|Year : 2015 | Volume
| Issue : 1 | Page : 30-34
Cancer and obesity: The cause, the connect, and the way ahead
JS Rajkumar, S Akbar, JR Anirudh, Deepa Ganesh, C. M. Kishore Reddy
Department of Minimal Invasive and Bariatric Surgery, Chairman and Chief Surgeon Surgical Registrar Surgical Registrar, Consultant Gynaecologist Consultant Surgeon, LifeLine RIGID Hospitals, Chennai, India
|Date of Web Publication||6-Jan-2015|
Life Line Rigid Hospital Pvt., Ltd., 47/3, New Avadi Road, Kilpauk, Chennai - 600 010
Source of Support: None, Conflict of Interest: None
This is been a remarkable amount of research linking obesity and cancer in the past few years. There seems to be a definitely increased incidence of certain cancers such as breast, esophagus, colorectal and endometrial, in patients with high body mass index. This article looks at the associations between obesity and these cancers, outlines the postulated mechanisms that account for the increased incidences, and highlights some putative strategies to utilize these mechanisms to battle neoplasia. The final part of the article connects the decreased incidence of malignancy after bariatric surgery with the postulated anticancerous mechanisms of metabolic surgery. The available data over the last few years has been accumulated, and the most important scientific points have been culled out for practicing surgeons and researchers.
Keywords: Cancer, obesity, adipokines, adiponectin, leptin
|How to cite this article:|
Rajkumar J S, Akbar S, Anirudh J R, Ganesh D, Reddy CK. Cancer and obesity: The cause, the connect, and the way ahead. J Obes Metab Res 2015;2:30-4
|How to cite this URL:|
Rajkumar J S, Akbar S, Anirudh J R, Ganesh D, Reddy CK. Cancer and obesity: The cause, the connect, and the way ahead. J Obes Metab Res [serial online] 2015 [cited 2020 May 28];2:30-4. Available from: http://www.jomrjournal.org/text.asp?2015/2/1/30/148609
| Introduction|| |
With the pandemic increase in obese and overweight children and adults, there has been recently noted a statistically increased risk of development of cancer of the breast, endometrium, esophagus, colon and rectum, pancreas and others. This article reviews the published work in relation to the putative factors in the oncogenesis, and the relevant verticals of translational research that are ongoing. ,,,,,, Specific risk reduction strategies, if available, have also been highlighted.
In 2007, the National Cancer Institute Surveillance Epidemiology and End Results data  indicated that 4% of male cancers and 7% of female cancers were directly obesity related. This amounted to 34,000 and 50,500 respectively. Based on data, the percentage of newly appearing cancers attributable to increased body mass index (BMI) varied widely, but was as high as 40% for some cancers, especially carcinoma of the endometrium and esophagus.
Far more significantly, the projection of current global obesity trends indicated an additional cancer caseload of 500,000 cases annually in the USA alone by 2030.
| Oncogenesis|| |
Several mechanisms have been postulated to explain the risk of cancer in obese individuals. Although the available data is not massive, the logical link is given below:
- Fat tissue, through the pregnenolone pathway of hydroxylation, produces excess amounts of estrogen. This has been linked to postmenopausal estrogen receptor positive breast cancer and cancer of the endometrium
- Obesity is closely linked to hyperinsulinemia and high insulin-like growth factor-1 (IGF-1) levels.  Patients with diabetes have a higher incidence of malignancy because fluctuating insulin levels stimulate nuclear DNA and increase cellular proliferation. Thus, type 2 diabetics have a higher incidence of malignancy than type 1. Obesity is an independent and cumulative risk factor along with diabetes that triggers oncogenesis through insulin stimulation
- Adipokines released by fat cells may either stimulate or inhibit the growth phase of cells. For example, leptin, a hormone found in higher levels in obesity, promotes cellular growth and proliferation, whereas adiponectin, with lowered levels in obesity, is an anti-proliferative chemical. 
