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.

Insulin resistance causes inflammation in adipose tissue

“…Obesity-induced insulin resistance is a major risk factor for type 2 diabetes, hyperlipidemia, cardiovascular disease, and some types of cancer (1)(2)(3). Although the mechanism by which obesity causes insulin resistance is unclear, inflammation has been linked to the development of local and systemic insulin resistance, especially when the inflammation occurs in white adipose tissue (WAT) (4,5).…”

A link between TP53 polymorphisms and metabolism

“…In light of these findings it will be interesting to determine whether this SNP plays a role in cancers known to be linked to metabolic dysfunction, such as endometrial cancer or postmenopausal breast cancer. 10 These hypotheses await testing.…”

Tumor-extrinsic discoidin domain receptor 1 promotes mammary tumor growth by regulating adipose stromal interleukin 6 production in mice

“…Excessive adiposity has been linked to increased breast cancer recurrence and mortality in both pre-and post-menopausal women [1][2][3][4][5][6] . The underlying mechanisms of adiposity-associated cancer burden are likely multifactorial, including elevated production of hormones, cytokines, reactive oxygen species, and extracellular matrix (ECM).…”

“…Given the abundance of tumor-surrounding adipocytes in breast tissue, communication between tumor and mature adipocytes has naturally been the primary focus of mechanistic studies of obesity-related cancer burden [7][8][9] . However, it is increasingly evident that, in addition to mature adipocytes, altered abundance and properties of human adipose stem/stromal cells (ASCs) and elevated fibrosis contribute to tissue remodeling associated with tumor-associated adipose tissue 2,[10][11][12] .For example, we and others previously showed that human ASCs are a significant source of local estrogens that stimulate ERa+ breast tumor growth 11,[13][14][15] .…”

“…Emerging evidence indicates that adipose tissue-derived stem/progenitor cells are a significant source of stroma-secreted factors that have profound impact on tissue regeneration as well as pathogenesis including in cancer 2,35,36 . Obesity is a well-known factor associated with poor prognosis for multiple cancer types including breast cancer.…”