In recent decades, obesity has ceased to be seen merely as a cosmetic issue or a cardiovascular risk factor. Today we know that excess body fat is intimately linked to the development of numerous types of cancer. In a comprehensive review published by Konstantinos I. Avgerinos, Nikolaos Spyrou, Christos S. Mantzoros, and Maria Dalamaga in the journal Metabolism (2019), the authors delve into the emerging biological mechanisms that explain this association and offer a comprehensive view of how overweight can predispose tissues to malignant transformation. This study not only summarizes decades of research but also articulates new perspectives on how obesity acts as a systemic modulator of cancer risk.
The magnitude of the problem is alarming. It is estimated that 13.1% of cancers in women and 11.9% in men can be directly attributed to excess body weight. This figure translates into millions of cases worldwide, with a growing burden especially in industrialized countries. The link between obesity and cancer has been confirmed for at least 13 types of tumors, including endometrial, esophageal (adenocarcinoma), kidney, pancreatic, liver, gallbladder, colorectal, thyroid, postmenopausal breast, ovarian, stomach (cardia), multiple myeloma, and meningioma. These findings are not based on simple statistical correlations but on consistent and robust data from meta-analyses, prospective studies, clinical trials, and basic research.
One of the most thoroughly analyzed aspects in the article is the role of the insulin system and insulin-like growth factor I (IGF-1). Under conditions of obesity, insulin resistance induces hyperinsulinemia, which in turn reduces circulating levels of IGF-binding proteins, increasing the bioavailability of free IGF-1. Both insulin and IGF-1 directly stimulate cell proliferation, reduce apoptosis, and promote angiogenesis—fundamental processes in carcinogenesis. At the molecular level, these signals activate pathways such as PI3K/AKT/mTOR and MAPK, which drive tumor growth. Animal studies have shown that inhibiting mTOR significantly reduces the progression of obesity-induced tumors, reinforcing the importance of this pathway in the link between metabolism and cancer.
The authors also devote an important section to the hormonal dysfunction generated by adipose tissue. In particular, in postmenopausal women, fat tissue becomes the main site of conversion of androgens into estrogens via the enzyme aromatase. This increase in free estrogen levels stimulates cell proliferation in hormone-sensitive tissues such as the breast and endometrium. Furthermore, low levels of sex hormone-binding globulin (SHBG) in obese individuals increase the biologically active free fraction of these hormones, exacerbating their proliferative effect. In men, by contrast, obesity tends to lower testosterone levels, which may favor the emergence of more aggressive tumor phenotypes in prostate cancer.
Beyond hormonal factors, obesity is associated with chronic low-grade inflammation, mediated by macrophage infiltration into adipose tissue and the sustained secretion of pro-inflammatory cytokines such as TNF-α, IL-6, and leptin. These molecules not only alter systemic metabolism but also modify the tumor microenvironment, promoting cell proliferation, migration, angiogenesis, and resistance to apoptosis. In contrast, adiponectin—an anti-inflammatory hormone also produced by adipose tissue—drops significantly in obese individuals. Hypoadiponectinemia has been consistently linked with a higher risk of cancers such as colon, breast, endometrial, and prostate. The imbalance between leptin and adiponectin is, therefore, a hallmark of obesity-related adiposopathy in cancer.
A notable finding highlighted in the article is the role of the gut microbiome. In obese individuals, there is an alteration in bacterial composition, with a higher proportion of Firmicutes and lower proportion of Bacteroidetes. These changes can enhance energy extraction from food and, more concerningly, increase intestinal permeability. This “metabolic endotoxemia” allows bacterial lipopolysaccharides (LPS) to enter the bloodstream, activating Toll-like receptors (TLR4) and triggering inflammatory cascades that facilitate tumor initiation and promotion, particularly in the liver, colon, and pancreas. Studies in mice have shown that transferring the microbiome from obese animals can induce a tumor-prone phenotype even in lean animals, underscoring the causal impact of the microbial ecosystem.