- Obese patients may have chronic low-level inflammation due to pro-inflammatory cytokines like Tumor necrosis factor-alpha (TNF-α), which itself could eventually cancer
- At least two varieties of kinases, functioning as cell signal factors and integrating connections between growth factors and hormones are directly and indirectly impacted upon by adipose tissue cytokine release. One of these is the mammalian target of rapamycin, which is an atypical serine-threonine kinase.  The other signaling factor affected by fat cells is AMP-activated protein kinase
- The overall oxidative stress levels of obese patients seems to be higher and this could be an added factor, as the T cell surveillance, destroying abnormal cells early, maybe rendered dysfunctional by free radicals
| Obesity and Individual Cancers|| |
Obesity and breast cancer
Increased BMI seems to be associated with increased breast cancer risk in postmenopausal women whereas, an inverse relationship has been found between weight and breast cancer in the premenopausal group. This has been seen in most but not all case-control and prospective cohort studies. The data citing an increased risk of postmenopausal breast cancer seems to be more robust. There is also a suggestion that a higher BMI is associated with a more advanced stage of breast cancer at diagnosis in terms of tumor size, but the data on lymph node status is still inconsistent. More importantly, all the available treatment modalities for breast cancer such as surgery, chemotherapy, radiation and hormones, may be negatively impacted by a high BMI. Thus, the build of a woman seems to be a prognostic factor too, with overall survival and disease-free survival being poorer in obese women with breast cancer. 
Obesity and esophageal cancer
There is a strong epidemiological association between esophageal cancer and obesity, one that is stronger than links to other obesity-related cancers. The central obesity (apple pattern) so typical of men, is strongly associated with adenocarcinoma of the esophagus, more so than BMI alone.
Of the two common varieties of esophageal cancer, an adenocarcinoma, which was much rarer than the squamous celled type, has risen to account for nearly 50% of all esophageal cancers in the west. The incidence of distal and junctional adenocarcinoma of the esophagus has gone up six-fold in the last 30 years with a true increase in disease burden. Initially, it was proposed that obese patients had a higher incidence of GERD and Barrett's esophagus and then finally adenocarcinoma of the esophagus; however the associations between adiposity and carcinoma esophagus seem independent of the symptoms of GERD indicating a separate carcinogenic pathway for obesity.
Several molecular mechanisms could contribute, and research is emerging to shed light on the same.
- The IGF pathway, associated with obesity, exerts strong mitogenic and anti-apoptotic actions on various cancer cells
- Recent studies have shown that polymorphisms in genes that encode proteins belonging to the IGF family could be markers of increased risk of esophageal adenocarcinoma. The 1013G polymorphism, when present in obese individuals had a higher risk of developing cancer esophagus
- High serum leptin levels also stimulate the proliferation and inhibit apoptosis in esophageal cancer cells
- In addition, epidermal growth factor is activated by leptin that in turn promotes cell proliferation
- Serum concentrations of adiponectin and inversely related to BMI. In 75% of patients with esophageal adenocarcinoma, obesity was associated with up-regulated expression of leptin receptors, and 2 adiponectin receptors
- Estrogen has been found to influence leptin receptor expression, driving subcutaneous body fat accrual over visceral fat. The accumulation of visceral fat is associated with an increased risk of various gastrointestinal malignancies especially adenocarcinoma esophagus. Thus, the male to female ratio is 8:1
Obesity and endometrial cancer
The fact that obese and overweight women are 2-4 times more prone to the development of endometrial cancer has been established for more than a century. This seems to especially affect women who have not been on HRT and there seems to be a higher incidence of those who rapidly increased weight in early adulthood. Like in breast cancer, the postulated hypothesis seems to link the higher serum levels of free estrogen to the occurrence of the corpus cancer syndrome. The importance of this finding is that a significant avoidance of cancer risk is brought about by decreasing the BMI. ,,,
Obesity and colorectal cancer
Obesity is definitely associated with an increased colorectal cancer incidence. Colorectal surgeons are now encountering obese patients more frequently, and this may influence the technical parts and the surgical outcomes of these patients. For example, the higher BMI patients present with more co-morbidities adding to the risk of postoperative complications. For laparoscopic colorectal surgery, the conversion to open surgery is significantly more in the morbidly obese, as is the operating time. Fortunately at the time of print, there's a fair body of evidence suggesting that survival rates are not negatively influenced by a high BMI. ,
Obesity and pancreatic and prostatic cancers
These carcinomas are also associated with obesity but to a far less extent than those mentioned above. 
