Causes of and Risk Factors for Pancreatic Cancer
While the exact cause of pancreatic cancer is not known with certainty, several factors—including smoking, nutrition, glucose levels, hormones, and genetics—are thought to be involved in its initiation and development.
Genetic susceptibility is thought to account for 10% to 20% of cases, but ongoing research may reveal that the role of genetics exceeds these estimates (Brand 2000). About 40% of cases are associated with inflammatory conditions caused by poor nutrition, excessive alcohol consumption, chronic pancreatitis, obesity, and chemical exposure (Greer 2009).
Modifiable/Acquired Risk Factors
Smoking. Thirty percent of all pancreatic cancers are associated with smoking and tobacco use (Tranah 2011). Both active cigarette or cigar smoking, as well as exposure to tobacco smoke, increase pancreatic cancer risk. That risk, however, is reduced to levels of non-smokers within 5-10 years of quitting. Heavy cigarette smokers and cigar smokers have roughly a 50 – 60% increased risk compared to non-smokers (Bertuccio 2011). People who smoke and drink are diagnosed with pancreatic cancer at a younger age compared to never-smokers (Brand 2009).
Diabetes Mellitus. Long-standing diabetes (diabetes diagnosed at least 5 years prior to the diagnosis of pancreatic cancer) increases the risk of pancreatic cancer by 40-100%. Recent-onset diabetes (within 3 years) is associated with a 4- to 7-fold increase in risk, such that 1-2% of patients with recent-onset diabetes will develop pancreatic cancer within 3 years (Magruder 2011; Yang 2009).
Glucose levels. Over-consumption of sugar, sugar-sweetened soft drinks or foods, and foods that elevate after-meal blood sugar levels increase the risk of pancreatic cancer, particularly in individuals with insulin resistance (Larsson SC 2006; Bao Y 2008). A high glycemic load (glucose load in the blood) and fructose were associated with a greater risk of pancreatic cancer (Michaud 2002) and hyperglycemia (high blood sugar/glucose levels) promotes pancreatic cancer progression in cell-based studies (Liu 2011; Bao 2011).
Dietary factors. Dietary factors play a major role in the development of pancreatic cancer. High intake of dietary fat of animal origin, saturated fats and oils (Zhang 2009), cholesterol (Lin 2005), including omega-6 fatty acids (Funahashi 2008), fried foods, meat, and dairy products clearly increase the risk (Thiébaut 2009). Likewise, intake of excess calories, carbohydrates and processed meat (which are sources of dietary nitrates, nitrites and nitrosamines) increase the risk (Johnson 2011; Aschebrook-Kilfoy 2011).
Vitamin and Micronutrient Deficiency. Deficiency in folate, vitamin B6, B12 and methionine, as well as reduced intake of vitamins C, D, and E, calcium, potassium, and selenium increase the risk of pancreatic cancer development (Schernhammer 2007). Conversely, a high dietary intake of vitamins C, D and E, selenium, fruits, vegetables, and fiber lower the risk (Bidoli 2011; Bravi 2011). Higher vitamin D intake (greater than or equal to 600 IU per day) is associated with a 41% lower risk of pancreatic cancer compared to those with the lowest intake (<150 IU/day) (Skinner 2008; Bao 2010).
Folate. Folate deficiency increases risk of pancreatic cancer, due to hypomethylation of DNA (Friso 2002). Conversely, higher folate intake from food sources (or fortified foods with folic acid) and methionine, significantly decrease the risk of pancreatic cancer by 53% (Oaks 2010; Schernhammer 2007).
Periodontal Disease. Those with a history of periodontal disease have a 54% to 100% greater risk of pancreatic cancer. Tooth loss was positively associated with pancreatic cancer development (Michaud 2007; Michaud 2008). In addition, helicobacter pylori (H. Pylori) are found in dental plaque and are associated with periodontal disease and pancreatic cancer (Stolzenberg-Solomon 2003).
