Available at www.veterinaryworld.org/Vol.6/Sept-2013/10.pdf REVIEW ARTICLE Open Access Does contemporary canine diet cause cancer? ; A review

Recent discoveries have discerned the presence of advanced glycation end products (AGEs) and their impact on chronic diseases that include cancer in dogs. AGEs are closely allied with chronic systemic inflammation (metaflammation). These two occurrences are observed in many cancers in both humans and dogs. AGEs are exogenous and endogenous. Exogenous AGEs occur from, among other causes, ingestion of food that is affected by the Maillard reaction in its preparation. The result is an accumulation of AGEs and progressive metaflammation that is linked with many cancers in both humans and dogs. Aspects of AGE ingestion and formation are reviewed in association with the contemporary canine diet that is primarily a kibbled meal based diet. A novel canine diet paradigm is offered as one that diminishes the AGE/ metaflammation axis. This is proposed to be less carcinogenic than the current canine diet in use by much of the civilized world. The proposed paradigm is a unique approach that offers opportunities to be tested for AGE and metaflammation accumulation that results in diminished prevalence and incidence of cancer in dogs. The paradigm diet is suggested as a prevention, treatment, and recovery aide from cancer.

inflammation, is proposed as a diagnostic indicator of canine mammillary tumors [4]. Recent research discoveries of advanced glycation -Vascular endothelial growth factor (VEGF), correlated end products (AGEs) with the generation of chronic with angiogenesis and various malignancies, is directly systemic inflammation (metaflammation) on the related to unfavorable prognosis [6]. physiology of cells that result in significant chronic -Cancer is a chronic inflammatory disease [7][8][9][10][11]. disease over time is changing the paradigm for much of -Canine obesity, a chronic systemic inflammatory chronic disease. This is occurring in humans and dogs, (metaflammation) [12] disease, is associated with some as well as other mammals. The contribution to that cancers [13]. pathology by exogenous AGEs in the diet is beginning -Hickman reports that diminished inflammation via to be appreciated and offering unique opportunities for increased Omega-3 fatty acid (O3) consumption as it prevention, treatment, and recovery in many chronic relates to fermentable fiber is important in decreasing diseases including cancer. This brief report offers key intestinal inflammation and diminishing the occurrence information on canine diet and cancer as it relates to of intestinal cancer in dogs [14]. current evidence from this rapidly expanding area of -Much more as the evidence continues to mount by the research. Dietary factors related to chronic disease, that association of physiological effects caused or contributed include cancer, are associated with these pathologies to by the nutrition. that accumulate in the body over time.
There is accepted use of dogs in human research At the foundation of these chronic disease symptoms [15,16]. Frequently, human data and research is used are metaflammation and AGEs with their receptor; and as necessary modified to be applicable to dogs [17receptor for advanced glycation end products (RAGE). 19]. By defining the known variables and continuing to This is observed in the following: identify evolving knowledge, it is common for the -The RAGE has been demonstrated to display work with one mammalian species to be applied to the significant effects on metastasis and tumor growth other [20], at least as far as paradigm development is concerned. There is enough evidence to strongly -The presence of metaflammation in dogs is linked to suggest that the canine and human pathophysiology benign hyperplasia prostrate (BHP) and prostate share enough of the same physiological principles that cancer [3].
information from one should and could be used to -Serum gelatinase is associated with inflammation and suspect and test the effect on the other [1, 13,17,[21][22][23]. tumor aggressiveness in canine tumors [4,5].
The differences between the species often help to -Interleukin-8, a chemotactic cytokine as a result of clarify knowledge [18]. Gil et al [24] noted that mammals have both white and brown adipose tissue; a significant commonality. The endocrine functions of adipose tissue are being appreciated for its role in chronic disease that includes cancer [25]. the mother through a process known as developmental There is extensive evidence linking metafla-programming [30]. Since many mammals have similar mmation with many human cancers. Teté et al [26] physiological functions [31][32][33][34], there is a strong noted the link between inflammation and cancer in reason to suspect that the same occurs with dogs. In humans as it relates to the nutrition of the subjects.
dogs, maternal milk is a conduit for bioactive factors Metaflammation creates an environment for cancer passed from mother to the pup [35]. Unlike majority of production [8] (Figure-1).
