Prostate Cancer-2

Lycopenes and Their Critical Role in Cancer Prevention

a)Tomato-Based Products
b)Tissue Lycopene Levels
c)Assimilation
d)Lycopenes And Strawberries Lower Risk
e)Gene Up-regulation of Connexin 43
f)Lycopene and Vitamin D
g)Reduce Cardiovascular Risk Factors
h)Decreases Insulin-like Growth Factor Levels
i)Increase Lycopene Consumption and Plasma Levels

Of all nutritional literature currently in existence relating to PC, the relationship between lycopene ingestion and the health of the prostate is the clearest. Lycopene consumption been found to decrease not only the risk of PC in multiple studies,14-16 but also the risk of BC17 and pancreatic and stomach cancer,16 as well as lung cancer.18


Tomato-Based Products Are the Richest Sources of Lycopene
In these positive studies that correlated lycopene consumption with decreased risk of PC, the lycopene sources were tomato-based products. The richest sources of lycopene in the U.S. diet are ketchup, tomato juice, and pizza sauce; these account for over 80% of the total lycopene intake of Americans.19 In one study from Athens, Greece, the authors concluded that the incidence of prostate cancer in Greece could be reduced by about 40% if the population increased the consumption of tomatoes, reduced the intake of dairy products, and substituted olive oil for other added lipids.20


Lycopene Consumption Correlates with Blood and Tissue Lycopene Levels
The correlation between increased tomato-based consumption of lycopenes and the decreased risk of PC and other cancers is also found in the laboratory, where serum levels of lycopene are correlated with lycopene intake. The same holds true in studies in which tissue levels of lycopene have been studied in prostate pathology specimens.16,17

Lycopene concentrations in the serum of healthy men are typically 0.60-1.9 nmol/mL (nanomoles per milliliter).21 Biochemically, lycopene is composed of two main chemical structures or isomers: all-trans-lycopene and cis-isomers. Tomato sauce contains primarily all-trans-lycopene (83% of total lycopene). The ingestion of tomato sauce results in substantial increases in total lycopene levels in both the serum and prostate tissue and a substantial increase in all-trans-lycopene in prostate tissue but with relatively smaller increases in the serum.22 Serum lycopene levels are predominantly composed of the cis-isomer of lycopene, which represents 58-73% of the total serum lycopene, while the all-trans-isomer composes 27-42% of the serum lycopene.21

Among 72 studies identified, 57 reported that higher tomato intake or blood lycopene levels reduced the risk of cancer at a defined anatomic site; 35 of these associations were statistically significant.23 The evidence for a benefit was strongest for cancers of the prostate, lung, and stomach. Data were also suggestive of a benefit for cancers of the pancreas, colon and rectum, esophagus, oral cavity, breast, and cervix. The relative risk (RR) was determined, comparing high tomato intake or high lycopene levels with low tomato intake or low lycopene levels. In such comparisons, about half of the RR was close to 0.6 or lower.23 In another study, the odds of contracting aggressive PC were significantly lower when plasma lycopene levels were high. Plasma lycopene levels were divided into five quintiles. The highest level, the fifth quintile, showed an odds ratio (OR) of 0.56.14 These findings add up to about a 40% reduction in risk of being diagnosed with these cancer types for those with high tomato intake or the highest plasma lycopene levels.


The Proof of the Pudding Is Not in the Eating but in the Assimilation
The proof of the pudding, in the matter of dietary issues, relates more to how we assimilate what we have eaten rather than to just a history of having eaten something. It should not be surprising then that the correlation between serum or plasma lycopene levels and a lower incidence of PC is greater than the correlation between the oral intake of lycopenes and PC incidence. In a study by Lu et al., significant reductions in PC incidence were observed with higher plasma concentrations of the following carotenoids: lycopene, OR 0.17; and zeaxanthin, OR 0.22, when comparing highest and lowest quartiles.24 This translates into about an 80% reduction in PC incidence when the highest blood levels of either lycopene or zeaxanthin are achieved.