High Body Mass Index (BMI) and/or Obesity. Individuals who are overweight and have a high BMI have an increased risk of developing pancreatic cancer (Li 2009). A high BMI and hyperinsulinemia often occur together, and it is well-established that insulin promotes pancreatic cancer growth and development (Fisher 1996; Dandona 2011). Those who are overweight or obese from the ages of 20 to 49 years have an earlier onset of pancreatic cancer (Berrington de Gonzalez 2003). Obesity at an older age is associated with a lower overall survival in pancreatic cancer patients (Li 2009).
Alcohol. Heavy drinking (>9 alcoholic drinks per day) and binge drinking increase pancreatic cancer risk (Lucenteforte 2011; Gupta 2010). A significant increase in risk was seen among men consuming 45 or more grams of alcohol from liquor per day (Michaud 2010). Drinking >3 liquor drinks (but not beer or wine) was associated with death from pancreatic cancer (Gapstur 2011).
Chronic Pancreatitis. Chronic pancreatitis is associated with a 13- to 18-fold increase in the subsequent development of pancreatic cancer (Kudo 2011; Talamini 1999). Chronic pancreatitis is associated with heavy alcohol consumption; approximately 10% of heavy drinkers develop chronic pancreatitis (Nitsche 2011).
Chemical Exposure. Chemical exposure has been implicated in the cause of pancreatic cancer. Chemicals such as DDT (dichlorodiphenyltrichloroethane), formaldehyde, petroleum products, synthetic rubber, resins, polyesters, plastics, and styrene are involved in causing pancreatic cancer (National Toxicology Program 2012; Huff 2011).
Helicobacter Pylori (H.Pylori) Infection. Recently a population-based case control study, and a meta-analysis evaluating 2335 patients, demonstrated an association between the development of pancreatic cancer and H. pylori infection, particularly for individuals with non-O blood types (Risch 2010; Trikudanathan 2011).
Intrinsic/Unmodifiable Risk factors
Age, sex, race, and ethnicity. The disease is more common in the elderly, men, and among African-Americans (Ghadirian 2003).
Inherited pancreatic disease. Individuals with hereditary pancreatitis have a higher lifetime risk for developing pancreatic cancer (Langer 2009). Individuals with immediate family members affected by the disease are at increased risk (up to 57-fold with 3 or more family members affected) and should consider pancreatic cancer screening if it becomes available (Zubarik 2011; Stoita 2011).
Are Hormones Involved?
Clinical studies indicate that pancreatic cancer patients have sex steroid hormone imbalances and respond to various hormonal therapies. However, the treatment outcome may be dependent on individual patient and tumor characteristics, such as hormone receptor expression (Stolzenberg-Solomon 2009; Ganepola 1999).
Testosterone. A recent study indicates that hormone imbalances in pancreatic cancer patients are associated with shortened survival (Skipworth 2011).
Male pancreatic cancer patients often have lower levels of free testosterone and progesterone and higher levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol. Female pancreatic cancer patients often have higher levels of estradiol and lower levels of LH, FSH and progesterone (Fyssas 1997). In addition, pancreatic cancer patients have significantly lower testosterone / dihydrotestosterone (DHT) ratios (Jansa 1996; Robles-Diaz 2001).
A low serum testosterone in men and excess estrogen in women is associated with shortened survival in advanced pancreatic cancer, indicating a critical need for hormone manipulation and dietary intervention. Hypogonadal males have a 3 times greater risk of death compared with those with balanced hormones (Skipworth 2011).
Systemic inflammation (determined by C-reactive protein [CRP], and interleukin-6 [IL-6] levels) and opioid use are associated with decreased total testosterone and free testosterone and worsened survival (opioid use almost doubles the risk of death). Furthermore, women with high estrogen showed worsened survival (2.43 times greater risk of death) compared with those with balanced hormones (Skipworth 2011).
Hormone levels (total testosterone, free testosterone, FSH and LH and pro-inflammatory mediators (CRP, IL-6) can be measured by a simple blood test to determine hormone and inflammation status, both of which can be improved with nutritional supplementation. Studies indicate that poor nutritional status correlates with lower total testosterone levels in pancreatic cancer patients (Sperti 1992).
