Emerging Concepts Linking Obesity with the Hallmarks of Cancer

Donohoe, Claire L.; Lysaght, Joanne; O'Sullivan, Jacintha; Reynolds, John V.

doi:10.1016/j.tem.2016.08.004

Cited by 103 publications

(97 citation statements)

References 128 publications

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“…A developing area of research within the broader field of cancer immunology is to determine whether obesity has a net positive or negative impact on specific facets of anti-tumor immunity, then discern the mechanisms by which obesity either diminishes or promotes protective anti-tumor mechanisms and tumor-promoting/ immunosuppressive factors. [120][121][122] We have found that in a preclinical model of orthotopic renal cancer, obesity is associated with an increased accumulation of regulatory dendritic cells within tumors. 123 When sort-purified, these CD11b+ dendritic cells were unable to activate naive CD8 T cells and induce their proliferation.…”

Section: Host Obesity Impedes Protective T Cell Responses To Solid mentioning

confidence: 99%

Obesity and CD8 T cell metabolism: Implications for anti‐tumor immunity and cancer immunotherapy outcomes

Turbitt

Rosean

Weber

et al. 2020

Immunological Reviews

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Obesity is an established risk factor for many cancers and has recently been found to alter the efficacy of T cell–based immunotherapies. Currently, however, the effects of obesity on immunometabolism remain unclear. Understanding these associations is critical, given the fact that T cell metabolism is tightly linked to effector function. Thus, any obesity‐associated changes in T cell bioenergetics are likely to drive functional changes at the cellular level, alter the metabolome and cytokine/chemokine milieu, and impact cancer immunotherapy outcomes. Here, we provide a brief overview of T cell metabolism in the presence and absence of solid tumor growth and summarize current literature regarding obesity‐associated changes in T cell function and bioenergetics. We also discuss recent findings related to the impact of host obesity on cancer immunotherapy outcomes and present potential mechanisms by which T cell metabolism may influence therapeutic efficacy. Finally, we describe promising pharmaceutical therapies that are being investigated for their ability to improve CD8 T cell metabolism and enhance cancer immunotherapy outcomes in patients, regardless of their obesity status.

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Section: Host Obesity Impedes Protective T Cell Responses To Solid mentioning

confidence: 99%

Obesity and CD8 T cell metabolism: Implications for anti‐tumor immunity and cancer immunotherapy outcomes

Turbitt

Rosean

Weber

et al. 2020

Immunological Reviews

View full text Add to dashboard Cite

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“…Hypoxia, TNF-a, and IL-6 Reduce the Cilium Length in ln-ASCs Obesity is characterized by hypoxia and increased pro-inflammatory factors like TNF-a and IL-6 (Donohoe et al, 2017). Murine bone marrow stromal cells have been reported to lose their cilia upon subjection to hypoxia (Proulx-Bonneau and Annabi, 2011).…”

Section: Deficient Hh Signaling In Ob-ascsmentioning

confidence: 99%

Primary cilia are dysfunctional in obese adipose-derived mesenchymal stem cells

Ritter

Friemel

Kreis

et al. 2018

Geburtshilfe Und Frauenheilkunde

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Adipose-derived mesenchymal stem cells (ASCs) have crucial functions, but their roles in obesity are not well defined. We show here that ASCs from obese individuals have defective primary cilia, which are shortened and unable to properly respond to stimuli. Impaired cilia compromise ASC functionalities. Exposure to obesity-related hypoxia and cytokines shortens cilia of lean ASCs. Like obese ASCs, lean ASCs treated with interleukin-6 are deficient in the Hedgehog pathway, and their differentiation capability is associated with increased ciliary disassembly genes like AURKA. Interestingly, inhibition of Aurora A or its downstream target the histone deacetylase 6 rescues the cilium length and function of obese ASCs. This work highlights a mechanism whereby defective cilia render ASCs dysfunctional, resulting in diseased adipose tissue. Impaired cilia in ASCs may be a key event in the pathogenesis of obesity, and its correction might provide an alternative strategy for combating obesity and its associated diseases.

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“…Local pro-tumorigenic effects of ASCs have been also highlighted as important in this process, with a dual role in the dynamics of WAT expansion and in tumor progression by inducing proliferation and survival of some cancer cells through the release of angiogeneic and proinflammatory factors. 9, 10 In this context, we have recently shown that the clinical phenotype exerts a profound influence on the behavior of ASCs, with enhanced proliferation but impaired adipogenic differentiation in ASCs isolated from obese subjects, 11 underscoring the notion that obesity is linked to defective adipocyte turnover. However, the apoptotic sensitivity of ASCs in an obese context is unknown.…”

mentioning

confidence: 99%

Survivin, a key player in cancer progression, increases in obesity and protects adipose tissue stem cells from apoptosis

et al. 2017

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Adipose tissue (AT) has a central role in obesity-related metabolic imbalance through the dysregulated production of cytokines and adipokines. In addition to its known risk for cardiovascular disease and diabetes, obesity is also a major risk for cancer. We investigated the impact of obesity for the expression of survivin, an antiapoptotic protein upregulated by adipokines and a diagnostic biomarker of tumor onset and recurrence. In a cross-sectional study of 111 subjects classified by body mass index, circulating levels of survivin and gene expression in subcutaneous AT were significantly higher in obese patients and positively correlated with leptin. Within AT, survivin was primarily detected in human adipocyte-derived stem cells (hASCs), the adipocyte precursors that determine AT expansion. Remarkably, survivin expression was significantly higher in hASCs isolated from obese patients that from lean controls and was increased by proinflammatory M1 macrophage soluble factors including IL-1β. Analysis of survivin expression in hASCs revealed a complex regulation including epigenetic modifications and protein stability. Surprisingly, obese hASCs showed survivin promoter hypermethylation that correlated with a significant decrease in its mRNA levels. Nonetheless, a lower level of mir-203, which inhibits survivin protein translation, and higher protein stability, was found in obese hASCs compared with their lean counterparts. We discovered that survivin levels determine the susceptibility of hASCs to apoptotic stimuli (including leptin and hypoxia). Accordingly, hASCs from an obese setting were protected from apoptosis. Collectively, these data shed new light on the molecular mechanisms governing AT expansion in obesity through promotion of hASCs that are resistant to apoptosis, and point to survivin as a potential new molecular player in the communication between AT and tumor cells. Thus, inhibition of apoptosis targeting survivin might represent an effective strategy for both obesity and cancer therapy.

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Emerging Concepts Linking Obesity with the Hallmarks of Cancer

Cited by 103 publications

References 128 publications

Obesity and CD8 T cell metabolism: Implications for anti‐tumor immunity and cancer immunotherapy outcomes

Obesity and CD8 T cell metabolism: Implications for anti‐tumor immunity and cancer immunotherapy outcomes

Primary cilia are dysfunctional in obese adipose-derived mesenchymal stem cells

Survivin, a key player in cancer progression, increases in obesity and protects adipose tissue stem cells from apoptosis

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