Figure 1. Mechanisms by which obesity promotes cancer development. Excess body fat activates hormonal (IGF-1, estrogens), inflammatory (cytokines such as TNF-α and IL-6), adipokine imbalance (leptin/adiponectin), gut dysbiosis, and ectopic fat deposition pathways, increasing the risk of malignant transformation in multiple organs.
The article also explores less conventional factors, such as circadian rhythm disruption, which has been associated with a higher incidence of liver cancer—possibly due to hormonal and metabolic imbalances induced by desynchronization of the biological clock. In parallel, the role of ectopic fat deposition—especially in organs like the liver, pancreas, mammary tissue, and bone marrow—is analyzed. In these locations, fat acts as an inflammatory and endocrine reservoir that alters local cellular function, favoring mutations and malignant transformations.
In terms of somatometric indicators, the study notes that BMI is an insufficient measure to capture the complexity of adiposity and its oncological risks. Measures such as waist circumference (WC) and waist-to-hip ratio (WHR) have a closer correlation with visceral fat, which is the most metabolically active and oncogenic. Nevertheless, even these measurements may fall short in distinguishing subcutaneous from visceral fat. For this reason, the authors advocate for more precise techniques, such as computed tomography or magnetic resonance imaging, in specific population-based studies.
An additional dimension addressed by the authors is the so-called “obesity paradox,” a phenomenon in which some studies have observed better survival in patients with certain types of cancer—such as renal, metastatic colorectal, or non-small cell lung cancer. Although intriguing, this paradox likely reflects methodological biases such as exclusive use of BMI without assessing body composition, confounding factors like smoking, or even survival bias in retrospective studies. Current evidence does not yet allow for the conclusion that obesity is protective in certain oncological contexts.
From a public health perspective, this article delivers a powerful message: preventing and reversing obesity is not only a cardiovascular measure but also a cancer prevention strategy. Although intentional and sustained weight loss remains difficult to achieve, studies on bariatric surgery have shown significant reductions in the incidence of several types of cancer. In the long term, it will be essential to assess the impact of non-surgical interventions—such as dietary and exercise programs—on cancer risk, especially those that positively influence inflammation, insulin sensitivity, and hormone profiles.
In short, the work by Avgerinos and colleagues represents a fundamental contribution to the understanding of cancer as not only a genetic or environmental disease but also a metabolic one. Obesity, far from being an isolated condition, acts as a powerful modulator of the cellular microenvironment, affecting gene expression, endocrine signals, innate immunity, inflammation, and the microbiota. In a world where obesity rates continue to rise and where cancer prevention strategies still struggle to integrate metabolic factors into predictive models, this review is a timely call to reframe our clinical and societal priorities. Understanding this relationship is not only key to designing better treatments but also to preventing millions of cancer cases in future generations.
Main Reference:
Avgerinos, K. I., Spyrou, N., Mantzoros, C. S., & Dalamaga, M. (2019). Obesity and cancer risk: Emerging biological mechanisms and perspectives. Metabolism: clinical and experimental, 92, 121–135. https://doi.org/10.1016/j.metabol.2018.11.001
Other Reference:
Berger N. A. (2014). Obesity and cancer pathogenesis. Annals of the New York Academy of Sciences, 1311, 57–76. https://doi.org/10.1111/nyas.12416
Pischon, T., & Nimptsch, K. (2016). Obesity and Risk of Cancer: An Introductory Overview. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer, 208, 1–15. https://doi.org/10.1007/978-3-319-42542-9_1
Aleksandrova, K., Mozaffarian, D., & Pischon, T. (2018). Addressing the Perfect Storm: Biomarkers in Obesity and Pathophysiology of Cardiometabolic Risk. Clinical chemistry, 64(1), 142–153. https://doi.org/10.1373/clinchem.2017.275172