| Discussion|| |
With researchers exploring the cancer obesity link to great depths, not only have mechanisms been elucidated, but opportunities for prevention have also surfaced. Understanding of the exact molecular change that contributes to the pathogenesis of varying cancers has permitted clinicians to at least invoke a number of rational strategies for the prevention of cancer in these high-risk groups. The strategies could be behavioral, pharmaceutical or surgical.
It is well-known that malignancy cells, especially colorectal pancreatic etc., are in constant requirement of ATP. There seems to be a lower incidence of malignancies in patients who fast for long periods of time. Decreased calorie consumption seems to be a definite behavioral strategy to decrease the incidence of cancers. Moreover, several studies have shown that periods of fasting and decreased intake of calories also give a slightly better prognosis in patients undergoing multimodality therapy for endometrial ovarian and colorectal cancers.
It is well-known that AMP kinase system, the nuclear β and g receptor system, and several other cell signaling the mentor system (see above) and several other signaling pathways are involved in the nexus between obesity and cancer. This raises the issue of targeting these cellular signaling receptors to prevent further onward cascading of the molecular chain of events that leads to oncogenesis.
As far as surgical strategy is concerned, bariatric surgery definitely seems to have come of age in terms of cancer prevention in the obese. Several studies have shown that the incidence of malignancy in longitudinally followed-up patients who undergo bariatric surgery is less than in their age and sex matched counterparts. How does this work? First, the entire oncogenic process that is linked to high insulin levels, the IGF-1 levels, and cellular receptors activation is blunted by bariatric surgery as the insulin resistance is lowered. Bariatric surgery causes low caloric state and low caloric lessens oncogenesis as shown above, and thus contributes to a decreased incidence of malignancy in these patients.
Several immune changes after bariatric surgery seem to happen in patients who have undergone bariatric surgery. For e.g., morbidly obese women who underwent bariatric surgery were found to have changes in immune response e.g., higher expression of CD20 + receptor in the endometrial receptors and this could indicate a lower incidence of endometrial cancer in this group. Natural killer cell activity and natural killer related cytokine synthesis are impaired in inpatients with morbid obesity. , After bariatric surgery there is a much higher production of g interferon interleukin 12 and 18 etc., and these are part of the immunological surveillance system that clears the bloodstream of early malignant cells. The fact that insulin and IGF levels comedown after surgery also mitigates the possibility of cancer development. A large study in France where 15% of population is obese has shown clearly that bariatric surgery, in weight dependent and weight independent manner seem to exert a positive impact on incidence as well as the final mortality due to cancer.
Endometrium and bariatric surgery
The other question that is begged is whether bariatric surgery is direct option for women with gynecological cancer either at or immediately after a gynaec-oncological procedure is done. The last word however has not been said. Women presenting for weight loss surgery often have menstrual dysfunction. If they are properly informed that the fact that they are obese could increase the risk of uterine cancer it would be probably good in the long term for these patients to have both bariatric surgery as well as careful surveillance of their endometrium before further conclusions are available. 
The adoption of bariatric surgery and metabolic surgery on a worldwide basis has undoubtedly decreased the incidence of above-mentioned cancers in a group of patients who have undergone the surgery. But how exactly do this work? The theories of down-regulation of oncogenic receptors are many but a few will be discussed here:
By disrupting the dynamic role of the adipocyte in energy homeostasis, there is a chronic inflammation setup in the adipose compartment of the body with an alteration of signaling from the adipokines (which are leptin and adiponectin). Insulin signaling and deregulation of lipids may also foster an environment in which cancer could develop. Decrease of the overall adipose compartment especially the visceral one decreases the amount of free oxide radicals available in the body. This decreases the amount of lipid peroxidation and release of free oxygen radicals that trigger off the cell signals that cause micro RNA instability. Bringing down the lipid peroxidation content with metabolic and bariatric surgery should decrease the oxidative stress to a given individual. 
