The epidemic rising prevalence of obesity worldwide is causing a major health threat in terms of morbidity and mortality. Obesity has been linked to a variety of health problems, including diabetes mellitus, cardiovascular diseases, reproductive disorders, osteoarthritis, gallstones, nonalcoholic fatty liver disease, respiratory disease and, of particular interest to our proposed study, some types of cancers Citation[1]. Obesity follows cigarette consumption in public health relevance as a cause of avoidable cancer Citation[2]. It has been shown that an increased BMI is associated with increased risk of some types of cancer, such as esophageal adenocarcinoma, melanoma, leukemia, multiple myeloma, non-Hodgkin’s lymphoma, and with colon, thyroid, endometrial, renal, gallbladder, rectal, breast and pancreatic cancers, among others Citation[3].
Why are obese people more prone to developing cancers? The biological mechanisms that link obesity to many forms of cancer seem to be multifactorial and involve a network of metabolic and immunological factors. Several mechanisms by which obesity induces or promotes tumor genesis have been proposed, including insulin resistance and resultant chronic hyperinsulinemia, increased bioavailability of steroid hormones, high intake of foods rich in fat and lack of physical activity Citation[3,4].
Relevant for our considerations, alterations in the immune system may have an important role in the higher prevalence of cancer in obese patients, as suggested by some (very few) studies.
Obesity has been associated with decreased immunocompetence in experimental animals Citation[5–8] and in humans Citation[9–12]. The main cell type of the immune system that is critically involved in the control of cancer is the natural killer (NK) cell. NK cells represent a subset of lymphocytes that are an important constituent of the innate immune system, aimed at defending the host against unforeseen invaders, such as viruses, parasites, bacteria and transformed (precancerous or cancerous) cells Citation[13]. NK cells have two major properties: the production of immunostimulatory cytokines that attack abnormal cells and direct cytotoxicity against particular target cells Citation[13]. NK-cell activity is also stimulated by cytokines released by other immune cells, mainly IL-2, IL-12, IL-18 and interferons Citation[14]. Human NK cells target various human cancer cells of different origins, such as colon carcinoma, melanoma, sarcoma, ovarian carcinoma or leukemic cells in vitroCitation[15].
In fact, some studies suggest a striking relationship between low NK-cell cytotoxic activity and the development of cancers. In an 11-year prospective study, lower NK-cytotoxicity was associated with increased cancer incidence Citation[16]. Patients with Chediak Higashi syndrome, an autosomal recessive disorder characterized by abnormal NK cytotoxic function, have a 200-fold increased risk of developing malignancy Citation[17]. In patients suffering from hepatic cirrhosis, low NK cell activity was also associated with an increased incidence of hepatocellular carcinoma Citation[18]. Moreover, reduced NK-cell function in patients with tumors is correlated with a poor prognosis, notably a higher risk of developing regional and distant metastases, an increased risk of recurrence following surgery and increased mortality Citation[19,20]. Therefore, the role of NK-cell activity seems to be very important in the prevention and control of cancer.
Although obesity is related to a higher incidence of cancer (it was estimated that excess bodyweight accounts for 5% of all cancers incidents – 3.5% in men and 6.5% in women Citation[2]), studies on NK-cell function in obese patients and the effect of long-term weight loss in this parameter of immunity are limited. Some evidence of the relationship between obesity and impaired NK-cell activity can be obtained from studies in animals. Diet-induced obese rats, considered a comparable model for human obesity, showed a reduced level of cytotoxic activity of NK cells, which was restored by energy restriction Citation[6]. Recently, we have shown that severely obese patients have a significantly lower level of NK-cell activity compared with normal individuals matched to age and gender. Existing medical therapeutic strategies to achieve and maintain clinically significant weight loss remain limited, especially in relation to more severe cases of obesity Citation[21]. Bariatric surgery is currently the only truly successful treatment for patients with morbid obesity that is highly effective in achieving substantial and sustained weight loss Citation[22].
Considering these aspects, we studied the number and activity of NK cells and the production of cytokines related to their activity in 28 patients with obesity grade III before and after 6 months of Roux-en-Y gastric bypass surgery. The most striking result of our study was that we observed a normal total number of NK cells but a very significant decrease in the activity of these cells in obese patients before surgery and a very impressive increase in this activity after weight loss (∼26% of initial weight) induced by bariatric surgery. Moreover, we observed that the production of cytokines involved in the activity of NK cells (particularly IL-12 and IL-18) also increased significantly. As these cytokines are important regulators of NK-cell activity, it seems that the correlation between its increase and the improvement in the NK-cell activity is very plausible.
In our opinion, these results are of utmost importance because they show, unequivocally, that the immune function (particularly regarding NK-cell activity) is severely impaired in grade III obese patients (and probably in many patients with lower grades of obesity). This could be one of the possible explanations for the higher incidence of cancer in these patients that is unequivocally shown in the literature. This could also explain the lower incidence of neoplasia in obese patients who were submitted to surgery (and lost weight) compared with obese control patients (who did not lose weight), as shown by Adams et al.Citation[23].
Moreover, according to our data, it seems very possible that weight loss (induced in our patients by Roux-en-Y gastric bypass surgery, but may apply to weight loss obtained by other methods too) can be very beneficial, not only for cardiovascular and other outcomes, but also for prevention of cancer, at least partially, via a recovery of NK-cell function. The restoration of their activity is another possible reason for indicating bariatric surgery in these patients.
This study requires confirmation by other experiments that are specifically directed to analyze immune function in obese patients and to observe the results of weight loss, but undoubtedly opens an interesting road towards understanding the relationship between obesity and cancer risk through alterations in immune (particularly innate) function.
Financial & competing interests disclosure
This study was supported by grants from The Foundation for Aid to Research of the State of São Paulo (Fundação de Amparo à Pesquisa do Estado de São Paulo [FAPESP]). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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