Despite the established link between obesity and cancer, the molecular mechanisms remain under investigation.
Obesity is characterised by excess fat storage and adipocyte mass, leading to local changes (chronic low-grade inflammation, altered adipokine/cytokine secretion) and systemic disorders (insulin imbalance, IGF-I axis abnormalities, changes in hormone biosynthesis, and inflammation-related mediators like IL-1β, TNF-α, and IL-6).
These factors can impact cancer cell survival and proliferation, influencing both the tumour phenotype and its microenvironment. Key mechanisms include:
Inflammation: Chronic inflammation in adipose tissue promotes tumour initiation, growth, angiogenesis and metastasis leading to poorer outcomes and reduced therapeutic response. Obesity-induced adipocyte hyperplasia/hypertrophy and death trigger the release of inflammatory molecules and macrophage infiltration creating a pro-inflammatory state sustained by a paracrine loop involving macrophages and adipocytes
Insulin/IGF-1 Axis: Obesity, particularly visceral fat, contributes to insulin resistance, hyperinsulinemia and hyperglycaemia. Insulin and IGF-1 promote carcinogenesis through direct and indirect pathways including the Ras/Raf/ERK and PI3K/Akt/mTOR signalling cascades.
Adipokines: Adiponectin and leptin, key adipokines, play significant roles in obesity-related tumorigenesis. Low adiponectin levels are linked to obesity and insulin resistance, while high leptin levels correlate with poor cancer prognosis.
Various cancers
Obesity significantly increases colorectal (CRC) risk. A meta-analysis of 12,837 CRC cases showed that abdominal obesity, measured by waist circumference (WC) and waist-to-hip ratio (WHR), raises CRC risk equally across genders and regions. Greater WC and WHR were linked to higher risks for total colorectal, colon and rectal cancers.
Obese CRC patients also face higher all-cause and cancer-specific mortality, disease recurrence, and worse disease-free survival. Even moderate weight gain increases CRC risk, especially in men. High BMI in individuals under 30 is also associated with higher CRC risk. Elevated leptin levels in obese individuals further connect obesity to CRC.
Obesity significantly increases the incidence and mortality of breast cancer, especially in postmenopausal women. Studies show that overweight and obese women are more likely to develop hormone receptor-positive and HER2-negative breast cancer, as well as more aggressive types like triple-negative breast cancer (TNBC).
A meta-analysis of 12 studies with 22,728,674 women reported a 2% increase in breast cancer risk for every 5kg/m² rise in BMI among postmenopausal women, whereas a higher BMI might be protective for premenopausal women.
Obesity increases the risk of cervical cancer, as shown in a study of over 900,000 women, where obese women had the highest five-year cumulative risk of cancer. Maintaining a healthy BMI and regular physical activity can reduce cervical cancer risk. A Korean study found that class II obesity significantly increased cervical cancer risk, regardless of menopausal status.
Studies show that visceral adiposity, rather than BMI alone, increases the risk of ovarian cancer. A 2019 study involving 6,681,795 participants found that higher BMI, especially from early adulthood, raises ovarian cancer risk.
Endometrial cancer is strongly associated with obesity. A meta-analysis of over 22,300 cases found that higher BMI significantly increases endometrial cancer risk. This association is independent of factors like diabetes, hormone therapy and reproductive history.
Assessment and prevention
Traditional BMI measurement is insufficient to distinguish between subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), which have different implications for cancer. VAT is more metabolically active, produces more adipokines, and is closely associated with internal organs, making it more relevant for cancer development. Advanced imaging techniques like CT and MRI are recommended for assessing VAT in cancer patients.
Leptin (a 16-kDa hormone) regulates food intake, energy expenditure, immune response and reproductive processes. In cancer, leptin binds to its receptor (ObR), part of the class 1 cytokine receptor family, influencing cell proliferation, metastasis, angiogenesis, and chemoresistance. Leptin is well-known for its significant role in the biology of various cancers, although its function in lung cancer remains debated and is still being studied.
High-grade breast cancer has been shown to exhibit overexpression of leptin and its receptor (ObR), which is associated with poor prognosis and increased risk of distant metastasis.
A documented positive correlation exists between circulating leptin levels and the risk of endometrial cancer. Some studies have reported higher levels of leptin and its receptor (Ob/ObR) in endometrial cancer tissues compared to normal endometrial tissues.
Future therapeutics
In addition to its vital physiological functions, leptin plays a significant role in tumour development and progression. Consequently, there is an increasing need to design new therapies that can disrupt leptin signalling in cancer. Over the past few decades, various leptin-related agonists and antagonists have been developed. Among these, leptin mutants, leptin receptor antagonists, and neutralising antibodies have shown considerable promise.
A small peptide based on the wild-type sequence of the leptin binding site I (LDFI), synthesised by Andò et al. in 2015, competes with leptin to block its receptor signalling, showing significant results in various cancers, including breast cancer, seminoma and glioblastoma.
Inhibition of leptin signalling correlates with decreased cell proliferation and tumour growth, as evidenced by xenograft experiments. Another ObR antagonist, Aca1, reverses the mitogenic and angiogenic effects in glioma cell lines on endothelial cells.
Specific anti-leptin-receptor monoclonal antibodies (anti-LR mAbs) may be more efficient due to their high molecular mass and longer circulation half-life.
Key messages
- Obesity is linked to increased risk and mortality in various cancers, including colorectal, breast, and gynaecological cancers
- Adipose tissue, through its chronic inflammation, drives the obesity-cancer connection
- Understanding the mechanisms connecting obesity and cancer could lead to novel biomarkers and therapeutic interventions.
– References available on request
Author competing interests – nil