Another Distinct Link Between Cancer and Obesity: the AEG-1 Protein

Evidence-Based Diabetes Management, September 2015, Volume 21, Issue SP13

Research primarily at Virginia Commonwealth University focuses on a key regulator of metabolic diseases as well as cancer.

Emerging research has consistently pointed to the association between cancer and obesity, and 1 protein in particular is evolving as a key regulator of metabolic diseases as well as cancer. Astrocyte elevated gene-1 (AEG-1), an established oncogene and important contributor to the various steps of carcinogenesis in diverse organs and tissues, has for the first time, been associated with obesity.

Work that primarily came out of the Virginia Commonwealth University Massey Cancer Center has identified this oncogene’s role in lipid metabolism. Scientists generated a mouse that did not express AEG-1 (knockout or KO); the KO mice were viable, fertile, leaner than the wild type (control) mice, and also lived significantly longer than the control mice. To test the role of this oncogene in lipid metabolism, the animals in both groups were stressed with a high fat and cholesterol diet—while the control mice showed rapid weight gain, the scientists discovered that the KO mice remained lean. An attempt to tease out the mechanism of this phenotype indicated a reduction in fat absorption from the intestines of the KO mice, while the rate of fat synthesis was not altered.1

An interesting observation from the study was that despite being expressed in neurons, knocking out AEG-1 did not influence feeding behavior of the KO mice. The authors believe that calorie restrictions, caused by reduced fat accumulation in the body, might account for their longevity. Regulation of lipid metabolism, they write, might also implicate AEG-1 in obesity-associated illnesses such as non-alcoholic fatty liver disease and obesity-associated cancers.1

“There are many labs working extensively on AEG-1, and our collective work using human cells (with overexpression and knockdown of AEG-1) and AEG-1 knockout and transgenic mice conclusively demonstrate that AEG-1 is a bona fide target for cancer and a valid target for obesity,” said Devanand Sarkar, MBBS, PhD, lead author of the study in an e-mail. Sarkar is associate professor in the department of Human and Molecular Genetics, Massey Cancer Center at Virginia Commonwealth University.

Indicating that their preliminary studies were conducted in a nude mouse xenograft model, he added, “We will continue our evaluations in more stringent mouse models that develop spontaneous HCC [hepatocellular carcinoma]. Once we obtain these baseline data we plan on submitting an IND [investigational new drug] application to FDA for phase 1/2 clinical trials in HCC patients.”

OBESITY AND CANCER

Of the several lifestyle factors responsible for causing cancer, including tobacco and use of tanning devices, the American Association of Cancer Research Cancer Progress Report for 2014 also listed obesity and lack of physical activity as causative factors.2 The report attributes nearly 25% of cancer incidence to being overweight or obese, second to tobacco. Add to it a poor diet and absence of physical activity, and together they are responsible for 33% of cancer incidence. A position statement by the American Society of Clinical Oncology released in 2014 even went as far as to state that obesity is overtaking tobacco as the leading “preventable” cause of cancer.3

Survival is worse in obese cancer patients The American Cancer Society released a report over a decade ago indicating that obesity was an added risk for cancer associated death in men (prostate 34%, kidney 70%, colorectal 84%, esophagus 91%, stomach 94%, pancreas >2-fold, liver >4-fold) and in women (colorectal 46%, ovarian 51%, breast 2-fold, cervical 3-fold, kidney 5-fold, uterine 6-fold).4 Two large cohort studies conducted over more than 2 decades studied the relation between prediagnosis body mass index (BMI) and survival in pancreatic cancer patients and found that higher BMI resulted in a statistically decreased survival.5

Complications associated with dosing in obese patients might also contribute to reduced survival. A study published in JAMA Oncology in July 2015 retrospectively evaluated survival in 806 ovarian cancer patients who received treatment in Kaiser Permanente Northern California healthcare settings; 30% of the 806 were obese and 31% were overweight. These patients were treated with adjuvant first-line carboplatin and paclitaxel with curative intent. Having received lower doses of chemotherapy per pound of their body weight (38% and 45% lower dose in mg/kg for paclitaxel and carboplatin) compared with their normal weight counterparts, the lower relative dose intensity was an independent predictor of mortality in these patients, the study concluded.6

NCI-FUNDED RESEARCH

While research by scientists like Sarkar helps identify targets that are common to obesity and cancer, the National Cancer Institute (NCI) has rolling initiatives to provide funding support for numerous activities including web and data resources, extramural and intramural epidemiologic studies, basic science research, and dissemination and implementation.7 The TABLE lists NCI-funded projects and initiatives that address the obesity and cancer risk.

Data gathered over the years have provided sufficient evidence on the negative impact of weight on cancer outcomes. We now need integrated care models to translate these findings into patient care.

References

1. Robertson CL, Srivastava J, Siddiq A, et al. Astrocyte Elevated Gene-1 (AEG-1) regulates lipid homeostasis. J Biol Chem. 2015;290(29):18227-18236.

2. AACR Cancer Progress Report 2014. http://cancerprogressreport.org/2014/Documents/AACR_CPR_2014.pdf. Accessed August 12, 2015.

3. Ligibel JA, Alfano CM, Courneya KS, et al. American Society of Clinical Oncology position statement on obesity and cancer. J Clin Oncol. 2014;32(31): 3568-3574. http://jco.ascopubs.

org/content/early/2014/10/01/JCO.2014.58.4680. Accessed August 24, 2015.

4. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625-1638.

5. Yuan C, Bao Y, Wu C, et al. Prediagnostic body mass index and pancreatic cancer survival. J Clin Oncol. 2013;31(33):4229-4234.

6. Bandera EV, Lee VS, Rodriguez-Rodriguez L, Powell CB, Kushi LH. Impact of chemotherapy dosing on ovarian cancer survival according to body mass index [published online July 20, 2015]. JAMA Oncol. doi:10.1001/jamaoncol.

7. Obesity and cancer risk. National Cancer Institute website. http://www.cancer.gov/about-cancer/causes-prevention/risk/obesity/obesity-fact-sheet#q14. Accessed August 11, 2015.