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Dietary Fat and Prostate Cancer: An important update
James Meschino DC, MS, ROHP
In 2014, a review paper examining the role of dietary fat on prostate cancer development and progression was published in the journal,Nutrients, by K.M. Di Sebastiano and M. Mourtzakis. These authors did a stellar job of summarizing the available data on fat and prostate cancer, and their review paper sheds light on the importance of counseling men on the dangers of consuming too much bad fat in regard to prostate cancer prevention and adjunctive management in men who are prostate cancer survivors. This article highlights the key findings from their review of the literature.
Incidence and Dietary Fat as an Etiological Factor
On a worldwide basis prostate cancer is the second most common malignancy diagnosed in men, second only to lung cancer. Various lifestyle and dietary factors are associated with prostate cancer development, as is obesity. Dietary fat appears to be doubly lethal as it contributes to obesity, and on an independent basis, some types of fat have been shown to promote prostate cancer development, progression and metastasis. Overall, numerous studies appear to support the finding that high intake of dietary fat, especially high intake of animal and saturated fats, may be associated with increased prostate cancer risk. In comparison, a low-fat diet, specifically low in saturated fat, is associated with a beneficial effect in prostate cancer survivors as it appears to reduce tumor angiogenesis and cancer recurrence. The authors suggest that too much bad fat negatively influences the signal transduction pathway within prostate cells known as the insulin-like growth factor (IGF)/Akt signaling pathway. When this pathway is over stimulated or dysregulated it is known to promote prostate cancer development and progression. However, saturated fat,transfats and obesity itself, have been shown to promote prostate cancer via other mechanisms as well, which are outlined below.
Links between high fat diet and prostate cancer had been emerging for a number of years but the Health Professionals Follow-up Studyby E. Giovannucci et al, a prospective analysis of dietary fat and prostate cancer risk, showed a very strong association between fat and prostate cancer. This study used a semi-quantitative food frequency questionnaire to assess dietary fat in these men. They concluded that total fat consumption was related to the risk of advanced cancer and that this relationship was primarily related to animal fat consumption. Of special note was the fact that fat from dairy products, with the exception of butter, appeared to be unrelated to advanced prostate cancer risk, but still related to overall prostate cancer development.
In general, the scientific literature shows that specific categories of fats – saturated and animal fats – appear to pose the greatest risk for prostate cancer development, while EPA (eicosapentaenic acid from fish and fish oil) may have a protective effect.
As well, obesity itself is associated with increased incidence of high-risk or aggressive prostate cancer, as well as increased incidence of prostate cancer recurrence. A great paradox of prostate cancer treatment is that androgen deprivation (or ablation) therapy tends to encourage more body fat deposition, which in turn may promote prostate cancer recurrence. The authors conclude that “there are numerous nutritional factors associated with obesity and prostate cancer risk, including positive energy balance, red meat and dairy intake, saturated fat, trans-fatty acid intake and total dietary fat intake. Conversely, n-3 fatty acids have been identified as having a potentially protective effect against prostate cancer”.
Mechanisms by Which Bad Fats Promote Prostate Cancer
Various mechanisms have been identified that potentially explain how bad fats or too much animal fat can promote prostate cancer development and progression. These include changes in the insulin-like growth factor (IGF)-Akt pathway, androgen signaling, alterations in cell proliferation and angiogenesis, and via increased generation of reactive oxygen species (free radicals):
- IGF-1/Akt Signaling Pathway – It has been identified that the IGF signaling pathway is one of the main regulating pathways in which dietary fat can promote prostate cancer development and progression. Dietary fat intake is positively correlated with circulating levels of IGF-1(Insulin-like growth factor-1), which may ultimately result in increased signaling through the IGF signaling pathway. The IGF system plays a critical role in cell proliferation, differentiation, apoptosis and transformation. Dysregulation of this system is a common finding in prostate cancer pathophysiology. Fat intake also tends to be related to lower amounts of insulin-like growth factor binding protein-3 (IGFBP-3), the major binding protein of IGF-1 in plasma. Lower blood levels of IGFBP-3 allow more IGF-1 to stimulate IGF-1 receptors, which likely over stimulates the IGF-1/Aky pathway, encouraging prostate cancer development. Lower IGFBP-3 serum levels is independently associated with the risk of prostate cancer.
