexia as a multiorgan failure: Reconstruction of the crime scene

Ferrara

Samaden

Ruggieri

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

R‐ketorolac ameliorates cancer‐associated cachexia and prolongs survival of tumour‐bearing mice

Chrysostomou,

Eder,

Pototschnig

et al. 2024

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

BackgroundCancer‐associated cachexia (CAC) is a debilitating syndrome associated with poor quality of life and reduced life expectancy of cancer patients. CAC is characterized by unintended body weight reduction due to muscle and adipose tissue loss. A major hallmark of CAC is systemic inflammation. Several non‐steroidal anti‐inflammatory drugs (NSAIDs) have been suggested for CAC treatment, yet no single medication has proven reliable. R‐ketorolac (RK) is the R‐enantiomer of a commonly used NSAID. The effect of RK on CAC has not yet been evaluated.MethodsTen‐ to 11‐week‐old mice were inoculated with C26 or CHX207 cancer cells or vehicle control (phosphate‐buffered saline [PBS]). After cachexia onset, 2 mg/kg RK or PBS was administered daily by oral gavage. Body weight, food intake and tumour size were continuously measured. At study endpoints, blood was drawn, mice were sacrificed and tissues were excised. Immune cell abundance was analysed using a Cytek® Aurora spectral flow cytometer. Cyclooxygenase (COX) activity was determined in lung homogenates using a fluorometric kit. Muscle tissues were analysed for mRNA and protein expression by quantitative real‐time PCR and western blotting analysis, respectively. Muscle fibre size was determined on histological slides after haematoxylin/eosin staining.ResultsTen‐day survival rate of C26‐bearing animals was 10% while RK treatment resulted in a 100% survival rate (P = 0.0009). Chemotherapy resulted in a 10% survival rate 14 days after treatment initiation, but all mice survived upon co‐medication with RK and cyclophosphamide (P = 0.0001). Increased survival was associated with a protection from body weight loss in C26 (−0.61 ± 1.82 vs. −4.48 ± 2.0 g, P = 0.0004) and CHX207 (−0.49 ± 0.33 vs. −2.49 ± 0.93 g, P = 0.0003) tumour‐bearing mice treated with RK, compared with untreated mice. RK ameliorated musculus quadriceps (−1.7 ± 7.1% vs. −27.8 ± 8.3%, P = 0.0007) and gonadal white adipose tissue (−18.8 ± 49% vs. −69 ± 15.6%, P = 0.094) loss in tumour‐bearing mice, compared with untreated mice. Mechanistically, RK reduced circulating interleukin‐6 (IL‐6) concentrations from 334 ± 151 to 164 ± 123 pg/mL (P = 0.047) in C26 and from 93 ± 39 to 35 ± 6 pg/mL (P = 0.0053) in CHX207 tumour‐bearing mice. Moreover, RK protected mice from cancer‐induced T‐lymphopenia (+1.8 ± 42% vs. −49.2 ± 12.1% in treated vs. untreated mice, respectively). RK was ineffective in ameliorating CAC in thymus‐deficient nude mice, indicating that the beneficial effect of RK depends on T‐cells.ConclusionsRK improved T‐lymphopenia and decreased systemic IL‐6 concentrations, resulting in alleviation of cachexia and increased survival of cachexigenic tumour‐bearing mice, even under chemotherapy and independent of COX inhibition. Considering its potential, we propose that the use of RK should be investigated in patients suffering from CAC.

show abstract

Colorectal cancer: Metabolic interactions reshape the tumor microenvironment

Chen

Zhu

et al. 2022

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

View full text Add to dashboard Cite

Early Neutrophilia Marked by Aerobic Glycolysis Sustains Host Metabolism and Delays Cancer Cachexia

Cited by 11 publications

References 54 publications

Cancer cachexia as a multiorgan failure: Reconstruction of the crime scene

Cancer cachexia as a multiorgan failure: Reconstruction of the crime scene

R‐ketorolac ameliorates cancer‐associated cachexia and prolongs survival of tumour‐bearing mice

Colorectal cancer: Metabolic interactions reshape the tumor microenvironment

Contact Info

Product

Resources

About