The role of cytokines in cancer cachexia

Argilés, Josep Μ.; Busquets, Sı́lvia; Toledo, Míriam; López‐Soriano, Francisco J.

doi:10.1097/spc.0b013e3283311d09

Cited by 169 publications

(105 citation statements)

References 57 publications

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“…The mechanisms, by which these cytokines influence the disease progression and outcome, are complex and multifactorial [43]. Importantly, it was shown that IL-1, TNF-α and IL-6 are responsible for development of symptoms, characteristic for cancer like anorexia, anemia, altered energy metabolism, weight loss, depression and fatigue and non-responsiveness to chemotherapy [43,[45][46][47]. Elevated IL-6 levels, present in the EOC serum and malignant ascites, were associated to residual disease after debulking and to disease recurrence [48,49].…”

Section: Discussionmentioning

confidence: 99%

Assessment of Cytokine mRNA Expression Profiles in Tumor Microenvironment and Peripheral Blood Mononuclear Cells of Patients with High-grade Serous Carcinoma of the Ovary

Israelsson¹,

Labani‐Motlagh²,

Nagaev³

et al. 2017

J Cancer Sci Ther

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Objective: Tumor establishment, metastatic spreading and poor survival in ovarian cancer is strongly associated with progressive derangement of the patient's immune system. Accumulating evidence suggests that immune impairment is influenced by the production and presence of cytokines in the tumor microenvironment.Methods: Cytokine mRNA profiles in tumor tissue and peripheral blood mononuclear cells (PBMC) were analyzed in patients with high grade serous carcinoma (HGSC) of the ovary and compared it to patients with benign ovarian conditions and controls with normal ovaries. Cytokine assessment was done by real-time quantitative RT-PCR and specific primers and probes for 12 cytokines-IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-15, TNF-α, TNF-β/LTA, TGF-β1, and GM-CSF chosen to distinguish between cytotoxic Th1, humoral Th2, regulatory Th3/Tr1 and inflammatory responses. Results:The cytokine mRNA response in the HGSC patients was significantly up regulated compared to patients with benign ovarian conditions and normal ovary controls confirming the immunogenicity of HGSC and implying immune recognition and reaction locally in the tumor microenvironment and systemically in the peripheral blood.There was an up-regulation of inflammatory and inhibitory cytokine mRNA promoting tumor progression, T-regulatory cell priming and T-regulatory cell-mediated immune suppression. In contrast, there was an inability to mount the crucially important IFN gamma response needed for upregulation of the cytotoxic anti-tumor response in the local microenvironment. In addition, systemic IL-4-mediated Th2 response prevailed in the peripheral blood deviating the systemic defense towards humoral immunity. Conclusions:Taken together, these results suggest local and systemic cytokine cooperation promoting tumor survival, progression and immune escape. Our study confirms and extends previous investigations and contributes to the evaluation of potential cytokine candidates for diagnostic cytokine mRNA profiles and for future therapeutic interventions based on cytokine inhibition.

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Section: Discussionmentioning

confidence: 99%

Assessment of Cytokine mRNA Expression Profiles in Tumor Microenvironment and Peripheral Blood Mononuclear Cells of Patients with High-grade Serous Carcinoma of the Ovary

Israelsson¹,

Labani‐Motlagh²,

Nagaev³

et al. 2017

J Cancer Sci Ther

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“…We hypothesise that the reason for such an increase might be related with the participation of PPARg and TNF-a as upstream mediators of haptoglobin production. Cancer cachexia induces a scenario with elevated levels of pro-inflammatory cytokines (Argiles et al 2009, including TNF-a, which in turn could inhibit PPARg expression and activity but stimulate haptoglobin expression. In this regard, increased levels of gene and protein expression of TNF-a in MEAT of Walker 256 tumour-bearing rats is well characterised (Machado et al 2004.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous time-dependent response of adipose tissue during the development of cancer cachexia