humans, most puppies receive their initial post-partum To continue further referernces linking diet from their mother's teats. At about 6-7 weeks that metaflammation with chronic disease, including changes dramatically and from that point on the cancer would risk being redundant. It can be summed puppies eat what turns out, in many cases, to be up that the evidence is extensive and piling up as tantamount to a toxic diet i.e. the AGE laden diet that research continues to pour into the scientific community initiates the chronic inflammation (metaflammation) literature supporting a significant link between cancers process of chronic disease [3]. The process is associated with AGEs and metaflammation that are cumulative over time [36]. Depending on their linked to nutrition. Nutrition is a generator of both immunity; the process will soon begin to noticeably AGEs and their ligands that are linked to appear and will continue to accumulate as the animal metaflammation [27].
ages [21]. The metaflammation that occurs secondary to the AGE process is marked by inflammatory Primary Focus markers [37]. Inflammatory markers are low at birth, The primary focus of this paper is to present an but by three months they rise to adult levels [22]. evidence-based depiction for the chronic disease that The heating of food changes its chemical structure inflammation [11]. "The connection between and produces exogenous AGEs; a process known as the inflammation and cancer has moved to center stage in Maillard reaction [38]. Proteins and fats are more the research arena," noted by Robert A. Weinberg of the sensitive to this process than carbohydrates [39]. Massachusetts Institute of Technology's Whitehead Cooking with moist heat (vs. dry heat), using shorter Institute for Biomedical Research [11]. The evidence cooking times, cooking at lower temperatures, and by that advanced glycation end products underlie much of use of acidic ingredients such as lemon juice or vinegar the metaflammation associated with this process will diminish AGE formation [39]. Rendering of begins to interconnect much of this information into a animal meat and bone to produce meal is the opposite cohesive paradigm. The evidence is also piling up of this scenario. Rendering has negative effects on around diet's inflammatory and AGE generating protein and fat quality [40]. Add to that the pelleting of properties in both humans and dogs. As depicted in almost all animal food products; it has to be high AGE Table-1, there is association between many canine content [41]. Pelleting also decreases mineral cancers with inflammation and AGEs. Along the way absorption from meal [41]. we will note the close association between human and Acrylamide is a carcinogenic compound that can be a canine studies of inflammation, AGEs, and cancer.
byproduct of cooking at high temperature [42]. Protein medium for the Maillard reaction. Acrylamide is a chronic disease begin to appear after many years. concern and the AGE/ metaflammation axis cause Inflammatory markers are a hallmark and associated much chronic disease over time in both humans and pets.
with cancer as well as other diseases commonly seen in aging [61]. Testing for inflammatory markers is one AGEs effective way to assess a level of metaflammation in the AGEs appear to be at the foundation of chronic apparent state of normal health; much the same as disease and generates metaflammation seen chronic cholesterol is diagnostic of buildup of pathology over diseases including aging [45]. Chronic disease in dogs time [62]. and humans results from or is greatly contributed to by Canine diet and cancer glycation and the formation of AGEs with their RAGE [46]. This occurs both endogenously and exogenously Oglivie notes that canine diets low in simple in humans [47,48] and other mammals [49,50].
carbohydrates, but with moderate amounts of high Endogenously produced AGEs occur from high quality protein, fiber, and omega-3 fatty acids "reduce glycemic states (diabetes), aging, renal failure, the risk of developing cancer, or the growth and inflammation, and hypoxia [51]. There is a circular metastases of established malignant disease. Nutritional relationship between inflammation and AGEs.
intervention can be a powerful tool for controlling Exogenously, one the greatest source of AGEs is the malignant disease and for reducing toxicity associated diet [47]. Taken together (exogenous & endogenous) with chemotherapy and radiation therapy" [63]. they can be and are lethal. This AGE, RAGE, and Fermentable fiber is noted to improve incretin function inflammation process is at the base of chronic disease [64] and there is some evidence that it has a positive problems observed in humans and dogs [21,46]. Some influence on cancer of the colon [65]. The type of of the consequences from AGEs are: fermentable fiber influences digestion [66]. Diets rich AGEs accumulate in the body over time causing in Omega-3 fatty acids improved the disease free damage and destruction [21].
interval and survival time in dogs with lymphoma who AGEs have an adverse effect on the vascular have received chemotherapy [67]. endothelium [52].