Genetics and Pancreatic Cancer
Several key genes are overproduced and/or activated in pancreatic cancer, and these can be specifically targeted to stop tumor growth (Xu 2011). Therefore, genetic analyses may be valuable in helping to determine an optimal individualized treatment plan, involving gene targeting, to prevent cancer progression (Grutzmann 2003). These tests can be performed by Genzyme Genetics (www.genzymegenetics.com).
Activation of cancer-associated genes (oncogenes)
Four cancer-associated genes (oncogenes) are mutated in most cases of pancreatic cancer (K-ras, p16, p53, and MADH4 genes). Activation of the K-ras oncogene plus inactivation of tumor suppressor genes (p53, p16, DPC4, and BRCA2) are associated with the development of pancreatic cancer (Moore 2003). The transcription factors STAT3 and NFkB (nuclear factor kappa B) are aberrantly activated in pancreatic cancer. These mutated genes, transcription factors, and inactivated tumor suppressor genes can be specifically targeted by nutritional supplements and dietary-derived targeted therapies (see sections below).
Nearly 95% of all cases of pancreatic cancer have K-ras mutations, 90% have p16 mutations, (Bartsch 2002), 75% have p53 mutations, and 55% have DPC4 mutations (Cowgill 2003).
Ras genes. Ras proteins play a central role in regulating cell growth and multiplication. Mutations in the ras genes can transform normal cells into cancerous cells that grow rapidly and form tumors. Mutations in the ras oncogene is a molecular fingerprint of this disease (Brasiuniene 2003). Smoking, alcohol, milk, and dairy consumption have been linked with the occurrence of ras mutations in pancreatic tumors (Greer 2011).
Detection of K-ras mutations. The detection of K-ras mutations may help to predict treatment outcome (Bussom 2010). K-ras mutations are relatively easy to detect (Parker 2011) in different human tissues, including blood, intestinal fluid (Wilentz 1998), pancreatic fluid (Boadas 2001), stool (Caldas 1994; Kisiel 2011), regional lymph nodes and other bodily fluids, and the tumor itself (Brasiuniene 2003).
The cellular response to Ras gene activity can be inhibited in vitro by genistein, curcumin, green tea extract containing epigallocatechin gallate (EGCG) (Johnson 2011; Singh 2011; Lyn-Cook 1999) and fish oil containing the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Morales 2007).
Ras gene activity can be slowed by:
- D-Limonene and perillyl alcohol, natural monoterpenes from citrus fruits (Johnson 2011; Stayrook 1998).
- Black tea extract containing black tea polyphenols (Lyn-Cook BD 1999).
- Garlic’s bioactive constituent, diallyl disulfide (Lai KC 2011; Singh SV 2001).
HER2 (human epidermal growth factor receptor-2) is found in many pancreatic cancers and is associated with poor patient survival rates. Patients with HER2 overexpression tumors had significantly shorter survival times than those with HER2 normal expression tumors (median survival time, 14.7 vs 20.7 months, respectively (Komoto 2009). Therefore, nutritional supplements that target HER2 are crucial to improve survival of many pancreatic cancer patients:
- The tocotrienol form of vitamin E can cause pancreatic cancer cell death by downregulating HER2 and suppression of vital tumor cell survival pathways (Shin-Kang 2011).
- HER2 can be targeted specifically by the anti-HER2 monoclonal antibody drug trastuzumab (Herceptin®) (Mihaljevic 2009).
EGFR (epidermal growth factor receptor). In pancreatic cancer cells, EGFR is activated and levels are up to 4-fold higher than in normal healthy pancreatic cells (Friess 1999).
- Genistein is powerful in reducing levels of EGFR (McIntyre 1998) and disables the EGFR signaling pathway (Johnson 2011).
- Curcumin and EGCG from Green Tea also block EGFR activity in pancreatic cancer cells (Vaccaro 2011; Shehzad 2010).