Batista¹,

Neves²,

Peres³

et al. 2012

Journal of Endocrinology

101

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Cancer cachexia induces loss of fat mass that accounts for a large part of the dramatic weight loss observed both in humans and in animal models; however, the literature does not provide consistent information regarding the set point of weight loss and how the different visceral adipose tissue depots contribute to this symptom. To evaluate that, 8-week-old male Wistar rats were subcutaneously inoculated with 1 ml (2!10 7 ) of tumour cells (Walker 256). Samples of different visceral white adipose tissue (WAT) depots were collected at days 0, 4, 7 and 14 and stored at K80 8C (seven to ten animals/each day per group). Mesenteric and retroperitoneal depot mass was decreased to the greatest extent on day 14 compared with day 0. Gene and protein expression of PPARg2 (PPARG) fell significantly following tumour implantation in all three adipose tissue depots while C/EBPa (CEBPA) and SREBP-1c (SREBF1) expression decreased over time only in epididymal and retroperitoneal depots. Decreased adipogenic gene expression and morphological disruption of visceral WAT are further supported by the dramatic reduction in mRNA and protein levels of perilipin. Classical markers of inflammation and macrophage infiltration (f4/80, CD68 and MIF-1a) in WAT were significantly increased in the later stage of cachexia (although showing a incremental pattern along the course of cachexia) and presented a depot-specific regulation. These results indicate that impairment in the lipid-storing function of adipose tissue occurs at different times and that the mesenteric adipose tissue is more resistant to the 'fat-reducing effect' than the other visceral depots during cancer cachexia progression.

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“…There is an increase in pro-inflammatory cytokine activity during cancer progression [24,25] , and systemic inflammation is a hallmark of cancer cachexia, indicated by the production of acute-phase response (APR) proteins such as C-reactive protein (CRP) and fibrinogen [26,27] . CRP is considered to be an accurate measure of the pro-inflammatory cytokine activity [28] that has been implicated in muscle wasting [29] .…”

Section: Inflammationmentioning

confidence: 99%

Cancer cachexia, mechanism and treatment

Aoyagi¹,

Terracina²,

Ali³

et al. 2015

WJGO

369

282

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It is estimated that half of all patients with cancer eventually develop a syndrome of cachexia, with anorexia and a progressive loss of adipose tissue and skeletal muscle mass. Cancer cachexia is characterized by systemic inflammation, negative protein and energy balance, and an involuntary loss of lean body mass. It is an insidious syndrome that not only has a dramatic impact on patient quality of life, but also is associated with poor responses to chemotherapy and decreased survival. Cachexia is still largely an underestimated and untreated condition, despite the fact that multiple mechanisms are reported to be involved in its development, with a number of cytokines postulated to play a role in the etiology of the persistent catabolic state. Existing therapies for cachexia, including orexigenic appetite stimulants, focus on palliation of symptoms and reduction of the distress of patients and families rather than prolongation of life. Recent therapies for the cachectic syndrome involve a multidisciplinary approach. Combination therapy with diet modification and/or exercise has been added to novel pharmaceutical agents, such as Megestrol acetate, medroxyprogesterone, ghrelin, omega-3-fatty acid among others. These agents are reported to have improved survival rates as well as quality of life. In this review, we will discuss the emerging understanding of the mechanisms of cancer cachexia, the current treatment options including multidisciplinary combination therapies, as well an update on new and ongoing clinical trials.

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The role of cytokines in cancer cachexia

Abstract: The main aim of the present review is to summarize and evaluate the different molecular mechanisms and catabolic mediators (mainly cytokines) involved in cancer cachexia since they may represent targets for future promising clinical investigations.

Cited by 169 publications

References 57 publications

Assessment of Cytokine mRNA Expression Profiles in Tumor Microenvironment and Peripheral Blood Mononuclear Cells of Patients with High-grade Serous Carcinoma of the Ovary

Assessment of Cytokine mRNA Expression Profiles in Tumor Microenvironment and Peripheral Blood Mononuclear Cells of Patients with High-grade Serous Carcinoma of the Ovary

Heterogeneous time-dependent response of adipose tissue during the development of cancer cachexia

Cancer cachexia, mechanism and treatment

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