The obese adipose tissue microenvironment in cancer development and progression

Abstract

Obesity is associated with both increased cancer incidence and progression in multiple tumour types, and is estimated to contribute to up to 20% of cancer-related deaths. These associations are driven, in part, by metabolic and inflammatory changes in adipose tissue that disrupt physiological homeostasis both within local tissues and systemically. However, the mechanisms underlying the obesity–cancer relationship are poorly understood. In this Review, we describe how the adipose tissue microenvironment (ATME) evolves during body-weight gain, and how these changes might influence tumour initiation and progression. We focus on multiple facets of ATME physiology, including inflammation, vascularity and fibrosis, and discuss therapeutic interventions that have the potential to normalize the ATME, which might be translationally relevant for cancer prevention and therapy. Given that the prevalence of obesity is increasing on an international scale, translational research initiatives are urgently needed to provide mechanistic explanations for the obesity–cancer relationship, and how to best identify high-risk individuals without relying on crude measures, such as BMI.

Key points

  • Obesity is associated with increased cancer incidence and mortality.

  • Substantial changes occur within the adipose tissue microenvironment (ATME) with body-weight gain.

  • Metabolic and inflammatory changes related to the obese ATME contribute to cancer development and progression.

  • Targeting adipose tissue dysfunction through pharmacological or lifestyle interventions might be useful for the prevention and treatment of cancer.

  • Given the limitations of BMI as a measurement of adiposity, finding novel ways to identify individuals who are metabolically unhealthy with excess adipose tissue will be critical to pinpoint those at risk who might benefit from weight loss or other personalized interventions.

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Fig. 1: Major adipose depots and anatomical locations in adult humans and mice.
Fig. 2: Evolution of the adipose tissue microenvironment during obesity.
Fig. 3: Interactions between tumour cells and cells within the obese adipose tissue microenvironment.
Fig. 4: Vascular inflammation and fibrosis in the obese adipose tissue microenvironment.

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Acknowledgements

The authors thank Oakley C. Olson, Martin J. Richer and Azadeh Arabzadeh for their critical feedback on the manuscript. A.J.D. is supported by the Breast Cancer Research Foundation, the Botwinick-Wolfensohn Foundation (in memory of Mr and Mrs Benjamin Botwinick), NIH/NCI R01 CA215797 and NIH/NCI U54 CA210184. D.F.Q. is supported by Susan G. Komen CCR18548032 and Canadian Institutes of Health Research PJT-159742.

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D.F.Q and A.J.D. researched data for the article, contributed to the discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission. Both authors contributed equally to this work.

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Glossary

Adipocyte hypertrophy

Enlargement of adipocytes, which often occurs in association with obesity and increased numbers of crown-like structures in adipose tissue.

Metabolically obese normal-weight

(MONW). Individuals within a normal-range BMI category (18.5–24.9), yet with a high body fat composition, leading to qualitatively similar health risks as individuals who are obese.

Adipose tissue microenvironment

(ATME). The cellular and structural compartment of adipose tissue, including but not limited to the adipocyte.

Pyroptosis

Inflammatory programmed cell death, in which an immune cell bursts to release intracellular contents into the microenvironment to trigger a rapid immune response.

Myelopoiesis

Differentiation of haematopoetic progenitor cells within the bone marrow towards a myeloid lineage.

Monocytosis

Expansion of monocytes within the peripheral blood, which are precursors for macrophages and dendritic cells.

Crown-like structures

(CLS). A dying or dead adipocyte surrounded by a ‘crown’ of macrophages within adipose tissue; this structure is a histological biomarker of obesity-associated inflammation and the metabolic syndrome.

Metabo-inflammation

Inflammation within the adipose tissue microenvironment that has metabolic consequences irrespective of BMI status.

Benign breast disease

Heterogeneous group of lesions within the breast that might increase the risk of developing breast cancer.

CLS-associated macrophages

(CAMϕ). Macrophages that are directly associated with crown-like structures (CLS) in inflamed adipose tissue; these cells are phenotypically and transcriptionally distinct from other macrophages within the adipose tissue microenvironment.

Myofibroblasts

Contractile cells of the mesenchymal-fibroblast lineage that synthesize extracellular matrix and mediate tissue remodelling.

Adipose stromal cells

(ASCs). Multipotent mesenchymal progenitor cells found in adipose tissue that can differentiate into mesoderm lineages (such as adipocytes, myofibroblasts, chondrocytes and osteoblasts); several terms have been used in the literature to refer to these cells (for example, adipose-derived stem cells, pre-adipocytes, adipose mesenchymal stem cells or lipoblasts).

Neutrophilia

High number of mature neutrophils within the peripheral blood or within tissues, resulting from neutrophil leukocytosis.

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Quail, D.F., Dannenberg, A.J. The obese adipose tissue microenvironment in cancer development and progression. Nat Rev Endocrinol 15, 139–154 (2019). https://doi.org/10.1038/s41574-018-0126-x

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