Lycopenes and Strawberries Lower Risk, Especially for Aggressive and Extra-Prostatic PCA dietary history of significant lycopene and/or strawberry consumption correlated with a lower risk of aggressive and extra-prostatic PC.14 The lycopene source that was found to be most significant in most epidemiologic studies was the tomato, in the form of tomato sauce, stewed tomatoes, and pizza. In one large-scale study involving 812 new cases of PC over the years 1986-1992 with matched controls, of the 46 vegetables and fruits or related products significantly associated with lower PC risk, three of the four identified were related to lycopenes--tomato sauce, tomatoes, and pizza. In this study, the combined intake of tomatoes, tomato sauce, tomato juice, and pizza (accounting for 82% of lycopene intake) was associated with a reduced risk of PC for consumption frequency greater than 10 versus less than 1.5 servings a week. Lycopene intake was also associated with a 53% reduced risk for advanced PC (Stages III and IV). The other nonlycopene product identified with significantly lower PC risk was strawberries.15

The largest relevant dietary study, a prospective study in male health professionals, found that consumption of 2-4 servings of tomato sauce a week was associated with about a 35% risk reduction of total PC and a 50% reduction of advanced (extra-prostatic) PC. Tomato sauce was by far the strongest predictor of plasma lycopene levels in this study.25 These associations persisted in analyses controlling for fruit consumption, vegetable consumption, and olive oil use and were observed separately in men of Southern European or other Caucasian ancestry.26


Lycopene Inhibits Cancer Cell Growth by Gene Up-regulation of Connexin 43Lycopene functions as a very potent antioxidant. In this regard, lycopene can trap singlet oxygen and reduce mutagenesis (gene mutations) in the Ames test. Other mechanisms of lycopene action may be operative as well. Lycopene at physiological concentrations can inhibit human cancer cell growth by interfering with growth factor receptor signaling and cell-cycle progression--specifically in PC cells--without evidence of toxic effects or apoptosis of cells.27 Studies of human and animal cells have identified connexin 43, a gene, whose expression is up-regulated by lycopene and which allows direct intercellular gap junctional communication (GJC). GJC is deficient in many human tumors and its restoration or up-regulation is associated with decreased proliferation.


Lycopene Is Synergistic with Vitamin D, Inhibiting Tumor Cell Proliferation and Enhancing Differentiation
The combination of low concentrations of lycopene with 1,25-dihydroxyvitamin D3 exhibits a synergistic effect on inhibition of cell proliferation, and differentiation, and an additive effect on cell-cycle progression in the HL-60 promyelocytic leukemia cell line, suggesting some interaction at a nuclear or subcellular level.18


Lycopenes Reduce Cardiovascular Risk Factors
Lycopene levels decrease with advancing age. However, in contrast to other carotenoids, they are not found to be reduced by smoking or alcohol consumption.16,19 Lycopenes also have an inhibitory effect on cholesterol synthesis and may enhance LDL degradation. Available evidence suggests that intimal wall thickness and risk of myocardial infarction are reduced in persons with higher adipose tissue concentrations of lycopene.19


Lycopene Levels May Be Associated with Decreased Insulin-like Growth Factor Levels
The consumption of cooked tomatoes was substantially and significantly associated with reduced insulin-like growth factor-1 (IGF-1) levels, with a mean change of -31.5% for an increment of 1 serving a day. The authors concluded that the strongest known dietary risk factor for PC (lycopene deficit, as reflected in a reduced intake of cooked tomatoes) is somehow related to an important endocrine factor (IGF-1) in the cause of this disease.28 However, in another study, IGF-1 was not associated with any dietary factor studied, such as total fat, carbohydrate, protein, dairy products, tomatoes, or calcium.29


Suggested Ways to Increase Lycopene Consumption and Plasma Levels
The easiest way I have found to combine a healthy intake of lycopenes into my diet is by using marinara sauce on various foods. For example, at breakfast, an egg-white omelet containing eggplant and bell peppers (ratatouille omelet) covered with marinara sauce is a healthy source of protein, contains a substantial fiber content, and is restricted in the amount of simple carbohydrates. Stewed tomatoes can be served as a vegetable side dish with lunch or dinner.