Dysregulation of the IGF-1/Akt signaling pathway also activates NF kappa beta in cancer cells resulting in decreased cell death. More specifically, Akt activation promotes signaling in the IGF-1Receptor/IRS-1 axis, which contributes to the dysregulation of NF kappa beta, and, ultimately, cancer cell growth. The IGF-1R/IRS-1 axis also indirectly increases mTOR activity. The mTOR also promotes cell growth via specific signal transduction pathways. “Thus, increased dietary fat intake may potentially promote malignant cell growth through increased IGF-1 and decreased IGFBP-3, resulting in increased IGF-1 signaling through the IGF-1R, a receptor implicated in the transformation of healthy cells to cancerous cells and a mediator of cell growth through the IGF-1R/IRS-1 axis”.
- Androgen Signaling Pathway – Androgen signaling is another pathway by whichdietary fat intake appears to promote prostate cancer development. In fact, some studies show that decreased dietary fat intake is associated with decreased androgen and testosterone levels, which subsequently improves signaling mediated through the IGF-1 signaling pathway. Androgens play a key role in prostate development and function, but androgen signaling and, specifically, the androgen receptor, also known as nuclear receptor subfamily 3, group C, member 4, (NR3C4), is the principle stimulant of prostate cancer progression. Androgens stimulate prostate cancer cell growth via the Erk-2 pathway, where Erk-2 activation increases the androgen receptor complex content in the prostate cells. Androgens also increase IGF-1R expression, which is associated with prostate cancer development, as previously described.
In the early stages of development, malignant prostate cancer cells require androgen stimulation for growth. However, increased androgen receptor growth eventually leads to a transition to hormone-resistant cancers, the more aggressive form of prostate cancer, and activation of heat shock protein (HSP) 90. HSP90 is a chaperone protein of the androgen receptor. All of these changes further stimulate signaling through the androgen receptor pathway resulting in increasingly malignant behaviour of prostate cancer cells.
High-fat diets have been shown to increase stimulation through the IGF-1 axis, as well as being associated with increased androgen and testosterone levels. Diets low in total and saturated fat and high in n-3 fatty acids counter this pathway by inhibiting IGF-1 binding and decreasing HSP90 association with the androgen receptor, which results in androgen receptordegradation, reduction of androgen receptor proteins, and reduction in the number of androgen receptor-regulated genes. All of these factors reduce prostate cancer development and prostate cancer progression.
- Angiogenesis – Angiogenesis is the mechanism by which tumor cells encourage the synthesis of new blood vessels to feed more tumor growth. Angiogenesis greatly increases the metastatic potential of tumors and is associated with poor prognosis of many types of cancer. Of special note is the fact thatn-3 fatty acid intake has been shown to inhibit malignant cell proliferation and angiogenesis. n-3 fatty acids work both intrinsically (mitochondrial pathway) and extrinsically (death receptor pathway) to induce apoptosis (programmed cell death of cancer cells, but not healthy cells). Omega-3 fats appear to exert this anti-angiogenesis effect by inhibiting the PI3K activity (phosphatidylinositol-3 kinase), which activatesthe Akt complex. ActivatedAkt regulates a number of downstream signaling peptides that can directly affect apoptosis and the cell cycle. In short, activated Akt leads to decreased apoptosis whereas inhibition of these pathways via n-3 fatty acids ultimately results in increased cell death of tumor cells. As such, n-3 fatty acids may have an important role in inhibiting malignant cell proliferation and angiogenesis.
