Obesity and Pancreatic Cancer - How Are They Related?

Introduction:

Obesity is linked to several chronic medical conditions, including hypertension, hyperlipidemia, type 2 diabetes, cardiovascular disease, metabolic syndrome, and cancer, resulting in a shorter lifespan. Based on epidemiological studies, obesity has been linked to increased endometrial cancer, postmenopausal breast cancer, esophageal adenocarcinoma, colon cancer, hepatocellular carcinoma, gastric, liver, renal cell carcinoma, and prostate cancer. In particular, obesity has been linked to an increased incidence of pancreatic cancer, an almost universally lethal disease. Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death, and PDAC has a 5-year survival rate of about 80%.

The most prevalent type of cancer that causes death is pancreatic cancer. The incidence of pancreatic cancer is increasing rapidly, and it is predicted that by 2030, it will have surpassed colorectal cancer to be the second leading cause of cancer death, trailing only lung cancer. However, most pancreatic cancer patients are diagnosed late in the disease's progression with locally advanced disease or distant metastasis, and only a small number of patients are candidates for surgery. At some large tertiary centers, 5-year survival with margin-negative resection and negative lymph nodes can reach 40 % at best. Complete surgical resection drastically prolongs life.

What Are the Mechanisms by Which Obesity Is Related to Pancreatic Cancer?

1. Obesity, through various mechanisms, such as inflammation, resistance to insulin, circulating lipids, cytokines, and changes in the microbiome, has been related to an elevated risk of cancers.

2. Chronic inflammation has been linked to many cancers, including esophageal adenocarcinoma, gastric cancer, colorectal cancer, and hepatocellular carcinoma. Chronic pancreatitis is also a significant risk factor for pancreatic cancer.

3. Adipose tissue inflammation is a hallmark of obesity, and it can promote cancer growth by secreting pro-inflammatory cytokines. Adipose tissue releases various pro-inflammatory cytokines, like TNF (tumor necrosis factor), TGF (transforming growth factor), IL-6 (interleukin-6), and leptin, and contains (pre-) adipocytes, immune cells, fibroblasts, endothelial cells, and stem or progenitor cells. These factors, in turn, can promote cancer cell proliferation.

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4. The role of intestinal microbes in obesity is of great interest. It has been proposed that intestinal microbes regulate energy homeostasis and fat storage and may play a role in obesity. Obesity has been linked to changes in gut microbiota composition, decreased microbial diversity, and decreased gene richness.

5. Obesity is also frequently linked to insulin resistance and type 2 diabetes mellitus, with elevated insulin and insulin-like growth factor 1 level (IGF-1). Diabetes has been linked to an increased risk of cancer.

6. According to epidemiological studies, every 10 milligrams per milliliter increase in fasting blood glucose is connected with a 14 percent rise in pancreatic cancer. Increased insulin or insulin-like growth factor-1 signaling has also been linked to cancers like ewing sarcoma and breast, ovarian, and lung cancer. In addition, many cancers have increased expression of insulin receptors (IR) and insulin-like growth factor receptors (IGF-1R).

7. Homology of IR and IGF-1R can form heterodimers that bind insulin-like growth factors - 1 and 2. Hyperactivation of these pathways can result in increased cell division and activation of the Ras or ERK pathway (signaling pathways).

8. The IGF-1 pathway can also activate the PI3K or AKT or mTOR pathways, which promote proliferation while inhibiting apoptosis.

9. Diabetes medications have a high potential for lowering the risk of pancreatic cancer and extending the survival of the pancreatic cancer patient. For example, Metformin, a commonly used oral diabetic medication, lowers serum insulin and insulin-like- growth factor-1 levels.

10. At the molecular level, it indirectly blocks the AMP-directed Protein Kinase (AMPK) pathway by inhibiting complex I of the mitochondrial electron transport chain during oxidative phosphorylation. As a result, Metformin prevents pancreatic cancer cell growth and lowers mTOR or Sp6 expression levels in vitro.

What Is the Role of Weight Loss in the Prevention of Pancreatic Cancer?

1. Deliberate weight loss has been proven to lower the risk of cancer in women, particularly postmenopausal breast cancer and endometrial cancer. Moreover, the majority of these were observational studies. In animal models, calorie restriction has been proven to slow pancreatic cancer growth and development.

2. For obese patients, the calorie restriction can result in short-term weight loss. Moreover, most patients cannot maintain the calorie restriction over time and usually regain the lost weight.

3. To treat obesity, many experts recommend biologically based interventions such as new anti-obesity drugs and bariatric surgery. In addition, comorbidities like hypertension, hyperlipidemia, type 2 diabetes mellitus, and cardiovascular disease are common in obese patients.

What Is the Role of Bariatric Surgery in Obesity and Pancreatic Cancer?

1. Bariatric surgery provides long-term weight loss and the resolution of comorbidity conditions.

2. Various bariatric surgery methods are available, including Roux-en-Y gastric bypass, sleeve gastrectomy, and laparoscopic gastric banding. Significant weight loss (roughly twenty-five percent of initial body weight for Roux-en-Y gastric bypass) has been observed after twenty years.

3. The gold standard for modern bariatric surgery is the Roux-en-Y gastric bypass which results in long-term weight loss that is sustained. However, the use of gastric bands has decreased dramatically in recent years owing to their high long-term complication rate and poor weight loss.

4. Because of its technical simplicity, low complication rate, and excellent weight loss, laparoscopic sleeve gastrectomy has recently become broadly accepted as the most popular and definitive bariatric procedure in the United States.

5. Surprisingly, a few retrospective clinical studies have found that bariatric surgery reduces the risk of various cancers, including breast, endometrial, colorectal, melanoma, and non-Hodgkin lymphoma.

What Are the Mechanisms by Which Bariatric Surgery Can Reduce Cancer Risk?

There are several mechanisms by which bariatric surgery may decrease cancer risk. First, inflammatory cytokine secretion can be reduced by bariatric surgery. Bariatric surgery significantly reduced inflammatory markers such as C-reactive protein (CRP), interleukin-6 (IL-6), and tartrate-resistant acid phosphatase 5a (TRACP 5a) in obese diabetic patients. It has also been demonstrated that bariatric surgery reduces tissue inflammation. Bariatric surgery improves insulin resistance significantly.

Taylor and colleagues discovered that among T2DM (type 2 diabetes mellitus) patients who had undergone a low-calorie diet or gastric bypass surgery, the hepatic fat content decreased rapidly, accompanied by enhanced hepatic insulin sensitivity and normalization of fasting plasma glucose levels within seven days. Bariatric surgery also enhances the microbiota profile of the intestine. It has been proposed that intestinal microbes regulate energy homeostasis and fat storage and may have a role in obesity. Obesity has been linked to changes in gut microbiota composition, decreased microbial diversity, and decreased gene richness.

Conclusion:

Obesity has become endemic in recent decades and is linked to increased cancer incidence, mortality, and healthcare costs. Obesity, in particular, raises the risk of pancreatic cancer, possibly through various mechanisms, including inflammation, insulin resistance, and altered intestinal microbiota. Obesity, as a modifiable risk factor, can be managed through a multidisciplinary approach. Bariatric surgery has been proven to result in long-term weight loss and lower the risk of many cancers.