Dietary Fat Increases PC Growth Rates

There are studies that show that dietary fat increases tumor growth rates in an animal model of human PC. In a mouse model of PC involving androgen-sensitive human prostatic adenocarcinoma cells (LNCaP cells), mice fed a 40.5% fat diet had mean tumor weights more than 2 times greater than mice fed a 21% fat diet. The 40.5% fat diet approximates that found in the average American male diet, which has been determined to be 36%.30

The slower tumor growth associated with the low-fat diet occurred even after the formation of measurable tumors when the diets were changed from 40% fat to 21% fat. Serum PSA levels also were highest in the 40.5 kcal% fat group and lowest in another group fed only 2.3 kcal% fat.30


Reduction of Total Calorie Consumption Decreases Tumor Size by Decreasing VEGF, Angiogenesis, and IGF-1 and by Increasing Apoptosis

The emphasis on dietary fat, per se, has lessened our focus on the importance of caloric over-consumption. Fat excess, however, is linked to excessive calorie consumption, since fat contains twice as many calories, gram for gram, as protein or carbohydrate.

I believe that diet should be regarded as having serious biochemical relevance to the health of the individual. You are, for the most part, what you eat (or at least what you assimilate). Western societies, especially the United States, are consumers of excessive calories. Excessive caloric consumption, especially coupled with a sedentary lifestyle, is a significant factor that adversely affects longevity.

An important study demonstrated that energy intake (caloric intake) modulates the growth of prostate tumors in two animal models: the androgen-dependent Dunning R3327-H adenocarcinoma in rats and the androgen-sensitive LNCaP human adenocarcinoma in severe combined immunodeficiency (SCID) mice.31 Specifically, decreasing calorie consumption (energy restriction) by 20-40% from the control animals fed ad libitum resulted in:

Increased PC cell apoptosis (programmed cell death)
A two- to threefold reduction in PC angiogenesis as measured by microvessel density
A decrease in vascular endothelial growth factor (VEGF) expression
A decrease in circulating levels of IGF-1
A significant decrease in tumor size
Therefore, all of these findings were benefits observed in the calorie-restricted group. This study showed that the nutritional status directly or indirectly influenced interaction between tumor cells and local blood vessels by changing the expression of angiogenic growth factors. In the Dunning model, energy (calorie) restriction resulted in a striking inhibition of VEGF expression. In the LNCaP model, there was little baseline expression of VEGF. However, there was an almost threefold reduction from the baseline IGF-1 levels in blood samples from LNCaP-bearing mice that were subjected to energy restriction.


IGF-1 Levels Stimulate PC Growth, Up-regulate uPA, and Stimulate Angiogenesis

a)IGF-1 and uPA Increases Aggressive PC Growth
b)GLA and EPA Inhibit uPA

Higher IGF-1 levels are associated with a fourfold greater risk of developing PC.32 IGF-1 is a known mitogen (stimulator of cell division and tumor growth) for PC. IGF-1 receptors are found on the PC cell as well as on osteoblasts.33 IGF-1 stimulates the PC cell to make uPA (urokinase-type plasminogen activator), a cell product implicated in the invasiveness and metastasis of PC. The uPA receptors are on the PC cell and on osteoblasts. IGF-1 adds further insult by also acting as an angiogenic growth factor.34 A detailed illustration of these and other interactions is shown in Figure 1.

