Bacteria make cancers more mobile

Cancer occurs when DNA is damaged in such a way that cells begin to disregard the normal controls that regulate their behaviour. But in recent years scientists have discovered that tumour cells may have accomplices that make them more malignant, more likely to spread, and possibly even resistant to chemotherapy drugs. These accomplices are bacteria, including ones carried normally in the human mouth. They've been spotted in a range of cancers, but it wasn't clear whether they were there just because cancer cells are abnormal and have grabbed some harmless bacteria, or whether the microbes are actively contributing to the disease process. Now, Scott Verbridge at Virginia Tech has been able to show that, when these bacteria are present, tumour cells behave differently - growing and moving more actively. And not only that, but they can also alter the behaviour of adjacent cancer cells that don't even have any bacteria in them. He spoke with Chris Smith…

Scott - So there's this bug that is in basically everybody's mouth, and it's been known for roughly a decade that this bacterium has been present in colorectal cancer. So in cancers of the gut, they seem to be present in tumours that are worse for patients. More recently, we've started to discover that there are actually bacteria present in all kinds of tumours. So not just in the gut, but outside of the gut as well. So in breast cancers and lung cancers, pancreatic cancers, which is specific for this study, we're finding that these bugs are really present in a lot of different kinds of cancer where we used to think that these tissues should be sterile. And so our goal here was to understand what this particular microbe might be doing, and that's consistent among different tumour types.

Chris - I guess there are two questions here, which is really, is this cause or effect in the sense that, are these bacteria there because there's a cancer there and it's just abnormal so it picks them up? Or are they causing this cancer to behave the way it does? And are they playing a role in the progression of that cancer? Because cancers do that, don't they? They spread, they then progress, they invade other organs, and to what extent the bacteria might or might not be playing a role in that.

Scott -Yeah, that's exactly right and that's a great way of wording the question here. You know, a lot of the early work was just showing that these bacteria are there in tumour tissues and showing a correlation. People that had more of these microbes in their colorectal cancers would tend to have worse prognosis. But like you point out, that doesn't show that the bacteria are driving the aggressiveness of the cancer. It could just be that the more aggressive cancer is a better host to the bacteria, and there are reasons to think that these bacteria actually like to live inside of tumours. So, these bugs are what are referred to as anaerobes. What that means is that they like to live in an environment that doesn't have oxygen, and that tends to be one of the features of cancers as they grow, they become depleted in oxygen and they become anaerobic. So there's some reason to think that these bugs do well in tumours. And so yeah, we were interested in contributing to separating the correlation versus the causation. If we put the bugs in, do they actually make tumours more aggressive?

Chris - Are the bacteria in the cells, on the cells, next to the cells? What's the relationship?

Scott - Probably all of the above. But one of the interesting features of these microbes is that they do get inside the host cells. And that's really interesting because one of the observations that really drove us down this line of questioning was colorectal cancer cells, which are host to intercellular fusobacterium. Those cells were actually found, um, in liver metastases. The bacteria are not only able to get inside of the cancer cells, but they're able to survive inside those cells long enough to spread from a primary tumour in the colon to a distant tumour in the liver. And so that really was the main questions we have. Are those bacteria kind of just along for the ride or are they actually actively driving that migratory process?

Chris - And how did you test that?

Scott - We directly infected tumour cells and then measured their migratory capacity. We can watch, you know, in real time how they move, both with and without the bacteria in them.

Chris - And how does it make a difference?

Scott - So when we infect the cancer cells, they are more migratory. They move around faster, they're just more active in their movement. They're also more proliferative. They tend to divide rapidly, and the speed at which that happens is greater for the pancreatic cancer cells that have these microbes inside of them. Now, beyond that, what we've also shown is that cells that are next to cells that are infected also have that same set of effects. So what we've discovered in this work is that it's actually the cells that are infected are actively spitting out proteins that are accelerating proliferation and migration movement in both the infected cell as well as neighboring cells.

Chris - So one cell picks up some bacterial passengers, some freeloaders, that in some way manipulates the infected cell, but makes it then feed all its neighbors. So they all get a growth boost.

Scott - That's exactly right, yeah. So there's a kind of a built-in amplification there where you might not necessarily need to infect all of the cells in that tumour. You might have kind of an action at a distance where the infected cells are stimulating growth in the adjacent cells

Chris - And if the bacteria can turn this effect on, have you identified what factors are being turned on and therefore if you block those, does the effect go away?

Scott - So what we've done so far in terms of blocking has to do with understanding the physical structures that are in the membrane of the cancer cells that the bacteria seem to be binding to. These bacteria like to stick to a kind of a sugar that tends to be over regulated or upregulated in cancer cells. And the bacteria cells have a molecule in their own membrane that allows them to anchor to the sugars that are in the cancer cell membrane. And when we go ahead and interfere with that anchoring process, we can block the bacteria from invading in the first place. So that's where we've gotten a handle on interfering with this process so far.

Chris - The question that probably is foremost therefore in many people's minds is that we have drugs that kill bacteria. So if we were to give big doses of antibiotics to patients with cancers, would you speculate that that might have an attenuating effect on the rate of progression of a cancer?

Scott - It certainly might, and that's something that we're thinking about. There's some really wonderful animal work and colorectal cancer showing that you can actually improve outcomes for mice that have colorectal cancer by treating them with antibiotics that can destroy these bacteria. The challenge is that there's also a whole field of work looking into how your native microbiome, how that population might affect your response to cancer therapies. Some of that evidence seems to be that some of these microbes actually help the therapeutic response. So, there are some studies showing that broad spectrum antibiotics that just wipe out everything can actually reduce the efficacy of chemotherapies or immunotherapies. So it's not going to be as simple as just, you know, we want to get rid of all the bugs in our body because a lot of those bugs are really helpful. So we're thinking about ways of doing this in a more targeted way. Can we go after just this one species or can we go after treating just the tissue locally. So just get rid of the bugs that are in that pancreatic tissue versus a more systemic dose. Those are all the kinds of important therapeutic questions that we have moving forward.