Altered Plasma Fatty Acid Abundance Is Associated with Cachexia in Treatment-Naïve Pancreatic Cancer

Gumpper, Kristyn; Hart, Phil A.; Belury, Martha A.; Crowe, Olivia; Cole, Rachel M.; Pita-Grisanti, Valentina; Badi, Niharika; Liva, Sophia G.; Hinton, Alice; Coss, Christopher C.; Ramsey, Mitchell L.; Noonan, Anne M.; Conwell, Darwin L.; Cruz‐Monserrate, Zobeida

doi:10.3390/cells11050910

Cited by 7 publications

(10 citation statements)

References 53 publications

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“…It has been shown that abnormally high LIF expression in the tumor microenvironment can promote macrophage aggregation, which could secrete IL6 and IL-1α to induce muscle atrophy and cachexia [ 61 , 137 ]. It is well known that most patients with advanced PDAC are in a cachectic state [ 138 ], perhaps because LIF is highly expressed in the tumor cells, macrophages, and mast cells in the tumor microenvironment of PDAC patients [ 139 ]. In animal experiments, the removal of macrophages prevented and alleviated cachexia [ 140 ].…”

Section: Discussionmentioning

confidence: 99%

The Molecular Basis and Therapeutic Potential of Leukemia Inhibitory Factor in Cancer Cachexia

Zeng

Tong

Xiong

2022

Cancers

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Cachexia is a chronic metabolic syndrome that is characterized by sustained weight and muscle mass loss and anorexia. Cachexia can be secondary to a variety of diseases and affects the prognosis of patients significantly. The increase in inflammatory cytokines in plasma is deeply related to the occurrence of cachexia. As a member of the IL-6 cytokine family, leukemia inhibitory factor (LIF) exerts multiple biological functions. LIF is over-expressed in the cancer cells and stromal cells of various tumors, promoting the malignant development of tumors via the autocrine and paracrine systems. Intriguingly, increasing studies have confirmed that LIF contributes to the progression of cachexia, especially in patients with metastatic tumors. This review combines all of the evidence to summarize the mechanism of LIF-induced cachexia from the following four aspects: (i) LIF and cancer-associated cachexia, (ii) LIF and alterations of adipose tissue in cachexia, (iii) LIF and anorexia nervosa in cachexia, and (iv) LIF and muscle atrophy in cachexia. Considering the complex mechanisms in cachexia, we also focus on the interactions between LIF and other key cytokines in cachexia and existing therapeutics targeting LIF.

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Section: Discussionmentioning

confidence: 99%

The Molecular Basis and Therapeutic Potential of Leukemia Inhibitory Factor in Cancer Cachexia

Zeng

Tong

Xiong

2022

Cancers

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“…A recent report indicated that soft tissue changes are initiated in PDAC before skeletal muscle loss ( 19 ), and the significant loss of visceral adipose tissue has been observed in PDAC-CC ( 18 ). In a retrospective cohort study, PDAC-CC was associated with the accumulation of oleic acid in plasma, resulting from malnutritional compensatory mechanisms triggered by the lack of oleic acid uptake into tissue ( 105 ). In a pre-cachexia model, increased FA oxidation occurs before muscle mass reduction, suggesting that FA may serve as a dominant energy source in PDAC-CC ( 18 , 106 ).…”

Section: Eolt Hypothesis In Pdac-ccmentioning

confidence: 99%

“…In KPC and Kras LSLG12D/+ Trp53 f/f mice, adipose tissue browning is associated with increased UCP-1 expression and occurs prior to the onset of fat wasting, consistent with clinical observations ( 108 ). A few studies have suggested that fat loss is an early and precipitating event prior to muscle loss in PDAC-CC, even in the absence of muscle wasting ( 18 , 19 , 21 , 33 , 104 , 105 , 107 ). Clinical studies suggested that fat loss may serve as a driving force for cachexia mortality, emphasizing the important roles of adipocytes in PDAC-CC and supporting the need to monitor adipose in patients with CC ( 20 , 21 ).…”

Section: Eolt Hypothesis In Pdac-ccmentioning

confidence: 99%

“…PDAC-CC is initiated by a metabolic shift in fuel utilization, in which glycolysis, proteolysis, and lipolysis increase and lipogenesis and protein synthesis decrease ( Figure 4 ). During the pre-cachectic stage, patients experience these metabolic alterations as loss of appetite and impaired glucose metabolism before PDAC diagnosis or significant weight loss is apparent ( Figure 2 ) ( 19 , 67 , 105 ). Early inflammatory signals may trigger the initial muscle and adipocyte wasting signaling cascades ( 9 , 18 , 21 , 24 ).…”

Section: Eolt Hypothesis In Pdac-ccmentioning

confidence: 99%

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Review of the endocrine organ–like tumor hypothesis of cancer cachexia in pancreatic ductal adenocarcinoma

Ahmed

Lai

et al. 2022

Front. Oncol.

