Cancer: The Tumor-Driven Disease of the Host

Janowitz, Tobias

doi:10.1016/j.cmet.2018.06.016

Cited by 8 publications

(5 citation statements)

References 11 publications

(15 reference statements)

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“…The targeting of upstream molecules, such as GLUT1, show similar effects in inhibiting tumor growth but may cause normal cell death because they prevent oxygen transport and endothelial cell angiogenesis for red blood cells [ 52 , 53 ]. These findings provide a proof-of-concept that paradoxical tumor-host responses to treatment occur in vivo, warranting further investigation in the context of other treatments [ 54 ].…”

Section: Discussionmentioning

confidence: 95%

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

Petruzzelli

Ferrer

Schuijs

et al. 2022

Cancers

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An elevated neutrophil–lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, using murine model systems of colorectal and pancreatic cancer we show that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, similar to cancer cells. Although pharmacological inhibition of aerobic glycolysis slows down tumor growth in C26 tumor-bearing mice, it precipitates cachexia, thereby shortening the overall survival. This negative effect may be explained by our observation that acute depletion of neutrophils in pre-cachectic mice impairs systemic glucose homeostasis secondary to altered hepatic lipid processing. Thus, changes in neutrophil number, distribution, and metabolism play an adaptive role in host metabolic homeostasis during cancer progression. Our findings provide insight into early events during cancer progression to cachexia, with implications for therapy.

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Section: Discussionmentioning

confidence: 95%

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

Petruzzelli

Ferrer

Schuijs

et al. 2022

Cancers

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“…This is specifically the case for ketogenic diet interventions, which are currently tested in clinical trials. Here, the anti-cancer effect may be offset by the inability of the organism to utilize the fatty acid nutrients, because reprogramming of systemic metabolism, muscle and fat loss, and reduced food intake are hallmarks of organisms with cancer progression and cancer cachexia (Janowitz 2018).…”

Section: Discussionmentioning

confidence: 99%

Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia

Ferrer

Mourikis

Davidson

et al. 2023

Preprint

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The dependency of cancer cells on glucose can be targeted with high-fat low-carbohydrate ketogenic diet (KD). However, hepatic ketogenesis is suppressed in IL-6 producing cancers, which prevents the utilization of this nutrient source as energy for the organism. In two IL-6 associated murine models of cancer cachexia we describe delayed tumor growth but accelerated onset of cancer cachexia and shortened survival when mice are fed KD. Mechanistically, we find this uncoupling is a consequence of the biochemical interaction of two simultaneously occurring NADPH-dependent pathways. Within the tumor, increased production of lipid peroxidation products (LPPs) and, consequently, saturation of the glutathione (GSH) system leads to ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impairs the biosynthesis of corticosterone, the main regulator of metabolic stress, in the adrenal glands. Administration of dexamethasone, a potent glucocorticoid, improves food intake, normalizes glucose homeostasis and utilization of nutritional substrates, delays onset of cancer cachexia and extends survival of tumor-bearing mice fed KD, while preserving reduced tumor growth. Our study highlights that the outcome of systemic interventions cannot necessarily be extrapolated from the effect on the tumor alone, but that they have to be investigated for anti-cancer and host effects. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer.

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“…This specific metabolic feature seems to be associated with an improved survival outcome and, in particular, suggests a potential role of both UDCA and its derivatives as well as LCA and its derivatives in development and progression of mSTS. This result seems to suggest a complex interaction between the host BAs metabolism and the tumour development which, in turn, have the potential to result in significant and meaningful prognostic implications [6,19].…”

Section: Discussionmentioning

confidence: 90%

“…This extraordinary treatment outcome can only be partially attributed to the drug's mechanisms of action, which alter both the DNA cell nucleus and the tumour microenvironment activity, resulting in its oncostatic effect [5]. Accumulating data suggest that the efficacy of the trabectedin treatment may be attributed, besides tumour histology, also to differences in the overall host molecular and biochemical features [6][7][8][9][10]. In this context, the pivotal role of tumour microenvironmental matrix peptidases and their dynamic tumour interaction may be instrumental in shaping the overall anticancer activity of trabectedin.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Clues to Bile Acid Patterns and Prolonged Survival in Patients with Metastatic Soft-Tissue Sarcoma Treated with Trabectedin

Miolo,

Buonadonna,

Scalone

et al. 2023

Metabolites

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Metastatic soft-tissue sarcomas (mSTS) encompass a highly heterogeneous group of rare tumours characterized by different clinical behaviours and outcomes. Currently, prognostic factors for mSTS are very limited, posing significant challenges in predicting patient survival. Within a cohort of 39 mSTS patients undergoing trabectedin treatment, it was remarkable to find one patient who underwent 73 cycles of trabectedin achieving an unforeseen clinical outcome. To identify contributing factors to her exceptional long-term survival, we have explored circulation metabolomics and biohumoral biomarkers to uncover a potential distinct host biochemical phenotype. The long-term survival patient compared with the other mSTS patients exhibited a distinctive metabolic profile characterized by remarkably higher levels of ursodeoxycholic acid (UDCA) derivatives and vitamin D and lower levels of lithocholic acid (LCA) derivatives, as well as reduced levels of inflammatory C-Reactive Protein 4 (C-RP4) biomarker. Despite its exploratory nature, this study reveals a potential association between specific bile acid metabolic profiles and mSTS patients’ prognosis. Enhanced clinical understanding of the interplay between bile acid metabolism and disease progression could pave the way for new targeted therapeutic interventions which may improve the overall survival of mSTS patients.

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Cancer: The Tumor-Driven Disease of the Host

Cited by 8 publications

References 11 publications

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

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

Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia

Metabolic Clues to Bile Acid Patterns and Prolonged Survival in Patients with Metastatic Soft-Tissue Sarcoma Treated with Trabectedin

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