Cancer cachexia demonstrates the energetic impact of gluconeogenesis in human metabolism

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Summary

A review-based hypothesis is presented on the energy flow in cancer patients. This hypothesis centres on the hypoxic condition of tumours, the essential metabolic consequences, especially the gluconeogenesis, the adaptation of the body, and the pathogenesis of cancer cachexia.

In growing tumours the O2 concentration is critically low. Mammalian cells need O2 for the efficient oxidative dissimilation of sugars and fatty acids, which gives 38 and 128 moles of ATP per mole glucose and palmitic acid, respectively. In the absence of sufficient O2 they have to switch to anaerobic dissimilation, with only 2 moles of ATP and 2 moles of lactic acid from 1 mole of glucose. Since mammalian cells cannot ferment fatty acids, in vivo tumour cells completely depend on glucose fermentation. Therefore, growth of these tumour cells will require about 40 times more glucose than it should require in the presence of sufficient O2.

Since lactic acid lowers the intracellular pH, it decreases the activity of pyruvate dehydrogenase, stimulates fermentation, and thus amplifies its own fermentative production. Compensatory glucose is provided by hepatic gluconeogenesis from lactic acid. However, the liver must invest 3 times more energy to synthesize glucose than can be extracted by tumour cells in an anaerobic way. The liver extracts the required energy from amino acids and especially from fatty acids in an oxidative way. This may account for weight loss, even when food intake seems adequate.

In the liver 6 moles of ATP are invested in the gluconeogenesis of one mole of glucose. The energy content of 4 out of these 6 moles of ATP is dissipated as heat. This may account for the elevated body temperature and sweating experience by cancer patients.

Introduction

Cachexia is associated with many chronic or end-stage diseases, such as cancer, infectious diseases, AIDS, congestive heart failure, rheumatoid arthritis, tuberculosis, cystic fibrosis and Crohn’s disease. It can also develop in elderly people who do not have any obvious disease symptoms [1], [2]. Cachexia is commonly recognized as progressive weight loss with depletion of patient’s reserves of adipose tissue and skeletal muscle, and represents the complex metabolic state that is seen in these patients [1].

Just as many other investigators [1] we have tried to explain the relation between cachexia and cancer. Our starting points were the questions (i) how the human body handles massive amounts of lactate and cancer patients, and (ii) how the weight loss in these patients arises. From here we have created an hypothesis that also includes some important elements that have been hypothesized in 1968 by Gold [3] and in 1992 by Dills [4]. Our approach is mainly based on the production and usage (i.e., flow) of energy (as expressed in ATP-units), whereas the approaches of either Gold or Dills are mainly based on the coherence of dissimilatory biochemical processes as such in cachectic animals or humans with tumours [3], [4]. Seen from the approaches of Gold or Dills our hypothesis has become a refined working-out.

We postulate that cancer cachexia can be fully explained by the energetic consequences of the growing tumour, which locally changes from aerobic to anaerobic dissimilation and causes metabolic adaptation in the liver. In the patients with cancer the tumour cells are no longer subjected to the growth control of the body [5], [6]. When tumour growth is beyond a certain size, body weight decreases [7]. The substantial weight loss which is often observed, and which is known as cancer cachexia, can generally not be explained by a decreased dietary intake alone [8]. Cachectic patients appear to be in a catabolic condition. It has been known for 70 years that tumours demonstrate changed metabolic profiles with hypoxia in the growing tumour [9], [10] and increases in glucose uptake [11], glycolysis and lactic acid production. A human colorectal carcinoma has been reported to produce up to 43 times the normal lactic acid concentration in the draining vein [12]. It is known that in the patients with cancer cachexia the Cori-cycle has increased activity [13], [14], [15]. This cycle consists of the fermentation of glucose to lactic acid in the tissues, and the conversion of lactic acid to glucose in the liver [16]. To date, little attention has been paid to the energetic implications of this metabolic pathway, but in our view the Cori-cycle, especially the gluconeogenesis, may completely elucidate the cause of cancer cachexia and thus demonstrates its important role in the energy flow of life, especially in cancer patients.