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of solid tumors, associated with a high prevalence of cachexia (~80%). PDAC-derived cachexia (PDAC-CC) is a systemic disease involving the complex interplay between the tumor and multiple organs. The endocrine organ–like tumor (EOLT) hypothesis may explain the systemic crosstalk underlying the deleterious homeostatic shifts that occur in PDAC-CC. Several studies have reported a markedly heterogeneous collection of cachectic mediators, signaling mechanisms, and metabolic pathways, including exocrine pancreatic insufficiency, hormonal disturbance, pro-inflammatory cytokine storm, digestive and tumor-derived factors, and PDAC progression. The complexities of PDAC-CC necessitate a careful review of recent literature summarizing cachectic mediators, corresponding metabolic functions, and the collateral impacts on wasting organs. The EOLT hypothesis suggests that metabolites, genetic instability, and epigenetic changes (microRNAs) are involved in cachexia development. Both tumors and host tissues can secrete multiple cachectic factors (beyond only inflammatory mediators). Some regulatory molecules, metabolites, and microRNAs are tissue-specific, resulting in insufficient energy production to support tumor/cachexia development. Due to these complexities, changes in a single factor can trigger bi-directional feedback circuits that exacerbate PDAC and result in the development of irreversible cachexia. We provide an integrated review based on 267 papers and 20 clinical trials from PubMed and ClinicalTrials.gov database proposed under the EOLT hypothesis that may provide a fundamental understanding of cachexia development and response to current treatments.

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“…For instance, cachectic cancer patients have both adipose tissue and skeletal muscle wasting ( 61 ). Interestingly, the overall plasma fatty acid levels seem to be maintained and only oleic acid is significantly higher in patients with cachexia ( 62 ).…”

Section: Body Climate: Factors and Components Relevant To Cancermentioning

confidence: 99%

The underexplored links between cancer and the internal body climate: Implications for cancer prevention and treatment

Paul

Nedelcu

2022

Front. Oncol.

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In order to effectively manage and cure cancer we should move beyond the general view of cancer as a random process of genetic alterations leading to uncontrolled cell proliferation or simply a predictable evolutionary process involving selection for traits that increase cell fitness. In our view, cancer is a systemic disease that involves multiple interactions not only among cells within tumors or between tumors and surrounding tissues but also with the entire organism and its internal “milieu”. We define the internal body climate as an emergent property resulting from spatial and temporal interactions among internal components themselves and with the external environment. The body climate itself can either prevent, promote or support cancer initiation and progression (top-down effect; i.e., body climate-induced effects on cancer), as well as be perturbed by cancer (bottom-up effect; i.e., cancer-induced body climate changes) to further favor cancer progression and spread. This positive feedback loop can move the system towards a “cancerized” organism and ultimately results in its demise. In our view, cancer not only affects the entire system; it is a reflection of an imbalance of the entire system. This model provides an integrated framework to study all aspects of cancer as a systemic disease, and also highlights unexplored links that can be altered to both prevent body climate changes that favor cancer initiation, progression and dissemination as well as manipulate or restore the body internal climate to hinder the success of cancer inception, progression and metastasis or improve therapy outcomes. To do so, we need to (i) identify cancer-relevant factors that affect specific climate components, (ii) develop ‘body climate biomarkers’, (iii) define ‘body climate scores’, and (iv) develop strategies to prevent climate changes, stop or slow the changes, or even revert the changes (climate restoration).

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Altered Plasma Fatty Acid Abundance Is Associated with Cachexia in Treatment-Naïve Pancreatic Cancer

Cited by 7 publications

References 53 publications

The Molecular Basis and Therapeutic Potential of Leukemia Inhibitory Factor in Cancer Cachexia

The Molecular Basis and Therapeutic Potential of Leukemia Inhibitory Factor in Cancer Cachexia

Review of the endocrine organ–like tumor hypothesis of cancer cachexia in pancreatic ductal adenocarcinoma

The underexplored links between cancer and the internal body climate: Implications for cancer prevention and treatment

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