When we consider the dietary properties outlined AGEs are one of the prime reasons for aging [21].
above on the important areas of AGE's and AGEs are involved in the formation of chronic diseases metaflammation; the picture of cancer prevention, including cancer [53]. treatment, and incidence for reoccurrence is influenced considerably by the diet in both humans and dogs

Metaflammation (chronic systemic inflammation)
[1,10, [68][69][70]. The connection between AGEs and Metaflammation and acute inflammation are two metaflammation includes obesity, metabolic very different processes with quite different effects on syndrome, GI system dysfunction, CNS inflammatory the body [54]. Eggar  In the mid-19 century the first known commercial with Amidori rearrangement that produces AGEs [58] dog food, a biscuit, was developed by James Spratt in and metaflammation. The same is as likely applicable England. Spratt, who was from Ohio, brought his dry to dogs as it is for humans. Much of the scientific dog food to the USA [73,74]. After World War I with an community equates these responses with mammals as a abundance of horse meat, dog food was produced and whole [59]. Metaflammation creates an environment sold in cans. Prior to that time dogs were mostly given for cancer production [8] (Figure-1). This includes all scraps or just had food thrown out to them. Working chronic diseases that include cancer [36]. Metaflammation dogs ate whatever was available to them from their is referred to in the literature frequently as inflammaging working environment. During World War II cans [20] and occasionally as pseudo-inflammation [60].
become impractical due to the tin shortage. The use of Chronic inflammation or chronic systemic inflammation dry kibble evolved [74]. Since World War II dog food or sub-acute chronic inflammation terminology is also has become primarily dry with most being pelletized; encountered as this new concept still struggles for a made from an animal meat and bone meal. This appears universally accepted nomenclature. This is also not the to be a shift in the diet of dogs [74]. Much like the major chronic inflammation, such as chronic bronchitis or shifts in human nutrition [16,[75][76][77][78][79][80] that is now pancreatitis and many others, that can be a lingering associated with a pandemic of chronic disease. One effect of acute inflammation. Metaflammation is more sees a similar process occurring in the dog; another often silent until the accumulating effects of the mammalian species. Added to this animal meal are indices in beagles [90] as they have high glycemic various carbohydrates with corn, white potatoes, and indexes, i.e. 89 and 60 respectively [91]. High grains being commonly employed. Fiber is often added glycemic load diets increase incidence of some cancers that can be as poor quality as the dust and sweepings [92]. A meta-analysis [93] (EVL1) [88] done in 2008 from different sources. This can equal a very poor diet found that in humans that higher postprandial that is harmful to the short and long term health of the glycaemia is a universal mechanism for disease dogs.
progression; that included breast cancer as one of the In addition there is some evidence, at least at some chronic diseases. Whole grain consumption did not points in time when tested by FDA and some change inflammatory markers in a well-controlled independent sources; that meat sources from the 4D's evidence level 1 (EVL1) study [88,94]. Brownlee (dead, dying, diseased, disabled) are employed in the makes the point that all grains are not the same [94]. rendering [81,82]. That becomes a concern when the Poultry byproducts can include what is commonly animal meal contains pentobarbital after rendering. referred to as "beaks and feathers" [95]. Nachman et al There is some unease, since rendering may not [95] report that feather meal contains arsenic that may adequately safeguard against bovine spongiform be at risk for making it into the human food chain. encephalopathy (mad cow disease) [83] in the meal.
Feather meal and/or chicken by-products that likely While it has not been reported to be a problem in dogs it contain feathers are used in dog food [96]. When we is noted in cats [84]. There is also the mild risk of look at chicken meat itself; Lasky et al [97]found Creutzfeldt-Jakob disease in humans [83]. It has been arsenic levels higher than previously accepted which reported that some humans consume dog food [85]. On prompted this statement: "These concentrations are June 15, 2012 the CDC reported salmonella poisoning higher than previously recognized in chicken, which in infants that was traced to a major manufacturer of may necessitate adjustments to estimates of arsenic dog food in the United States [86].
ingested through diet and may need to be considered Dogs may have been forced to become more of an when estimating the overall exposure to arsenic." omnivore as opposed to a carnivore; but at what price?
