Rooting Around for Cancer Treatments

Traditional Chinese medicine has been used with beneficial effects on cancer for thousands of years and in more recent times has emerged in western medicine as a field in its own right. Herbal medicine-derived phytochemicals include curcumin, resveratrol and berberine.

Thus it would be no surprise if I revealed this month’s focus of work, from Joseph Tintelnot, Nicola Gagliani and colleagues from the University of Hamburg and other centres in Germany together with the New York University Grossman School of Medicine, to be about novel plant-derived chemicals that have anti-cancer effects.

But it isn’t.

Their study focuses on pancreatic ductal adenocarcinoma (PDAC), a disease predicted to be the second most deadly cancer by 2040. This is because when first detected it has a high incidence of metastatic disease, the result being that fewer than half of all patients respond to the primary treatment — chemotherapy — and the 5-year survival rate remains at about 6% (see Speed Dating Drugs for latest on development of drugs for PDAC).

What Tintelnot et alia did was to use shotgun metagenomic sequencing (i.e. sequenced all genes in all the organisms in the sample, including microbes) and metabolomic screening to show that a metabolite of the amino acid tryptophan, called indole-3-acetic acid (3-IAA), is present at higher levels in patients who respond to chemotherapy treatment. [By way of background, the standard treatment for metastatic PDAC is polychemotherapy, either with 5-fluorouracil, irinotecan and oxaliplatin in combination with folinic acid (known as FOLFIRINOX), or with gemcitabine and nab-paclitaxel (nab-paclitaxel is an albumin-bound nanoparticle formulation of paclitaxel)].

Gut bacteria boost chemotherapy. (a) Some gut bacteria use the amino acid tryptophan to produce 3-IAA. (b) 3-IAA is taken up by neutrophils (a type of white blood cell) and oxidized by the enzyme myeloperoxidase into toxic molecules. These enter cancer cells in which they increase the level of reactive oxygen species (ROS). This inhibits a cellular degradation process called autophagy, mediated by vesicles called autophagosomes, enhancing chemotherapy. From Li & McAllister 2023.

So far so useful — but here’s the remarkable bit. 3-IAA is a plant hormone widespread in bacteria that inhabit the rhizosphere of plants — the soil zone surrounding plant roots. Sometimes called the microbe storehouse, it’s where microbes interact with plant roots and  rhizobacteria release plant growth-promoting chemicals. Their presence is affected by nitrogen deposition and by drought.

Once the Hamburg folk had found 3-IAA their metagenomic screen came up with the source: two bacterial strains, Bacteroides fragilis and Bacteroides thetaiotaomicron, strains known to make 3-IAA in plant roots. These days you can guess the next experiment: take your mouse model of metastatic pancreatic cancer, use mice that lack their own microbiota (germ-free) and give them faecal transplants from people whose PDAC had responded to chemotherapy. Sure enough, the mice had smaller tumours after chemotherapy than mice given microbiota from human non-responders.

Next question: given that production of 3-IAA involves the amino acid tryptophan and is mediated by bacterial species in the gut, could a tryptophan-rich diet also result in an anticancer effect? Indeed such a diet had a striking anti-tumour effect in mice given chemotherapy (reduced tumour size by about half). The effect seems to be specific to 3-IAA because other tryptophan-derived metabolites, such as indole-3-propionic acid and hippuric acid, had no effect.

Furthermore, screening tumour environment for immune cells showed that 3-IAA production was associated with the presence of neutrophils — cells known to be involved in the anti-tumour effects observed in people who respond to chemotherapy.

So neutrophils can sense signals from microbes in the gut that are more usually associated with plant-nourishing microbiota! Neutrophils are known to affect tumour spread and in this PDAC model they convert a bacterial metabolite into something that inhibits autophagy and makes cancer cells more susceptible to toxic drugs.

How extraordinary is all that?

References

Tintelnot J, Xu Y, Lesker TR, Schönlein M, Konczalla L, Giannou AD, Pelczar P, Kylies D, Puelles VG, Bielecka AA, Peschka M, Cortesi F, Riecken K, Jung M, Amend L, Bröring TS, Trajkovic-Arsic M, Siveke JT, Renné T, Zhang D, Boeck S, Strowig T, Uzunoglu FG, Güngör C, Stein A, Izbicki JR, Bokemeyer C, Sinn M, Kimmelman AC, Huber S, Gagliani N. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature. 2023 Mar;615(7950):168-174. doi: 10.1038/s41586-023-05728-y. Epub 2023 Feb 22. PMID: 36813961; PMCID: PMC9977685.

