The Role of Nutrition in Cancer and Cachexia

2. The Role of Nutrition in Cancer and Cachexia

In some cases the demise of the patient with neoplasia is not due to the neoplasia itself, but to the overwhelming loss of body condition. Understanding these processes is important for appropriate nutritional intervention.

Nutritional Epidemiology of Cancer in Veterinary Medicine

The role of nutrition in cancer prevention has become the subject of tremendous research in human medicine because of the variability in the human diet, and the awareness that certain dietary regimens may decrease the relative risk of neoplasia. This may also be true for companion animals, although most veterinary patients are receiving a more balanced diet than most humans. There have been three epidemiologic studies in dogs examining dietary and body conformation risk factors for mammary neoplasia. The results of these studies reported that the fat content of the diet had no significant relationship to the incidence of neoplasia, yet obesity did increase the relative risk of mammary carcinoma (Sonnenshein et al., 1991).

The two major nutritional goals that need to be equally addressed in a cancer patient are:

1. Inhibiting tumor growth
2. Preventing or managing cachexia

Interestingly, one study showed that as the protein concentration of the diet increased, the relative risk of mammary neoplasia decreased, while a second study reported an increased relative risk of neoplasia in bitches fed raw meat as the primary source of caloric intake (Shofer et al., 1989; Perez-Alenza et al., 1998). When interpreting the results from these studies, it can be deduced that as the protein concentration in the dog food increases, the quality of the food is often better. Conversely, raw meat based diets are usually nutritionally unbalanced. Therefore, as the overall nutrient balance of the feed decreases, the incidence of neoplasia may increase. Hence, in veterinary patients it may be ideal to feed well balanced diets that comply with nutritional (National Research Council, NRC) guidelines for feeding dogs, when attempting to decrease the prevalence of certain neoplasias.

Energy Requirements and Neoplasia Metabolism

Understanding the metabolism of neoplastic cell growth is essential to understanding nutritional intervention in cancer.

In general, neoplastic cells have higher rate of anaerobic energy metabolism than normal cells, therefore they rely more heavily on glucose, i.e. an up-regulation of the glycolytic pathway. This up-regulation of glycolysis leads to an accumulation of pyruvate which is rapidly converted to lactate, thereby resulting in a mild lactic acidosis, which has been documented in canine cancer patients (Vail et al., 1990; Olgivie et al., 1997). Once lactate has been liberated from the neoplastic cell into the bloodstream it will be taken up by the liver, converted back into glucose, and may return to the neoplastic cell to undergo glycolysis, similar to the Cori Cycle (Olgivie & Vail, 1990; Howard & Senior, 1999) (Figure 2). During this process of converting glucose into lactate there has been a gain of 2 ATP from glycolysis in the cancer cell, yet the conversion of lactate back into glucose in the hepatic cell requires 4 ATP and 2 GTP yielding a net loss of 2 ATP.

Figure 2. Glucose metabolism (Cori cycle).

Many approaches have been taken over the past 40 years to influence neoplastic growth through nutritional modification (© JY Deschamps).

Additionally, it has been shown that the humoral release of certain cytokines from inflammatory tissue around the neoplasia or from the neoplasia itself leads to uncoupling of oxidative phosphorylation in mitochondria, which may result in reduced ATP production (Giordano et al., 2003).

Certain cytokines may also down-regulate endothelial lipoprotein lipase activity causing fatty acid and triglyceride accumulation in the bloodstream and prevent the storage of fatty acids within adipocytes. Together these changes may result in alterations in serum lipid profiles and hypertriglyderidemia which have been observed in dogs with lymphoma (Olgivie et al., 1994).

A major risk factor for cancer cachexia is the increase in energy requirements due to activation of proteolytic systems.

To supply adequate energy for the futile cycling of various systems, and in an attempt to alter the dependency of neoplastic processes on anaerobic glycolysis, alterations in dietary levels of the energy providing substrates (protein, fat and carbohydrate) are often made in an attempt to slow progression of disease and thus increase survival time (Argiules et al., 2003).

Cancer Cachexia

For many years it was thought that all patients with cancer cachexia had elevated resting metabolic rates due to the increased metabolism in cancerous tissue. However, many studies in human, and now veterinary medicine have shown that the resting metabolic rate after removal of tumors does not change. Furthermore, the resting metabolic rate can be extremely variable, and is often not correlated with the cachectic syndrome (Vail et al., 1990; Olgivie et al., 1997; Argiules et al., 2003). Until recently it was thought that excessive lean body wasting was due to increased degradation of amino acids to support cancer growth, and without adequate intake the body would catabolize skeletal muscle to meet these demands.

Over the past ten years the role of various proteolytic systems (capthesins, calpains and ubiquitin/proteasome) involved in skeletal muscle atrophy associated with cancer cachexia have been studied. The ubiquitin/proteasome system has recently received a lot of attention as this system is up-regulated in cancer cachexia and other diseases associated with lean body wasting (Baracos, 2000; Inui, 2002; Argiules et al., 2003). This is a complex system that marks a protein for degradation and then shuffles the tagged protein through a large multi-subunit protease called the proteasome. The process requires ATP, and may play a role in increasing the ATP consumption observed in neoplasia.

Though speculative, it is thought that the amino acids liberated from this process may be either used for energy production or lost in the urine. Many factors (i.e cytokines) have been implicated in the up-regulation of this system in cancer cachexia. Many of these factors are secreted into the blood stream by the primary or metastatic neoplastic tissue. Some of the more important factors include Tumor Necrosis Factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), and a newly identified factor called Proteolysis Inducing Factor (PIF). PIF may be the most important factor involved in cancer cachexia (Argiules et al., 2003; Baracos, 2000) (Figure 3).

Figure 3. Humoral and tumor derived factors associated with anorexia and cachexia in cancer. A lipid mobilizing factor may be secreted by the tumor cells which induces an increase in the cytoplasmatic activity of the lipoprotein lipase in the adipocytes, exacerbating the loss of fat (Hirai et al., 1998; Tisdale, 2001).