When combined with the combination of feather Hill [74] makes a case for dogs as primarily carnivores meal, meal from chicken and chicken by-products, and with omnivore capabilities based on dentation, and so called fresh chicken meal, that has been reduced to a intestinal length. There is evidence that dogs do not dry kibble state (Maillard reaction), there is concern need carbohydrates as long as there is sufficient protein about arsenic in dog food. We have long known that and fat in their diet to supply the glucose precursors arsenic causes many cancers [98]. [74,87].
One of the consequences in dogs over the past 50 This may be a bit extreme as there is also evidence years, as in humans, is an emerging incidence of of the beneficial effects of fermentable fiber [66] that chronic disease. Banfield Pet Hospital reports reported increased digestibility of dry matter: it also increased chronic disease in both cats and dogs in the indicated an inverse relation for crude protein past five years [99]. It is likely no coincidence that this digestibility. The dog food used was 77% grain and problem runs parallel with escalating pandemic of protein (56% rice and 21% poultry meal byproducts). chronic disease in humans worldwide. Whether this The dog food had a glycemic load of 43 per 150 basic dietary change from carnivore to omnivore, if it is g/serving which is classified as a high glycemic load. a change, is that important, is yet to be determined.

The primary variable component for the four study
There is reason to suspect that the problem may be as groups were the cellulose and pectin content that much food preparation and ingredient based as a drift, amounted to 10% of the four study dog groups diet. The from carnivore to omnivore, that would have occurred, foods used were prepared by Hill's Science and beginning 10,000 to 15,000 years ago, when dogs were Technology Center [66]. This is a poorly done cohort domesticated by indigenous humans [100]. study that might be an evidence level grade of 4 (EVL Li, Li, and Hutnik [101] noted the effect of dietary 4) [88]. Not sure this study gives us much useful components on angiogenesis and propose it as a information about the normal digestion of the dogs preventive measure for cancer. The scientific literature when we only test what appears like a badly glycated, is replete with studies concerning the role of inflammatory diet; the type diet that has become the angiogenesis in prevention and treatment of many norm for all our dogs on these meal based kibble diets.
cancers [10, 101,102]. While much of this is human There was a similar study done in 2008 that seems to related; there is good reason to suspect the same effects have the same problems noted in the prior study; will occur in dogs. although to be fair it does note the fermentation at An evidence based dietary prevention, various portions of the gut with various soluble fibers treatment, and recovery paradigm [89]. This could be useful if the canine is not primarily a carnivore.
The canine dietary paradigm incorporates an One has to wonder what the inflammatory effect AGE poor diet that utilizes an Omega-6 fatty acid to of the diet was on the endothelium of the digestive tract Omega-3 fatty acid ratio of less than 4 to 1. It of the dogs. Both rice and corn cause high glycemic incorporates anti-inflammatory fermentable fiber supported with anti-AGE and antioxidant natural metaflammation. ingredients with a low glycemic load.
-Offered a paradigm diet of known scientific evidence The canine diet would consist of non-processed, calculated to diminish or end the formation of these no or low heat, from low AGE protein and fat sources.
pathological processes related to chronic disease that includes cancer. It would attenuate the protein and fat sources to -The proposed unique diet paradigm offers opportunities diminish AGE formation by incorporating an acidic to be tested for diminished AGE and metaflammation ingredient. It is devoid of grain. Part of the protein/fat accumulation that results in diminished prevalence and source needs to be rich in Omega-3 fatty acids, incidence of cancer in dogs. preferably from cold water marine sources, as low on -The debate between dogs being a carnivore as the food chain as possible. Fish oil supplements have opposed to omnivore is touched upon. been shown to be beneficial [67]. Sources of -The paradigm diet is suggested as a treatment and fermentable fiber should be incorporated that are antirecovery aide from cancer as well. inflammatory. Foods should not be exposed to high temperatures and pressures to avoid the Maillard References reaction effect. If the protein sources were from grass-  This is not an exhaustive list, but a sample representative. * Inflammation unclassified in study, but the cancer responded to anti-inflammatory agents. Each numerical represents the reference no.