Section snippets

Tumour growth

Normally the growth rate of all body cells is continuously under control. The most important feature of a tumour cell is that to a great extent these cells withdraw from normal growth regulation. Tumour cell growth is determined by the rate of biosynthesis of essential cellular components (as various structural components, enzymes, chromosomes and membranes). Critical factors that affect the growth rate of tumour cells are: (i) the uptake rate of both energy-rich substrates and oxygen, (ii) the

Oxidative energy generation under normal conditions

The oxidative energy from glucose is generated in the next three major catabolic processes, viz., glycolysis, the tricarbonic acid cycle (TCAC) and the link between glycolysis and TCAC (Fig. 1). The oxidative energy generation from sugars and carbohydrates other than glucose occurs in the same way, but only after they have been converted to glucose. During glycolysis, one mole of glucose is converted to two moles of pyruvic acid; in this process two moles of ATP and two moles of NADH2 are

Consequences of tumour hypoxia

The delivery of oxygen to a living cell in an organism depends on several conditions. These include (i) oxygen pressure in the surroundings, (ii) lung capacity in exchanging oxygen, (iii) blood capacity in carrying oxygen (effective haemoglobin concentration), (iv) macro-circulation, (v) microcirculation for local perfusion, (vi) tissue diffusion geometry and (vii) the ability of the cell to use oxygen. In solid tumours the median pO2 is lower than in normal tissues of the same origin e.g.,

Fermentative energy generation

Glycolysis can occur even when it is uncoupled from TCAC. This means that oxygen-dependent energy generation by PDH and TCAC (30 moles of ATP per mole glucose) is inhibited, and that the maximal yield of one mole glucose can only be 8 moles of ATP. However, energy-rich electrons of glycolysis-related NADH2 will now enzymatically be transferred to pyruvic acid with lactic acid as by-product (this step is called “fermentation”; Fig. 2). The energy content of NADH2 molecules is not then all

Lactic acid-mediated amplification of fermentation

When the glycolytic supply of pyruvic acid exceeds its aerobic dissimilation, the surplus is reduced enzymatically at the expense of the concomitant surplus of NADH2 with simultaneous production of lactic acid. As soon as lactic acid is massively produced and not rapidly metabolized, it will lower the intracellular pH and thus inhibit the activity of PDH [20]. In other words, the intracellular fermentation will increasingly uncouple the TCAC from the glycolysis. An important consequence is that

Energy generation in tumours

The cellular uptake rate of relevant nutrients (i.e., both of energy-containing substrates, especially sugars, and of constituents of future cellular structures, such as amino acids) determines the growth rate of tumour cells. Increasingly anaerobic conditions inside tumour cells cause that energy generation by oxidative dissimilation of amino acids and fatty acids, and even of sugars (Table 1), per gram tumour mass will decrease. Therefore, the energy required for tumour growth-related

Metabolism

In general, a human being on a normal diet has a 2:1 intake of carbohydrates and fats, respectively, on a weight basis. The main energy source of a living mammalian cell is the oxidative metabolism of glucose and fatty acids. Amino acids will deliver energy only after transformation into glucose by gluconeogenesis in the catabolic status or after over-consumption of protein [21]. Some tissues, like the brain and bone marrow, depend merely on glucose metabolism. Nevertheless, under aerobic

Tumour-associated gluconeogenesis

Tumours are continuously growing, and therefore they increasingly withdraw glucose from tissue and organ cells. Since only a small part of the lactic acid is excreted, (hepatic) gluconeogenesis must have been switched on in order to lower the surplus of lactic acid and to assure the availability of glucose for energy generation inside the various tissue and organ cells. This salvage process means that (at a high rate) one mole of glucose is produced from two moles of lactic acid. Hepatic

Tumour-associated increase of temperature

Since the fermentation of glucose to lactic acid yields two moles of ATP, it might be expected that for gluconeogenesis the same amount of ATP would be required. However, it is an important characteristic of gluconeogenesis that it requires six moles of ATP for the re-synthesis of glucose from lactic acid, i.e., four additional moles of ATP. The energy from these four moles is lost inside the liver during three subsequent steps of gluconeogenesis (Fig. 3). This energy is then dissipated as heat

Cancer cachexia

The Cori cycle is essential for cachexia. The more the tumour dissimilates in an anaerobic way, the more the liver requires additional substrates (from food) for aerobic energy generation in favour of gluconeogenesis. From the moment the food uptake capacity becomes the limiting factor, the liver will also dissimilate substrates that originate from structural components of body tissues, such as fatty acids and amino acids. As a consequence loss of body weight, the first step of cachexia,

Discussion

This hypothesis is the third step in an attempt to understand the main relation between cancer and cachexia [3], [4] on the basis of the Cori-cycle. Important new aspects are the role of fatty acids, the lactic acid-mediated reduction of PDH activity and the gluconeogenetic energy dissipation. It is emphasized that this hypothesis reflects only the main energy flow and not the many factors, e.g., cytokines, such as tumour necrosis factor (TNF), interleukin (IL)-1 and IL-6, uncoupling proteins

Acknowledgement

For the English text corrections we thank Dr. E.N. Robertson, Department of Anesthesia.

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