Obesity and cancer--mechanisms underlying tumour progression and recurrence

Abstract

Over the past several years, the field of cancer research has directed increased interest towards subsets of obesity-associated tumours, which include mammary, renal, oesophageal, gastrointestinal and reproductive cancers in both men and women. The increased risk of breast cancer that is associated with obesity has been widely reported; this has drawn much attention and as such, warrants investigation of the key mechanisms that link the obese state with cancer aetiology. For instance, the obese setting provides a unique adipose tissue microenvironment with concomitant systemic endocrine alterations that favour both tumour initiation and progression. Major metabolic differences exist within tumours that distinguish them from non-transformed healthy tissues. Importantly, considerable metabolic differences are induced by tumour cells in the stromal vascular fraction that surrounds them. The precise mechanisms that underlie the association of obesity with cancer and the accompanying metabolic changes that occur in the surrounding microenvironment remain elusive. Nonetheless, specific therapeutic agents designed for patients with obesity who develop tumours are clearly needed. This Review discusses recent advances in understanding the contributions of obesity to cancer and their implications for tumour treatment.

Figure 1

Reciprocal signalling between cancer-associated adipocytes and cancer cells. Crosstalk between cancer-associated adipocytes and cancer cells within the tumour microenvironment is crucial for creation of a niche that is permissive for cancer cell growth and metastasis. Cancer cells stimulate lipolysis in adipocytes, which leads to delipidation and acquisition of a fibroblast-like phenotype in adipocytes. These alterations in cancer-associated adipocytes are associated with functional changes in the cells, such as loss of adipogenic markers, increased secretion of inflammatory cytokines and proteases, and increased release of free fatty acids, all of which support aggressive tumour growth and invasiveness.

Figure 2

Potential consequences of obesity-induced dysfunction of adipose tissue on tumour initiation, progression and recurrence. Obesity leads to development of dysfunctional adipose tissue, which produces abundant levels of proinflammatory cytokines, sex hormones and lipid metabolites, along with altered adipokine profiles. The altered adipose tissue is a source of various ECM proteins, cancer stem cells, cancer-associated adipocytes and adipocyte progenitors. Each of these factors contributes to various stages of tumour progression, including initiation, growth and recurrence. Obesity-associated systemic metabolic changes, such as hyperinsulinaemia and hyperglycaemia, also contribute to a tumour-permissive environment. Abbreviation: ECM, extracellular matrix.