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Obesity increases risk of 13 to 18 Cancers - April 2025

Seminars in Cancer Biology Vitamin D: What role in obesity-related cancer?
https://doi.org/10.1016/j.semcancer.2025.03.007 All references are online
Pierrick Martinez a 1, William B. Grant b 2

Obesity is an important risk factor for incidence and death for many types of cancer. Vitamin D reduces risk of incidence and death for many types of cancer. This review outlines the mechanisms by which obesity increases risk of cancer, how vitamin D reduces risk of cancer, and the extent to which vitamin D counters the effects of obesity in cancer. Vitamin D is a partial ally against some of obesity's pro-carcinogenic effects, notably by reducing inflammation and regulating sex hormone receptors, leptin resistance, cellular energy metabolism, the microbiome, and hypoxia. However, it can act stronger in against the renin-angiotensin system, insulin resistance, and oxidative stress in cancer. Additionally, excess fat tissue sequesters vitamin D and, along with its dilution in increased body volume, further reduces its bioavailability and serum concentration, limiting its protective effects against cancer. In conclusion, while vitamin D cannot reverse obesity, it plays a significant role in mitigating its pro-carcinogenic effects by targeting several mechanisms.

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Introduction

The global prevalence of obesity has been increasing at an alarming rate, more than one billion people worldwide live with obesity as of 2022 [1]. This increase impacts all age groups and income levels, with notable growth observed in high-income countries and urban areas of low- and middle-income nations, driven by lifestyle changes such as higher consumption of calorie-dense foods and reduced physical activity. These are recognized risk factors for several types of cancer, primarily due to complex biological mechanisms. Obesity is estimated to contribute to approximately 4–8% of all cancer cases, ranging from less than 1% in low-income countries to 7–8% in high-income countries [2]. For example, recent data from the National Health and Nutrition Examination Survey (NHANES) indicate a notable increase in obesity rates among non-Hispanic white (NHW) adults in the U.S. Between 1999–2000 and 2015–2016, obesity among NHW men aged 20 and older climbed from an average of 26.6% to 38.0%. Similarly, rates for NHW women rose from 33.5% to 41.5% over the same period [3]. Vitamin D is essential for overall health, supporting numerous physiological processes necessary for the body to function optimally, and it acts much like a hormone. Well-known for its role in bone health, vitamin D regulates calcium and contributes to immune system balance, helping to defend against infections and reduce inflammation. Research suggests that sufficient concentrations of 25(OH)D may lower the risk of many chronic diseases, including cancer. In fact, multiple meta-analyses of prospective observational studies strongly indicate that low vitamin D intake is associated with an increased risk of several types of cancer (see Table 6 of [4]). Recent meta-analyses of prospective observational studies? underscore the strong association between obesity and an elevated risk of multiple cancer types, including endometrial, colorectal, postmenopausal breast, kidney, and liver cancers [5]. Furthermore, weight gain over time has been linked to a heightened cancer risk, while excess body weight at diagnosis is associated with poorer cancer prognosis and reduced overall survival. Indeed, obesity is associated with a 17% increased risk of cancer-specific mortality [6]. In this review, we begin by examining the links between obesity and cancer, focusing on obesity-related cancer types and their underlying biological mechanisms. This is followed by an overview of the biological and metabolic pathways involved in vitamin D synthesis, as well as a discussion of vitamin D’s known anticancer mechanisms. We then explore the specific mechanisms that vitamin D can target in obesity-related cancers, along with those it may only partially affect or not influence at all. The review also summarizes epidemiological studies connecting vitamin D, obesity, and cancer, and offers recommendations for addressing vitamin D deficiency in obese individuals to optimize supplementation. We conclude by discussing the potential synergy between vitamin D and other treatments.

Section snippets

Obesity and Cancer: An Established Link
A recent study suggested that certain biological mechanisms impact cancer development: for breast cancer, reduced levels of sex-hormone-binding globulin and hormonal influences; for colorectal cancer, factors like steroid hormones and chronic inflammation; and for renal cell carcinoma, elevated estrogen levels [7]. However, in light of the understanding of the mechanisms whereby obesity increases risk of cancer in the present study, there are many more mechanisms. Indeed, there are many . . . .
Mechanisms of obesity as risk factors for cancer
1.Increased Inflammation:
Obesity leads to chronic inflammation, which promotes genetic mutations in normal tissues and activates epigenetic changes in epithelial cells. Cytokines released during inflammation can also expand the pool of cancer stem cells, thereby increasing cancer risk. Obesity increases oxidative stress (↑ROS and ↓antioxidant) [27]. Beyond cytokine-driven inflammation, obesity-induced oxidative stress is closely linked to mitochondrial dysfunction, which plays a pivotal role in . . . . .

Synthesis and metabolism of vitamin D
Vitamin D exists in two primary forms: Vitamin D (ergocalciferol) and Vitamin D3 (cholecalciferol). The latter is synthesized in the skin upon exposure to solar ultraviolet B (UVB) radiation (290-320 nm), which converts 7-dehydrocholesterol into pre-vitamin D3. Pre-vitamin D3 then undergoes a thermal isomerization to form Vitamin D3. Alternatively, both Vitamin D2 and D3 can be obtained from dietary sources. Once in the bloodstream, Vitamin D3 is transported to the liver, where it undergoes its . . . .