Gene expression of IGF-1 and its receptor are inhibited by 5-alpha-reductase inhibitors such as Proscar.35


IGF-1 and uPA Act Together to Increase Aggressive PC Growth
There are studies demonstrating that elevations of uPA and its receptor are associated with nonorgan-confined PC at radical prostatectomy (RP), disease progression with metastases, and a poorer overall survival.36 uPA works closely with IGF-1 and its receptors, cleaving IGF-1 from its binding proteins. uPA is also part of an autocrine pathway for the PC cell, allowing uPA to stimulate PC cell growth and make more uPA at the same time.


Good News! GLA and EPA Inhibit uPA
Of interest is the fact that uPA production is inhibited by gamma-linolenic acid (GLA) and eicosapentenoic acid (EPA).37 GLA and EPA, which are essential fatty acids, are among the important players in the prevention of disease and in maintenance of health. This is discussed by Barry Sears, Ph.D., in Omega Rx Zone.38 Sears beautifully presents the interconnection between restriction of calories, along with dietary adjustments of carbohydrate, protein, and fat intake, and the production of a class of fatty acids called eicosanoids. An understanding of these issues is fundamental to our ability to prevent disease and maintain or recapture health.


More Advantages to Caloric Restriction and Avoidance of Hyperinsulinemia

a)Carbohydrates Should Be Minimized
b)Glycemic Index
c)Volume of Food

Sears stresses the importance of caloric restriction by means of limiting the intake of high-density carbohydrates such as bread, pasta, grains in most cereals, and starches such as those found in potatoes. This reduction of caloric intake by lowering high-density carbohydrate intake decreases the stimulation of the pancreas to make insulin and limits all the adverse side effects associated with increased insulin levels (hyperinsulinemia).

Caloric restriction has been shown to be an important factor in augmenting the immune system and improving longevity. It reduces free radical production, which if otherwise unchecked, damages DNA and oxidizes polyunsaturated fats. Caloric restriction increases levels of superoxide dismutase (SOD), glutathione, melatonin, DHEA, peroxidase, and catalase. The latter substances are important defense mechanisms in our body that are known to decrease with aging. Caloric restriction is instrumental in lowering the production of cortisol. Cortisol is associated with increased stress levels, and an imbalance in cortisol production leads to immune deficiency and bone loss through resorption, leading to osteopenia and osteoporosis, as well as muscle breakdown and aging of the skin.

Calorie restriction, as proposed by Sears and others, has been shown to also reduce advanced glycosylated end-products (AGE). These are carbohydrate-protein complexes associated with hyperinsulinemic states and with cardiovascular disease, Alzheimer's disease, kidney disease, and other degenerative states.

We need to rethink how much food we need to eat. Our ideal body weight should be taken seriously. If we were to do this alone, we would eliminate most cases of diabetes, hypertension, hypercholesterolemia, stroke, heart disease, and a significant amount of cancer from our lives and those of our loved ones. healthy people should consume 500 calories permeal and 100 calories persnack. Modifications of this are based on the level of disease activity, age, and body surface area. Nutritional software and nutritional counseling should be an integral part of our approach to good health.

Insulin-Stimulating Carbohydrate Is the Damaging Subcomponent of Carbohydrate

If hyperinsulinemia is crucial to the development of many of our biochemical problems--from arthritis to neurodegenerative disease to cancer--then controlling the carbohydrate loads we subject our bodies to should be a major tool in maintaining good health. Carbohydrates can be characterized by the amount of insulin-stimulating carbohydrate (ISC) that they contain. The ISC is the total carbohydrate content (in grams) minus the amount of fiber (in grams) it contains. An example is 1 cup of broccoli containing a total of 7 grams of carbohydrate, of which 4 grams are fiber. The difference between the two equals the ISC content or 3 grams. Fruits and vegetables, which are high in fiber, generally have a lower ISC content than do starches, grains, and pasta. Therefore, analogous to PSA (benign-related versus cancer-related) and to cholesterol (total cholesterol versus LDL versus HDL), any intelligent discussion on carbohydrates must specify the components in question.