Obesity, a worldwide health concern, contributes to various health comorbidities such as cardiovascular disease, Type II diabetes, and certain forms of cancer. Among these, the link between obesity and lung cancer has been explored extensively by researchers, demonstrating a positive correlation between obesity and lung cancer, although the underlying mechanism remains somewhat elusive. Interestingly, a higher Body Mass Index (BMI), typically ranging from 25 to 34.9 kg/m^2, is seen to lessen mortality rates in lung cancer patients. Research shows that the p53 tumor suppressor gene is notably upregulated in obese individuals, potentially reducing lung cancer risk. Various studies indicate that the progression rates of lung cancer vary between smokers and non-smokers and suggest that waist size – encompassing waist circumference (WC), waist-to-hip ratio (WHR), and overall measures of obesity – is associated with an increased risk of lung cancer, irrespective of BMI. This review aims to uncover the complex association between obesity and lung cancer.
Several types of cancer, including those found in the breast (post-menopausal women), endometrium, esophagus, gallbladder, kidney, colon, and pancreas, have been linked with obesity. Recognized for its detrimental health impacts, obesity has been at the forefront of a global effort to mitigate its prevalence and associated disease risks. Despite advancements in medical science, including surgical and chemotherapeutic interventions, lung cancer continues to have a low survival rate. It stands as one of the leading causes of death worldwide. According to a 2012 World Health Organization (WHO) survey, lung cancer was most prevalent in men, accounting for roughly 16.8% of global cancer cases. Comparatively, breast cancer ranked second in women, with a prevalence rate of 12%, making it a major cause of mortality among women worldwide.
As the incidence of obesity in lung cancer patients increases, new challenges continually present themselves, posing significant difficulties for healthcare professionals. It’s been noted that obese individuals with a Body Mass Index (BMI) within the range of 25 to 34.9 kg/m^2, denoting a high BMI, show a protective effect against lung cancer, thereby reducing mortality rates post-surgery or chemotherapy.
Epidemiological studies suggest that obesity is linked with lower survival rates in various cancer types, and the development of cancer varies with differing levels and types of obesity. Specifically, general obesity and body fat distribution, particularly abdominal obesity, are crucial factors influencing the prognosis of lung cancer. Cohort studies have identified a positive correlation between obesity and lung cancer incidence within populations.
Despite these findings, the exact mechanism by which obesity impacts cancer remains largely unknown, and concrete evidence pinpointing the precise role of obesity in lung cancer development is scarce. Nevertheless, this review aims to delve into the intricate relationship between obesity—a global health issue—and lung cancer.
THE SURPRISING ADVANTAGES OF OBESITY
Intriguingly, individuals with a high body mass index (BMI) have been found to have a lower risk of developing lung cancer and, more notably, better outcomes when diagnosed with the disease. This “obesity paradox”—an apparent benefit of obesity that has been consistently observed across numerous cohort studies—remains unexplained. While theories such as a confounding effect from smoking or reverse causation due to weight loss associated with cancer have been proposed as possible reasons, they haven’t fully clarified the paradoxical relationship between obesity and lung cancer.
THE ROLE OF DIHYDROPYRIMIDINASE LIKE 4 (DPYSL4) IN SUPPRESSING LUNG CANCER CELLS
DPYSL4 is a target of the tumor suppressor gene p53, which regulates energy metabolism in both cancer cells and adipocytes. Researchers utilized RNA-seq and ChIP sequencing in lung cancer cells and preadipocytes to identify a set of p53-inducible genes that correlate with energy metabolism in both biological contexts. It was demonstrated that DPYSL4 directly impacts oxidative phosphorylation (OXPHOS) and ATP synthesis in mitochondria, based on the premise that cancer cells predominantly rely on glycolysis for energy generation as opposed to OXPHOS. The invasiveness of lung cancer cells into Matrigel matrices in vitro was reduced when p53 or DPYSL4 was overexpressed in obese individuals. According to in vivo studies using mouse xenograft and lung metastasis models, DPYSL4 expression significantly hampers lung metastasis and tumor growth. The mRNA levels of DPYSL4, CDKN1A, MCP1, and IFNg were also elevated in the adipose tissues of obese individuals with lung cancer compared to non-obese patients, and p53 was notably up-regulated in the adipocytes of obese individuals.