Mechanisms: How Vitamin D May Influence Obesity-Related Cancer risk
Obesity can have a direct impact on 25(OH)D concentrations. For example, a meta-analysis found that vitamin D deficiency is 35% more prevalent in individuals with obesity and 24% more common in those who are overweight [159]. Low plasma 25(OH)D concentrations are strongly associated with a higher prevalence of obesity across age groups, including children and adults [160], [161]. Moreover, low vitamin D intake may predict future obesity and metabolic syndrome [162]. This section on the . . . .

Clinical and Epidemiological Studies
Studies Linking Vitamin D, Obesity, and Cancer
Results from the VITAL study [152] in comparison with the 25(OH)D concentration-breast cancer risk shown in Fig. 1 in [235] can be used to determine whether obesity increases the serum 25(OH)D concentration required to combat cancer. From Table 2 in (3), the hazard ratio for invasive cancer was 0.76 (95% CI, 0.63single bond0.90) for BMI <25 kg/m2, 1.04 (95% CI, 0.90single bond1.21) for BMI 25 to <30 kg/m2, and 1.13 (95% CI, 0.94single bond1.37) for BMI >30 kg/m2. From Figure S1(B) in . . . .

Clinical and Therapeutic Implications
Optimization of doses to correct deficiencies in obese cancer individuals.
Many studies have shown that obesity is associated with significantly lower serum total 25(OH)D concentrations, likely due to reduced bioavailability of fat-soluble vitamin D and its storage in adipose tissue [239], [240], [241], [242]. For instance, the VITAL study reported that participants with obesity had lower mean serum total 25(OH)D concentrations at 1 year of supplementation (38.6 ng/mL) compared to those with . . . .

Conclusion
In this review, we have highlighted the anticancer effects that vitamin D may have on cancer-related risk factors associated with obesity. In summary, vitamin D is a partial ally against some of obesity's pro-carcinogenic effects, notably by reducing inflammation and regulating sex hormone receptors, leptin resistance, cellular energy metabolism, the microbiome, and hypoxia. However, it can act stronger in against the renin-angiotensin system, insulin resistance, and oxidative stress in cancer.

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VitaminDWiki - 35+ studies: weight loss augmented by Vitamin D

The Impact of Obesity on Cancer Risk: (by Perplexity AI)

Perplexity AI Deep Research - April 2025
Obesity is increasingly recognized as a major risk factor for multiple cancer types, with significant implications for public health. Current evidence indicates that obesity is the second biggest cause of cancer in the UK, accounting for more than 1 in 20 cancer cases [1]. In the United States, obesity contributes to approximately 5% of cancers in men and 11% in cancers in women, and is linked to about 7% of all cancer deaths [12]. Recent research suggests obesity is on track to overtake smoking as the leading cause of cancer, contributing to 40% of all cancer cases diagnosed in the United States in 2025 [13]. This report provides a comprehensive assessment of the specific cancer types affected by obesity and quantifies the associated risk increases.

13-18 Cancer Types Linked to Obesity

Research has established clear connections between obesity and numerous cancer types, with varying strengths of association. The list of cancer types with confirmed links to obesity has expanded over time, from previously established 13 types to as many as 18 cancer types according to recent research [2].

These cancer types have substantial evidence linking them to obesity:

Endometrial (Uterine) Cancer: 200% increase

Endometrial cancer shows one of the strongest associations with obesity among all cancer types. Compared to women of healthy weight, endometrial cancer is twice as common in overweight women (BMI 25-29.9) and more than three times as common in women with obesity (BMI ≥30) [11]. Studies indicate that over 50% of endometrial cancers are directly attributable to obesity [11].

Colorectal Cancer: 32% increase

Overweight and obese individuals have approximately 18% and 32% greater risk of colorectal cancer, respectively, compared to those with normal weight [5]. For colorectal adenomas, which are precursors to most colorectal cancers, the risk increases by more than 40% for both overweight and obese individuals [5]. A large cohort study found a relative risk of 1.05 (95% CI, 1.03–1.07) for participants with obesity [10]. Additionally, central obesity (measured by waist-to-hip ratio) appears to be a stronger predictor of colorectal cancer risk than BMI alone, with hazard ratios of 1.18 (1.14–1.22) per standard deviation increase in waist-to-hip ratio [15].

Postmenopausal Breast Cancer: 60% increase

The relationship between obesity and breast cancer differs by menopausal status. For postmenopausal women, studies show a 20%-60% higher breast cancer risk in those who are overweight or obese compared to women with normal weight [14]. A meta-analysis found a pooled odds ratio of 1.26 (95% CI: 1.19–1.34), indicating a 26% increased risk for obese postmenopausal women [4]. Interestingly, for premenopausal women, being overweight or obese is associated with a 10%-20% lower risk of breast cancer [14].