At the micro-environmental level the proinflammatory cytokines like interleukin (IL-1β), TNF-α released by white adipose tissue (in the omentum, mescentry, mesocolon) at the nucleocytoplasmic interface level of cells causing disorder tissue homeostasis and increased oxidative stress. Metabolic surgery causes a huge decrease in IL-6, C-reactive protein, Cyanic acid, plasminogen activator1 and von Willebrand factor. The decrease in postoperative insulin resistance after surgery is an independent factor and not directly related to the drop IL-6 and IL-12. More interestingly about 6 months after surgery there is an actual increase in g interferon IL-12 and IL-18, this is linked to a rise in natural killer cell activity which may help cell-mediated immune response against malignant cells, thus achieving surgical anticancerous effects. ,,,
Insulin resistance, so typical of the type II overweight diabetic, causes a high level of insulin and IGF-1. This could substantially increase anabolic effects inside cells to cause cell proliferation and cancer progression, activating IGF-1 on to normal and cancer cells via the phosphatidyl enositol 3 kinase/AKT signaling pathway. More importantly IGF1 may also stimulate the production of vascular endothelial growth factor which could trigger the vascular cascade and increase early growth of cancer cells. Postbariatric and metabolic surgery, when there is a resolution of the insulin resistance this is bound to improve and anticancerous effects noted in patients after these procedures might well be due to this ,
Leptin and Adiponectin are the adipocytokines or cytokines released directly by adipose tissue. Leptin acts on the hypothalamus to increase energy expenditure but in obese individuals there is a chronic hyperleptinemia. This could stimulate the proliferation of cancer cells whereas decreasing leptin is associated with remission of early cancers. ,
There are some GUT hormones that are known to contribute to cellular proliferation of cancer development e.g. Ghrelin released from the stomach may act as a carcinogenic factor through its action on the GH receptor (growth hormone receptor). High level of ghrelin is seen in some gastrointestinal tumors, prostatic cancer, and neuroendocrine tumors. In sleeve gastrectomy, there is a removal of ghrelin secreting fundus of the stomach and in Roux-en-Y gastric bypass it is not exposed to food content. The postoperative ghrelin levels are low after both procedures and may contribute to the reduction of cancer seen in these patients. 
the high estradiol levels that are found in obese patients secondary to hydroxylation of the cholesterol pregnenolone pathway in peripheral fat cause increased cellular proliferation and decreased apoptosis; this happens because of adipose aromatase. Metabolic surgery significantly decreases the estradiol and therefore decreases incidence of all tumors related to these hormones. Furthermore, the hyperinsulinimic state of these patients also leads to reduced levels of sex hormone binding globulin, which therefore allows a larger serum level of free testosterone and estradiol. Metabolic surgery may cure these effects by improving its sensitivity and maintaining sex hormone bind globulin levels. 
Metabolic surgery may also effect some of its anticancerous role through altered cellular energetic. Disruptive cellular energy acting through the AMP master switch may ultimately lead to cancer. These disruptive intracellular processes are set right after metabolic surgery 
| Conclusion|| |
Metabolic and bariatric surgeries are performed world over with increasing numbers. Cancer and obesity are both growing side by side at an alarming speed. This field requires increased careful research into clarifying the exact mechanism of prevention of cancer after these surgeries. Well validated in vitro and in vivo animal models of both carcinogenesis and metabolic surgery outcomes are required to throw light on this area. Genomic, genotoxic transcriptonic and metabolomic profiles will be necessary using a systems biology approach in order to start using other novel technologies to target cellular disruptions that happen at the early stage of oncogenesis. Perhaps, if further data is available as to which surgical operation is associated with the least risk of cancer in that group, that might be an additional reason in favor of that particularly procedure e.g. Roux-en-Y gastric bypass. Not only will this be a key driver to increase the consumer buy-in into metabolic/bariatric surgery, but it might also add to select one procedure as a possible Holy Grail because of anticancerous effects for the bariatric surgeons. Exciting times ahead. Let's wait and see.
| References|| |
Iyengar NM, Hudis CA, Danneenberg AJ. Obesity and cancer: Local and systemic mechanisms. Annu Rev Med 2015;66:1.