Extracellular vesicles (EVs) could be an additional mechanism through which p53-induced compounds with anticancer properties are transported from adipocytes to target tissue (lung cancer cells). Secreted EVs have the capacity to transmit metabolic alterations from distant recipient cells to adipocytes. As a new form of adipokines, EVs can alter the molecular traits of recipient cells by acquiring new proteins (such as receptors, enzymes) or even genetic material (mRNAs, miRNAs that regulate gene expression) from the originating adipocyte cells. Indeed, the increased quantity of exosomes released and the enhanced impact of each individual exosome in obesity substantiate this horizontal transfer. It’s noteworthy that previous attempts to elucidate the positive correlations between BMI and EVs have incorporated both inflammation and EV-related concepts.
Obesity is a significant contributing factor to various commonly occurring cancers. Interestingly, a high body mass index (BMI) has been observed as a lower risk factor for lung cancer, especially among smokers. The primary reasons for this anomaly have been identified as confounding due to smoking and reverse causation due to preclinical weight loss. Nevertheless, some studies have noted similar inverse relationships between BMI and lung cancer even among non-smokers, or after eliminating initial years of follow-up data, suggesting the possibility of other factors at work.
Most of these analyses, particularly those including non-smokers, had relatively small sample sizes. Thus, comprehensive collaborative analyses involving multiple cohort studies are required to properly understand the effects of confounding and reverse causation, especially since lung cancer is less common among non-smokers. Conversely, measures of central obesity like waist circumference (WC) and waist-to-hip ratio (WHR) have been linked to an increased risk of lung cancer, independent of BMI, but the evidence for this is less comprehensive than that for overall obesity.
There have also been reports indicating that the relationship between obesity and lung cancer might differ based on tumor histology and patient’s race or ethnicity. However, most previous studies lacked sufficient statistical power to explore these relationships, particularly for different histological specimens and among non-white individuals. In a large pooled analysis by Vanderbilt et. al., 2018, a generally negative correlation between BMI and positive associations of WC and WHR with lung cancer were discovered.
The relationship between obesity and lung cancer may vary depending on factors such as race/ethnicity, tumor histology, among others, and may not be entirely attributable to smoking or reverse causation. The “low BMI-high WC/WHR” phenotype could help identify high-risk groups associated with lung cancer, taking into account smoking history and other established risk factors. Our findings also underscore the need for further research into the roles of body composition patterns, fat distribution, and metabolic issues associated with obesity in lung cancer development.
Research concerning obesity and cancer has significantly advanced over the past decade, with increasing evidence highlighting the detrimental effect of obesity on cancer risk. There has also been an expansion in our understanding of the biology underpinning the link between obesity and cancer, coupled with a keen interest in disrupting this correlation to decrease cancer risk and improve cancer outcomes. Presently, the connections drawn from current literature that relate obesity to lung cancer risk and associated outcomes remain largely observational. The small correlations often observed may be subject to bias and/or confounding factors, and there is a scarcity of compelling evidence showing that the adverse effects of obesity on cancer can be mitigated by reducing patient weight or targeting potential biological or physiological mechanisms.
There remains a degree of ambiguity regarding whether weight reduction or prevention of overweight and obesity in individuals could mitigate the possible impacts of obesity on lung cancer causative risk or other associated implications. While preventing overweight and obesity will ultimately eradicate the risk of obesity-related cancer, it’s unclear if such prevention would positively affect the risk and outcomes associated with lung cancer.
Weight reduction strategies often result in minor weight loss (without necessarily achieving a normal weight). Hence, the evidence is still lacking to confirm that weight loss can reduce cancer risk and/or enhance outcomes, given the possibility that obesity may lead to irreversible cancer precursors or more aggressive, harder-to-treat malignancies.
In summary, this review has focused on the evidence relating obesity to lung cancer. Overall obesity and the general distribution of body fat appear to play a significant role in the development of lung cancer. Body mass index (BMI), a key indicator of obesity, is associated with several severe health conditions, including various cancers.
Numerous cohort studies have revealed a counterintuitive positive relationship between obesity and lung cancer, suggesting that the incidence of lung cancer decreases in obese individuals. However, the mechanisms underpinning this observation remain largely unknown. The DPYSL4 gene, a known tumor suppressor gene, seems to play a significant role in suppressing the p53 gene, thereby reducing malignancies.
It’s crucial to note that obesity alone is not responsible for lung cancer; other factors such as smoking also contribute significantly. Future research is needed to uncover the mechanisms by which obesity is associated with lung cancer. This will hopefully provide further insights into this complex relationship and potentially lead to improved strategies for prevention and treatment of lung cancer in the context of obesity.