Li L, McAllister F. A gut reaction can tune tumour fate during chemotherapy. Nature. 2023 Mar;615(7950):36-37. doi: 10.1038/d41586-023-00476-5. PMID: 36814015.

Secret Army: More Manoeuvres Revealed

 

I don’t know about you but I find it difficult to grasp the idea that there are more bugs in my body than there are ‘me’ cells. That is, microorganisms (mostly bacteria) outnumber the aggregate of liver, skin and what-have-you cells. They’re attracted, of course, to the warm, damp surfaces of the cavities in our bodies that are covered by a sticky, mucous membrane, e.g., the mouth, nose and especially the intestines (the gastrointestinal tract).

The story so far

Over the last few years it’s become clear that these co-residents — collectively called the microbiota — are not just free-loaders. They’re critical to our well-being in helping to fight infection by other microrganisms (as we noted in Our Inner Self), they influence our immune system and in the gut they extract the last scraps of nutrients from our diet. So maybe it makes them easier to live with if we keep in mind that we need them every bit as much as they depend on us.

We now know that there are about 2000 different species of bacteria in the human gut (yes, that really is 2,000 different types of bug) and, with all that diversity, it’s not surprising that the total number of genes they carry far exceeds our own complement (by several million to about 20,000). In it’s a small world we noted that obesity causes a switch in the proportions of two major sub-families of bacteria, resulting in a decrease in the number of bug genes. The flip side is that a more diverse bug population (microbiome) is associated with a healthy status. What’s more, shifts of this sort in the microbiota balance can influence cancer development. Even more remarkably, we saw in Hitchhiker Or Driver? That the microbiome may also play a role in the spread of tumours to secondary sites (metastasis).

Time for a deep breath

If all this is going on in the intestines you might well ask “What about the lungs?” — because, and if you didn’t know you might guess, their job of extracting oxygen from the air we inhale means that they are covered with the largest surface area of mucosal tissue in the body. They are literally an open invitation to passing microorganisms — as we all know from the ease with which we pick up infections.

In view of what we know about gut bugs a rather obvious question is “Could the bug community play a role in lung cancer?” It’s a particularly pressing question because not only is lung cancer the major global cause of cancer death but 70% lung cancer patients have bacterial infections and these markedly influence tumour development and patient survival. Tyler Jacks, Chengcheng Jin and colleagues at the Massachusetts Institute of Technology approached this using a mouse model for lung cancer (in which two mutated genes, Kras and P53 drive tumour formation).

In short they found that germ-free mice (or mice treated with antibiotics) were significantly protected from lung cancer in this model system.

How bacteria can drive lung cancer in mice. Left: scheme of a lung with low levels of bacteria and normal levels of immune system cells. Right: increased levels of bacteria accelerate tumour growth by stimulating the release of chemicals from blood cells that in turn activate cells of the immune system to release other effector molecules that promote tumour growth. The mice were genetically altered to promote lung tumour growth (by mutation of the Kras and P53 genes). In more detail the steps are that the bacteria cause macrophages to release interleukins (IL-1 & IL-23) that stick to a sub-set of T cells (γδ T cells): these in turn release factors that drive tumour cell proliferation, including IL-22. From Jin et al. 2019.

As lung tumours grow in this mouse model the total bacterial load increases. This abnormal regulation of the local bug community stimulates white blood cells (T cells present in the lung) to make and release small proteins (cytokines, in particular interleukin 17) that signal to neutrophils and tumour cells to promote growth.

This new finding reveals that cross-talk between the local microbiota and the immune system can drive lung tumour development. The extent of lung tumour growth correlated with the levels of bacteria in the airway but not with those in the intestinal tract — so this is an effect specific to the lung bugs.

Indeed, rather than the players prominent in the intestines (Bs & Fs) that we met in Hitchhiker Or Driver?, the most common members of the lung microbiome are Staphylococcus, Streptococcus and Lactobacillus.

In a final twist Jin & Co. took bacteria from late-stage tumours and inoculated them into the lungs of mice with early tumours that then grew faster.

These experiments have revealed a hitherto unknown role for bacteria in cancer and, of course, the molecular signals identified join the ever-expanding list of potential targets for drug intervention.

References

Jin, C. et al. (2019). Commensal Microbiota Promote Lung Cancer Development via γδ T Cells. Cell 176, 998-1013.e16.