The cancer dance

Cancer and inflammation are profoundly inter-connected. 

From a cytological perspective, tumours can be regarded as wounds that will not heal; they are inevitably infiltrated by many different kinds of inflammatory and immune cells. Some tumours are more inflamed than others, and the degree of inflammation tells us a good deal about how likely the tumour is to metatasise.  The more inflammation, and the more the tumour secretes matrix metalloproteases (enzymes that are activated in chronic inflammation), the more aggressively invasive it is (1). This is clinically important because it is usually the metastases that kill, rather than the primary tumour. 

We know that chronic inflammation drives the gradual destruction of tissue that underlies the chronic degenerative lifestyle diseases such as coronary artery disease and osteoarthritis, but how is it involved with cancer?

It has been understood for some time that inflammation enables cancer spread by chewing holes in the extra-cellular matrix, thus allowing the more mobile cancer cells to escape their micro-fibrous cage (1). Now another link has emerged; it seems that inflammatory cells and cancer cells in the tumour ‘talk’ to each other, each encouraging the other to misbehave (2). 

The immune cells are pushed by the cancer cells to become tumour-supporting cells, in a process called tumour-associated M2 polarisation (2). The tumour-supporting cells then instruct the cancer cells to become more mobile via a process called epithelial-to-mesenchymal transition, or EMT. Cancer-related EMT is an interesting phenomenon, as it is essentially the re-awakening of a foetal growth mechanism whereby cells can move into new configurations as the foetus grows and develops. But it is also a deadly one.

Now things go from bad to worse, because not only do cells that have gone though EMT become more mobile and more invasive, at the same time they become less likely to commit cellular suicide via the aoptotic sequence. They also produce more pro-inflammatory factors, causing more inflammation, which in turn induces more EMT. This catastrophic feed-forward loop is deeply involved in cancer spread and progression; it is an extremely vicious circle (2).

Due to the potentially devastating effects of excessive MMP activation, and thanks to the miracle of homeostasis which is at the centre of all life, tissues contain endogenous MMP inhibitors called TIMP’s (Tissue Inhibitors of MMP’s).

These are up-regulated by various phytonutrients including the carotenoids (3) and the polyphenols (4). Unfortunately, our intakes of these valuable and protective phytonutrients are at an all-time low, thanks to the degradation of our diet and our ever-increasing consumption of ultra-processed foods (5, 6). As the MMP’s are also directly inhibited by polyphenols (ie 7), their progressive removal from our processed food diets is doubly disastrous.

The resulting imbalance between MMP’s and their TIMP’s is one reason why increasing intake of ultra-processed foods is linked to an increased risk of cancer and early death (8, 9), but it is not the only one; the ultra-processed diet increases chronic inflammation in the body via multiple nutritional defects, tipping the balance even further in favour of excessive MMP activity.

One of the most notable defects in the ultraprocessed diet is the absence of prebiotic fibers.

These fibers – technically they are non-digestible, fermentable carbohydrates – are a substrate for gram-positive bacteria that form part of the microbiome, in the large bowel. If prebiotic fibers are removed from the diet, the gram-positive species are starved and as their numbers fall, their ecological niches in the bowel are taken over by gram-negative species. Gram-negative species are, by definition, coated in lipopolysaccharide (LPS), one of the most pro-inflammatory compounds known. It is also fat-soluble.

Back to ultra-processed ‘junk’ foods. Calorie-dense and nutrient-light (they are almost devoid of vitamins and phytonutrients), they starve the gram-positive bacteria which die off, and thus promote the growth of gram-negative species. The gut fills up with lipopolysaccharides, and, as the ultra-processed diet is also full of fats and oils, the LPS dissolves in the lipid components of diet. It is then absorbed into the chylomicrons, transferred into the portal circulation, transferred to lipoproteins in the blood, and finally dumped in our ever-expanding fat depots where it triggers inflammation (10). And so the cancer cycle spins faster … and faster again, as levels of the important anti-inflammatory compound butyrate, which is produced exclusively by the gram-positive bacteria (11), fall. And then faster again, as innate immune cells in the body, starved of butyrate, become less effective at resolving gram negative bacterial infections (12), leading to accumulation of even more LPS in the tissues. And then even faster, due to the calamitous and diet-determined fall in our omega 6:3 ratios (5), and faster yet again as the calorie-dense junk foods increase obesity – which is in itself pro-inflammatory. This is truly a Danse Macabre.

Are fats dangerous in themselves? I think not. The omega 3 fatty acids are in general anti-inflammatory and linked to many health benefits, especially if co-ingested with lipophilic polyphenols (13-15); the mono-unsaturates appear to be benign, and the latest findings exonerate the saturated fatty acids.

BUT …

A high-fat diet does seem to be pro-inflammatory (16-18), and I think this is because the high fat diet is generally a low-prebiotic diet, which produces lots of lipopolysaccharide; and which could explain why levels of LPS in the blood rise after a high-fat meal (19).

SO …

If you were to eat a diet high in both fats and prebiotic fibers (a combination found in the paleo diet), the otherwise deleterious effects of the high fat would be reduced or perhaps even nullified. And this, I believe, is a part of the reason why the recent WHO big data review found that higher fiber intakes were so very effective in reducing reducing both vascular and cancer mortality (20).

For those who cannot stomach the paleo diet, you can easily design a more modern and more palatable version by adding prebiotic fibers to standard foods such as yoghurt, porridge, or bake them into bread, cookies etc. 

A word of caution: do not rely on single fiber types. It makes far more sense to utilize a blend of prebiotics of various chain lengths and complexity, thus ensuring microbiomal diversity and a gram-negative to gram-positive shift throughout the length of the colon.

Bon appetit.

REFERENCES

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16. Kyung-Ah Kim, Wan Gu, In-Ah Lee, Eun-Ha Joh, Dong-Hyun Kim. High Fat Diet-Induced Gut Microbiota Exacerbates Inflammation and Obesity in Mice via the TLR4 Signaling Pathway. PLoS One. 2012; 7(10): e47713.
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