ASCO 2011 Annual Meeting, 3—7 June 2011, Chicago

Importance of metastases in cancer growth

Professor Larry Norton – Memorial Sloan-Kettering Cancer Center, New York, USA

This is an incredibly exciting time for trying to understand the fundamental thing that makes cancer cancer, which is metastasis. The vast majority of people who die of cancer die from metastases. What we discovered, this is the work coming out of Joan Massagué’s laboratory and Mi-Young Kim and colleagues over the last few years, is that a lot of primary cancer growth, the growth of the primary cancer, is actually metastatic growth. Cancer cells can metastasise, cancers can metastasise to themselves. Cells leave, they circulate, they come back to the tumour and there they invigorate tumour growth by bringing in white cells, monocytes and macrophages in particular, and by inducing blood vessel growth which are also marrow derived cells. So the distinction between primary tumour growth and metastatic growth is starting to become very blurred. Therefore, a better understanding of the process of metastasis is going to help us to control primary tumours as well.

How do you go about doing that?

The first thing is to identify the cells and here there’s just an enormous amount of excitement in what are the characteristics of cells that have this capacity to seed.

Are they CTCs or low CTCs? Probably not.

Well, you never say no in science but there’s a very strong suspicion that they are CTCs, there’s a very strong suspicion that they are cells that have undergone what Bob Weinberg is calling EMT.

Sorry, what’s that?

Epithelial-mesenchymal transformation, this is the transformation from the epithelial markers to more mesenchymal markers which is all about cell mobility. It’s also the cells that people are talking about as cancer stem cells or tumour initiating cells. I think that the likelihood is very high that we’re talking about the exact same process. These are the mobile cells. What’s really fascinating is the system in the body that’s all about cell mobility is, of course, the immune system; you cut your finger, cells are mobilised from the marrow, they go there and a whole variety of cells are implicated in fighting infection and in promoting wound healing. So it’s not surprising that the same toolkit that cells use to be inflammatory cells and move around the body are related to the mobility of cancer cells. And one of the key things that we’re learning is the importance of the relationship of the cancer cell to the infiltrating white cells, the monocytes and the macrophages.

Do they piggy-back?

I’m starting to think that a cancer cell by itself is a totally benign thing. It’s a cancer cell married to a macrophage that’s dangerous. So it’s the cross-talk; it’s the relationship between them, it’s the biochemical signals that are passing back and forth that really is the key thing. And we may have to start thinking that that’s the real Achilles’ heel of cancer, not the driver mutation that makes the cancer cell what it is but the drivers that are making the cancer cell communicate with the white cells and the drivers in the white cells that are allowing them to communicate with the cancer cells. Those targets are very vulnerable and that’s something that we’re focussing a lot of our energies on now. 

So linking up with a macrophage gives you a sort of built-in bodyguard who goes with you everywhere you go, plus a fast transport system with outriders getting you through the crowds.

Oh it does everything and I think it does everything involved in all stages of the process for cell survival, for their ability to colonise. The actual step of seeding probably doesn’t require a white cell helper, but once the cell gets to the organ of origin. And there’s even evidence now that those macrophages may get to the metastatic site before the cancer cell does and once it gets to the metastatic site, of course, it promotes the tumour growth. 

So you’re going to interfere at the earliest step, and what would that be?

This is a very key question, both scientifically and philosophically: is a disseminated cancer cell that never colonises, is that a cancer? And it isn’t a cancer as far as the patient is concerned because you could have disseminated cells all the time that just sit there and even if they survive, if they don’t grow into tumours and they don’t metastasise to other sites, they’re never going to cause a problem. I think that this may be more common than we think and that the real problem with cancer is not the seeding capacity but the likelihood of colonising, of surviving first, which is separate, and then colonising once it wakes up the metastatic sites. We may, therefore, not truly eradicate all the cancer cells by the next generation of therapy but we may prevent them from relating to the stroma in such a way that they could ever turn into a disease because it’s the disease of cancer that we’re trying to cure, not necessarily the cancer cells. I’m thinking that you worry, for example, how come people with BRCA1 or BRCA2 heterozygosity have a high tendency to form cancers of the breast or of the ovary preferentially? Well maybe they don’t, maybe little cancers form all over the body by DNA repair defects but they never turn into clinical cancer because the cells that are so transforming don’t have the capacity to move or to colonise or to form tumours. So modern metastases research are just making us rethink the whole process of what cancer is.

The next steps?

We’ve lots of them. Classical biochemistry, trying to determine the processes in these communications. I am, of course, interested in developing interventions, particularly drugs, that may interfere with that communication; I think that’s probably our next step. Scientific steps – proving that self-seeding occurs in humans is going to require certain advances in single cell sequencing, and that work is going on.

And imaging.

And imaging too, in collaboration with Cold Spring Harbor Laboratory and Memorial Sloan-Kettering are working together on that particular process. I’m thinking a lot about the notion of how to deal with the primary cancer this way. We have a very strong suspicion that the primary cancer is both a source of seeds and a recipient of seeds. What if we can turn the primary cancer into a poisoned sponge? A sponge that can suck up circulating cancer cells and once they get there they can’t grow, they can’t cause trouble. Can we use immunotherapeutic tools? For example, we’re about to start a trial, we’ll use cryoablation of primary breast cancers and give a single shot of the anti-CTLA4 antibody, the same drug that has been so successful in melanoma, ipilimumab, and give that so that then we can unleash the body’s immune reaction against cells that are drawn back into the primary tumour with all these antigens being released by the cryoablation, that’s one approach. Radiotherapy may also be useful in this regard and we’re even thinking about synthetic ways of designing essentially poisoned sponges where we can actually pick up these seeds as they travel through the blood. So there’s a lot of really interesting research ahead of us.

Larry, thank you very much indeed. Time is ticking, you’d better get on.

Always a pleasure. Thank you.