Cancer metastasis: why does cancer spread?

What's the latest strategy to try and prevent cancer from spreading?
23 November 2020

Interview with 

Sakari Vanharanta, MRC Cancer Unit and Cancer Research UK Cambridge Centre


Cancer metastais occurs when rogue cancer cells break away from a tumour and spread, often via the bloodstream or the lymphatic system to other parts of the body. But why do cancer cells but not healthy cells do this, and what determines where these cells tend to spread to? Sakari Vanharanta is a cancer biologist at the MRC Cancer Unit in Cambridge and Cancer Research UK Cambridge Centre, and his lab studies this process, as he told Chris Smith...

Sakari - I think they don't necessarily want to spread, but cancer is a disease of uncontrolled growth. And these tumour cells divide and divide. And there's so many of them that they end up just spilling out of the primary tumour and ending up in different organs. And then some of those cells eventually survive there, and form a secondary tumour. So I don't think this is an orderly process in cancer. They just move randomly and end up in secondary organs because of that.

Chris - But some cancer types do seem to "prefer" in inverted commas, to spread to certain parts of the body, and certain other organs don't they?

Sakari - Absolutely, there is organ specificity to the metastatic process. And this is something that is kind of poorly understood still, but it seems that there's a match between a certain cancer types and a certain secondary sites and cancer cells when they end up at there, or if they end up there, they have a higher chance of surviving, and that's why there's this predominance of certain types of metastatic sites.

Chris - Is it just the cancer cells, the abnormal cells that have made the primary tumour, that then go off and spread, or do they have the potential to subvert and manipulate other healthy cells in other places, to make their spread and invasion into other sites in the body, more likely?

Sakari - Cancers are more like ecosystems, there's multiple different cell types there. And cancer cells recruit various types of normal cells, and they exploit those, and they do this for many purposes, including migration and for the purpose of leaving. So some cancer cells can follow, or tag along with other normal cells, and that will help them move. So absolutely it's a process in which cancers very much exploit normal cells.

Chris - We were hearing earlier about the amazing journey that these neural crest cells take when they're migrating from where they're formed, in a developing embryo, to end up all over the body and giving rise to all kinds of important structures, presumably since cancer cells have access to all of the same genetic programs that a developing embryo would have, can they just turn on those developmental programs and basically pretend as though they're back in an embryo, and go wherever they want, is that part of the reason why they're so destructive?

Sakari - So in cancer, many of these developmental programs are activated in the wrong place. And I think an example of this would be melanomas, which develop from the melanocytes that were just discussed in the context of neural crests. So the normal function of the developing neural crest, is to migrate through the developing embryo. Now melanocytes don't normally do that, but the cancer causing mutations may allow them to activate the same programs. And that's one of the reasons melanomas can form metastases in many secondary sites.

Chris - And is there any evidence that cancers, when they're in situ, and they've got these distant metastases, these deposits in other parts of the body, are those cancers in cahoots? Do they talk to each other? Is there a sort of chemical conversation going on between tumour deposits around the body?

Sakari - Between the different metastatic sites I think it is difficult to measure whether those sites communicate, but cells travel from one metastatic site to the next. So through these kind of messengers, they would be exchanging information.

Chris - So you're saying a cancer can not only spawn a new tumour in a new place, but sometimes cancer cells will come out of one metastatic deposit and go to another one?

Sakari - Absolutely. So there's genetic evidence showing that again, like an ecosystem of different tumours in different parts of the body, and there's clones that move from one place to another, and then start growing there.

Chris - And does that affect the way that the tumours grow? If one of them discovers a really good way to grow, can it take that information or that know-how to another tumour site, and stimulate that to grow more?

Sakari - Yes. For example, if you have cancers under therapy, you could have resistant clones that emerge in one metastatic site, and then if it's migratory, it could colonise new sites or preexisting metastatic sites, and then help them grow as well.

Chris - Oh goodness. So that would explain why, when you have advanced disease, it can suddenly accelerate uniformly. So it's not just one bit of it that discovers how to grow better. The whole lot seems to progress, and progress increasingly quickly as the disease advances.

Sakari - Very true. So metastatic tumours can behave exactly like that, when you get resistance, it can happen in multiple places simultaneously, but it can also happen independently. So they could have mutations that target the same gene, independent mutations in different sites. And that could also lead to the same outcome.

Chris - But now that we know all these things, and we understand a lot more about the processes that lead up to cancers beginning to spread, the fact they get into tissues and establish metastases. How does an understanding of that mechanism inform how we treat patients?

Sakari - I think if we understand how metastatic sites, for example grow, of course it can help us develop targeted therapies for those very specific processes. And there are examples, like anti-oestrogen therapy in breast cancer. We know that breast cancer cells like oestrogen, so to prevent metastasis, we give patients anti-oestrogens to prevent that from happening.

Chris - And are there any specific things we've noticed that do by and large repeatedly lead to cells wanting to go walkabout? And by interrupting that, we have a chance to interrupt across the board, the spread of cancer? So we would turn a cancer from something that's highly progressive and virulent and nasty, into just a chronic indolent thing that we live with, a bit like high blood pressure, I suppose.

Sakari - I think that's the hope, but I don't think we are there yet, because we don't understand the process well enough. I think to inhibit the initial spread of cancer is very difficult because it's difficult to find the time window of applying such a therapy, but trying to prevent already disseminated cells from forming clinically meaningful metastases, I think that's why we should try to go.


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