Esophageal Cancer

Esophageal adenocarcinoma shows a strong association with obesity, though specific risk percentages were not provided in the search results [7] [12].

Kidney Cancer

Kidney cancer risk is significantly elevated in individuals with obesity, with obesity accounting for a substantial number of kidney cancer cases [3] [7] [12].

Liver Cancer

While specific risk percentages for liver cancer were not detailed in the search results, it is consistently listed among cancers with established links to obesity [7] [12].

Pancreatic Cancer

Pancreatic cancer appears on multiple lists of obesity-related cancers, indicating a consistent association [7] [12].

6 other Cancers linked to Obesity

These cancers also show associations with obesity:
- Gallbladder cancer [7] [12]
- Stomach cancer [7] [12]
- Thyroid cancer [7] [12]
- Ovarian cancer [12]
- Multiple myeloma [12]
- Meningioma (tumor of the lining of the brain and spinal cord) [12]

Emerging Evidence for 6 more Cancers

Recent research suggests potential links between obesity and:
- Leukemia [2] [3]
- Non-Hodgkin lymphoma [2] [12]
- Bladder cancer (particularly among non-smokers) [2]
- Male breast cancer [12]
- Cancers of the mouth, throat, and voice box [12]
- Aggressive forms of prostate cancer [7] [12]

General Risk Increase by BMI Category

Research demonstrates a dose-response relationship between body mass index (BMI) and cancer risk:

For Women: 18%

- BMI 25-29.9: 8% higher risk of developing cancer
- BMI 30-34.9: 18% higher risk
- BMI 35-39.9: 32% higher risk
- BMI ≥40: 62% higher risk [3]

For Men: 9%

- BMI 30-34.9: 9% higher risk
- BMI 35-39.9: 20% higher risk
- BMI ≥40: 52% higher risk [3]
Additionally, for every 5 kg/m² increase in BMI, cancer mortality increases by approximately 10% [3].

Mechanisms Linking Obesity to Cancer

Several biological mechanisms explain how obesity increases cancer risk:

Hormonal Effects

Extra fat tissue isn't merely passive storage; it actively produces hormones and other biological signals that affect cancer risk:

  1. Growth hormones: Excessive body fat raises levels of growth hormones, which can increase cell division rates and the likelihood of cancer cell development [1].
  2. Sex hormones: In postmenopausal women, fat cells produce estrogen, which can stimulate cell division in the breast and uterus, increasing cancer risk [1] [16]. Higher insulin levels due to obesity can also lead to more available estrogen [16].
  3. Insulin resistance: Obesity can cause insulin resistance, leading to higher insulin production. Increased insulin triggers more cell production and affects hormone control, potentially leading to tumor growth [16].

Inflammation

Obesity triggers chronic inflammation in the body, which plays a key role in cancer development:

  1. Immune response: Immune cells migrate to areas with high concentrations of fat cells, leading to inflammation that accelerates cell division [1].
  2. Low-oxygen environment: Visceral fat cells are large and numerous, creating a low-oxygen environment that triggers inflammation [16].
  3. Long-term effects: Chronic inflammation damages normal cells and tissues over time, increasing cancer risk by promoting cell mutation and tumor growth [7].

Special Considerations

Age and Timing of Weight Gain

The timing of weight gain appears to influence cancer risk. Having excess weight during childhood and young adulthood may pose a greater risk for some cancers than gaining weight later in life [12]. A recent cohort study of 2.6 million adults found that the longer the duration, greater the degree, and younger the age of overweight and obesity, the higher the associated risk of developing 18 different cancers [2].

Geographic Variations

Research indicates geographical differences in how obesity affects cancer risk. For instance, Asian and North American postmenopausal women with obesity were found to have a higher likelihood of developing breast cancer (49% and 21% increased risk, respectively) compared to European women (10% increased risk, which was not statistically significant) [4].

Central vs. General Obesity

Central obesity (measured by waist-to-hip ratio) appears to be a stronger predictor of certain cancers, such as colorectal cancer, than general obesity measured by BMI alone. A recent study found that central obesity may account for most of the colorectal cancer risk linked to obesity [15].

Conclusion: 5% to 200% increased risk

Obesity significantly increases the risk of multiple cancer types, with the strongest associations seen in endometrial, colorectal, and postmenopausal breast cancers. The risk increments vary by cancer type, sex, age of weight gain, and pattern of fat distribution, with risk increases ranging from as little as 5% to more than 200% for certain cancers.
The biological mechanisms linking obesity to cancer involve complex interactions between hormones, inflammation, and cellular processes. Understanding these relationships is critical as obesity rates continue to rise globally, potentially making obesity the leading preventable cause of cancer in the near future.
Maintaining a healthy weight through regular physical activity and a balanced diet remains one of the most important modifiable factors for reducing cancer risk. With obesity potentially contributing to 40% of all cancer cases diagnosed in the United States in 2025 [13], addressing this epidemic represents a major opportunity for cancer prevention.

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Obesity increases risk of 13 to 18 Cancers - April 2025        
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