- The pharmaceutical agent erlotinib inhibits signaling of EGFR, and is FDA approved for use in combination with gemcitibine for patients with locally advanced unresectable or metastatic pancreatic cancer (FDA 2005; Mountzios 2011). In clinical trials, erlotinib has performed well in combination with gemcitibine and other chemotherapeutic agents (Oh 2011), but survival is not significantly prolonged. Some preliminary evidence suggests that erlotinib may improve chemosensitivity in pancreatic cancer (Saif 2011).
Important genes turned off in pancreatic cancer
Compared to other major types of cancer, pancreatic cancer displays a loss of activity of genes known to suppress tumor development, such as p16, DPC4, BRCA2, and most importantly p53.
P16: Ninety percent of pancreatic carcinomas suffer a loss of p16 function. Moreover, carriers of p16 germline mutations have a 12- to 20-fold increased risk of developing pancreatic cancer (Schutte 1997).
DPC4: The absence of this gene is associated with more invasive cancer growth (Cowgill 2003). However, pancreatic cancer cells with a DPC4 homozygous (complete) deletion are sensitive to nontoxic doses of alpha-tocopherol succinate (Greco 2010).
BRCA2: This is the most common mutation in patients with hereditary pancreatic cancer. Carriers of BRCA2 mutations have a 3.5- to 10-fold increased risk of developing pancreatic cancer. A clinical case study suggests that patients with metastatic pancreatic carcinoma and BRCA2 mutations may have disease that is more sensitive to camptothecin-11 chemotherapy and consequently have prolonged survival (James 2009).
p53: Because the p53 gene is a tumor suppressor gene involved in repairing damaged DNA, when the gene is inactive (turned off) or malfunctions, damaged DNA is able to proliferate and form cancerous cells (Berrozpe 1994).
Nutritional supplements known to restore function of the p53 tumor suppressor gene include:
- Curcumin and resveratrol both upregulate p53 in pancreatic cancer cells (Goel 2008; Zhou 2011).
- Omega-3 fatty acids activate p53 (Wendel 2009).
- Gamma-tocotrienol reduces cell survival proteins through the p53 pathway (Kannappan 2010).
- Red grape seed proanthocyanidins (Roy 2005; Joshi 2001).
- Phytochemicals such as genistein from soy (Lian 1999), indole-3-carbinol (I3C) from cruciferous vegetables, the green tea polyphenol EGCG (Shankar 2007; Katdare 1998), and resveratrol (Zhou 2011).
Regulation of Transcription Factors.
A transcription factor controls whether a particular gene is turned on (active) or turned off (inactive). Transcription factors can be activated or deactivated selectively by other proteins, often as a final step in the process of transmitting their signals. The presence and activity of these factors can differ in normal and cancerous tissues.
STAT3. STAT3 is a dormant transcription factor activated in pancreatic cancer but not in normal pancreatic tissue; it plays an important role in the progression of pancreatic cancer. Silencing of the STAT3 gene using nutritional agents such as I3C and genistein (Lian 2004) may be a novel therapeutic option for treatment of pancreatic cancer (Huang C 2011). Omega-3 fatty acids inhibited the proliferation of pancreatic cancer cells by decreasing STAT3 phosphorylation (Hering 2007).
NF-kappa B (NFkB). NFkB is another transcription factor activated in human pancreatic cancer but not in normal pancreatic tissue. Blocking NFkB activity prevents cancer invasion and spread (metastasis) in animals with tumors. Furthermore, preventing NFkB activity reduces levels of molecules involved in tumor blood-vessel development, thereby retarding tumor growth and slowing cancer spread (Fujioka 2003).
- Gamma-tocotrienols inhibit human pancreatic tumor growth and sensitize them to gemcitabine by suppressing NFkB-mediated inflammatory pathways linked to the formation of tumors (Kunnumakkara 2010).
- Genistein and curcumin both reduce NFkB activation (Jutooru 2010; Kim 2007; Li 2004).
- The omega-3 fatty acid EPA inhibits NF-kB (Ross 2003)