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Review
. 2021 Aug;125(4):495-509.
doi: 10.1038/s41416-021-01393-y. Epub 2021 Apr 28.

Targeting obesity-related dysfunction in hormonally driven cancers

Maria M Rubinstein  1 , Kristy A Brown  2 , Neil M Iyengar  3
Affiliations
Review

Targeting obesity-related dysfunction in hormonally driven cancers

Maria M Rubinstein et al. Br J Cancer. 2021 Aug.

Abstract

Obesity is a risk factor for at least 13 different types of cancer, many of which are hormonally driven, and is associated with increased cancer incidence and morbidity. Adult obesity rates are steadily increasing and a subsequent increase in cancer burden is anticipated. Obesity-related dysfunction can contribute to cancer pathogenesis and treatment resistance through various mechanisms, including those mediated by insulin, leptin, adipokine, and aromatase signalling pathways, particularly in women. Furthermore, adiposity-related changes can influence tumour vascularity and inflammation in the tumour microenvironment, which can support tumour development and growth. Trials investigating non-pharmacological approaches to target the mechanisms driving obesity-mediated cancer pathogenesis are emerging and are necessary to better appreciate the interplay between malignancy, adiposity, diet and exercise. Diet, exercise and bariatric surgery are potential strategies to reverse the cancer-promoting effects of obesity; trials of these interventions should be conducted in a scientifically rigorous manner with dose escalation and appropriate selection of tumour phenotypes and have cancer-related clinical and mechanistic endpoints. We are only beginning to understand the mechanisms by which obesity effects cell signalling and systemic factors that contribute to oncogenesis. As the rates of obesity and cancer increase, we must promote the development of non-pharmacological lifestyle trials for the treatment and prevention of malignancy.

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Conflict of interest statement

M.M.R. and K.A.B. report no competing interests. N.M.I. reports consulting and speaking fees from Novartis and Seattle Genetics unrelated to this work.

Figures

Fig. 1
Fig. 1. Affects of Obesity on Insulin and Estrogen Signaling.
IR-A Insulin Receptor A, IR-B Insulin Receptor B, IGF-1 Insulin Growth Factor-1, IGF-2 Insulin Growth Factor 2, IGF-1R Insulin Growth Factor Receptor 1, SHBG Sex Hormone Binding Globulin, ER Estrogen receptor.
Fig. 2
Fig. 2. Effects of obesity on adipokine signalling.
ObR leptin binding receptor, HIF-1 hypoxia-inducible factor, TNF-alpha tumor necrosis factor alpha, IL-6 interleukin 6, TME tumor microenvironment.
Fig. 3
Fig. 3. Effects of obesity on oestrogen signalling.
AI aromatase inhibitor, GnRH gonadotropin releasing hormone, SERM selective estrogen receptor modulator (i.e; tamoxifen), SERDselectve receptor degrader (i.e.; fulvestrant), CDK4/6 cyclin dependent kinases 4 and 6 inhibitors, GPER G-coupled estrogen receptor.
Fig. 4
Fig. 4. Summary of mechanisms through which obesity promotes tumorigenesis.
HIF1α hypoxia- inducible factor 1- alpha, VEGF vascular endothelial growth factor, TNFα tumor necrosis factor alpha, IL-1β interleukin 1 beta, IL- 6 interleukin 6, COX-2 cyclooxygenase isoenzyme 2, IGFR- insuline-like growth factor receptor, JAK-STAT Janus kinases-signal transducer and activtor of transcription proteins, MAPK mitogen-activated protein kinase.
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