- Free Radicals or Reactive Oxygen Species – Total dietary fat and saturated fat have also been shown to enhance cell proliferation and angiogenesis through the generation of reactive oxygen species (ROS). ROS generated endogenously and externally are associated with cancer progression by inducing a number of cancerous changes within the cell. ROS alter the conformational structure of the p53 protein, resulting in a mutated phenotype of the protein. P53 protein is a key protein that directs the process of apoptosis of cancer cells. Changes to the p53 protein inhibit the ability of cells to induce apoptosis, via intrinsic pathways, when cancer cells are emerging. These types of p53 mutations are specifically important in prostate cancer progression. Total dietary fat, especially n-6 fatty acids, as well as androgens can all serve as oxidants, directly increasing the level of ROS in the cells and its subsequent damage and consequences, including up-regulation of transcription factors that speed up cell replication (another risk factor in cancer development). The authors also note that “oxidative stress has been shown to be higher in the benign epithelium of men with prostate cancer when compared to men without prostate cancer, while Lee et al, demonstrated that inactivation of glutathione-s-transferase pi, a pro-oxidant scavenging enzyme, is critical in the development of prostate cancer carcinogenesis. Specifically, dietary fat consumption may contribute to the carcinogenesis of prostate tissue via lipid peroxidation, thus resulting in increased oxidative stress”.
Prostate Cancer Survivors
It is too early to confirm that bad fats promote cancer recurrence in prostate cancer survivors, but preliminary studies demonstrate that fat intake, specifically saturated fat intake, may decrease disease-specific survival. In one study, Fradet and colleagues followed a group of men diagnosed with prostate cancer for an average of 5.2 years. After controlling for cancer grade, clinical stage, treatment age and total energy intake, men in the lowest tertile of saturated fat intake had a decreased risk of dying from prostate cancer, as compared to those in the highest tertile of saturated fat intake. Findings such as these may prompt health practitioners to encourage prostate cancer patients to reduce their intake of total animal fat (with the exception of fish) and saturated fat, while we await the findings of well-designed intervention studies that are needed to confirm if manipulating dietary fat can have positive effects on survivorship.
Other studies have combined a low-fat diet with supplementation of flaxseed, noting beneficial effects on prostate health. For instance. Demark-Wahnefried et al. demonstrated decreased proliferation rates in the men supplemented with flaxseed and that the low-fat diet group had significantly reduced serum cholesterol levels following ~30 days of supplementation. Heymach et al.demonstrated that, as compared to the control arm, a low-fat diet, a flaxseed-supplemented diet and a low-fat diet with a flaxseed supplementation for 30 days had each decreased a number of angiogenic factors, though the results were greatest in the low-fat diet alone group.
The emerging data tends to support the findings that dietary fatand, in particular, high intake of animal and saturated fats, may be associated with prostate cancer risk. The IGF/Akt signaling pathway appears to be the key signaling pathway moderating malignant cell growth and changes in androgen receptor signaling. Overall, saturated fat and trans fatty acids appear to promote prostate cancer development, while omega-3 fats may have a protective effect, For prostate cancer survivors, a diet low in fat and particularly low in saturated fat may be beneficial, as it may reduce tumor angiogenesis and cancer recurrence. The addition of flaxseed supplementation may also be beneficial in these cases.
As one of the ways to help patients prevent prostate cancer development and recurrence, health practitioners may wish to counsel patients about the potential for bad dietary fats to promote prostate cancer. As prostate cancer is the second leading cause of cancer death in men, it seems prudent to discuss with patients evidence-based methods that mayhelp reduce the risk of this disease and its recurrence. In my view the evidence linking a high-animal fat/saturated fat diet with increased prostate cancer risk is sufficient for us toadvise men to make appropriate dietary changes that would eliminate or greatly reduce their intake of these fats. Reducing these fats also helps to reverse obesity, another documented risk factor for the development of advanced prostate cancer.
Di Sebastiano KM and Mourtzakis M. The Role of Dietary Fat throughout the Prostate Cancer Trajectory. Nutrients. 2014 Dec; 6(12): 6095–6109. Published online 2014 Dec 22. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277017/