Bifulco M, Pisanti S. "Adiponcosis": A new term to name the obesity and cancer link. J Clin Endocrinol Metab 2013;98:4664-5.
Henretta MS, Copeland AR, Kelley SL, Hallowell PT, Modesitt SC. Perceptions of obesity and cancer risk in female bariatric surgery candidates: Highlighting the need for physician action for unsuspectingly obese and high risk patients. Gynecol Oncol 2014;133:73-7.
Kaaks R, Kühn T. Epidemiology: Obesity and cancer - The evidence is fattening up. Nat Rev Endocrinol 2014;10:644-5.
Stefaniak TJ, Håkansson IG, Ahlström M, Sandström A, Proczko-Markuszewska M. Comparison of cancer risk reduction after bariatric surgery demands an adequate control group. Annals of Surgery 2013 ;Volume 00, Number 00.
Møller H, Mellemgaard A, Lindvig K, Olsen JH. Obesity and cancer risk: A Danish record-linkage study. Eur J Cancer 1994;30A: 344-50.
Czernichow S, Carette C. Does bariatric surgery reduce cancer risk?. Ann Endocrinol (Paris) 2013;74:67-8.
Vucenik I, Stains JP. Obesity and cancer risk: Evidence, mechanisms, and recommendations. Ann N Y Acad Sci 2012;1271:37-43.
Khandekar MJ, Cohen P, Spiegelman BM. Molecular mechanisms of cancer development in obesity. Nat Rev Cancer 2011;11:886-95.
Carroll KK. Obesity as a risk factor for certain types of cancer. Lipids 1998;33:1055-9.
Menéndez P, Padilla D, Villarejo P, Menéndez JM, Lora D. Does bariatric surgery decrease gastric cancer risk? Hepatogastroenterology 2012;59:409-12.
Schmandt RE, Iglesias DA, Co NN, Lu KH. Understanding obesity and endometrial cancer risk: Opportunities for prevention. Am J Obstet Gynecol 2011;205:518-25.
Neff R, McCann GA, Carpenter KM, Cohn DE, Noria S, Mikami D, et al. Is bariatric surgery an option for women with gynecologic cancer? Examining weight loss counseling practices and training among gynecologic oncology providers. Gynecol Oncol 2014;134:540-5.
Giovannucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann Intern Med 1995;122:327-34.
Moulin CM, Marguti I, Peron JP, Halpern A, Rizzo LV. Bariatric surgery reverses natural killer (NK) cell activity and NK-related cytokine synthesis impairment induced by morbid obesity. Obes Surg 2011;21:112-8.
Lashinger LM, Ford NA, Hursting SD. Interacting inflammatory and growth factor signals underlie the obesity-cancer link. J Nutr 2014;144:109-13.
Linkov F, Elishaev E, Gloyeske N, Edwards R, Althouse AD, Geller MA, et al. Bariatric surgery-induced weight loss changes immune markers in the endometrium of morbidly obese women. Surg Obes Relat Dis 2014;10:921-6.
Ashrafian H, Ahmed K, Rowland SP, Patel VM, Gooderham NJ, Holmes E, et al. Mechanisms of decreased tumor generation and growth after metabolic surgery. Cancer 2011;117:1788-99.
Hursting SD, Dunlap SM. Obesity, metabolic dysregulation, and cancer: A growing concern and an inflammatory (and microenvironmental) issue. Ann N Y Acad Sci 2012;1271:82-7.
Ward KK, Roncancio AM, Shah NR, Davis MA, Saenz CC, McHale MT, et al. Bariatric surgery decreases the risk of uterine malignancy. Gynecol Oncol 2014;133:63-6.
Hursting SD. Obesity, energy balance, and cancer: A mechanistic perspective. Adv Nutr Cancer Treat Res 2014;159:21-3.