Hereditary Breast and Ovarian Cancers Meeting 2011, New York, USA

Symmetrical and asymmetrical stem cell proliferation

Dr Wenjun Guo – Whitehead Institute for Biomedical research, Cambridge, USA

Professor Guo, Wenjun, thank you for coming to our little studio here at New York University. It’s a very exciting meeting, Franco Muggia and Angelo Paradiso have done a good job. Basics talks, clinical talks, genetics talks, counselling talks, it’s really good stuff. Now you gave a super talk about stem cells, what have they got to do with hereditary breast and ovarian cancer?

Right, I think there’s a new paradigm starting emerging that we need to look at the cancer cells differently, so not every cancer cells in the tumour are equal. So these are, in a way, very much similar to what we have in normal tissue, so they are stem cells and more differential cells. Stem cells are a special type of cell, they have an unlimited ability to proliferate while the differential cells tend to rest once they proliferate a few times. So in cancer there is a similar paradigm going on, so some cells are able to proliferate unlimitedly. Those types of cells, this group of cells, are more important in terms of tumour progression and also more important in terms of tumour recurrence after treatment. So we need to understand what are the mechanisms, what are the molecular pathways governing these type of cells, therefore we will be able to treat the cancer more efficiently.

So why don’t stem cells die when you give them chemotherapy or radiotherapy?

That’s a mystery that we don’t understand.

But they don’t, do they?

But the evidence suggests that. So hopefully by understanding the stem cell biology more, we may be able to uncover why those cells are more resistant to chemotherapy, radiation therapy and so on.

You were talking about symmetrical and asymmetric division, what’s that got to do with it?

The stem cells will divide in two fashions, as you mentioned – symmetrical and asymmetrical. The symmetrical is basically one stem cell makes another stem cell and they are identical functionally. Asymmetrical, a stem cell will divide into one stem cell and one more differential cell. That differential cell will gradually lose their ability to form a tumour or, in a normal setting, form a new tissue. So if we can find a way to prevent symmetrical division and make the stem cells only give rise to differential cells then there’s a hope, people are starting to call this differentiation therapy, so we may be able to induce the differentiation of cancer stem cells, therefore gradually eliminate those cells which drive the tumour growth.

But you said that mature cells in the breast cancer tissue can actually be persuaded to go back, in reverse, to stem cell, to cancer stem cells. Slug or sox or something like that, tell us about that story.

There’s a wrinkle here. So we just started to find, especially in cancer because they’re abnormal cells so they have particularly high plasticity. Under some circumstances, under certain conditions, they can convert, they can reacquire the stem cell status, capability. Our work actually has identified a molecular pathway that can mediate this process so hopefully this will… firstly, this is very early days, hopefully down the road we will be able to find a way of intervention to prevent this molecular pathway, therefore to prevent the reversion of non-stem cells back into stem cells, therefore prevent the normal generation of cancer stem cells and hopefully this can keep the cancer stem cells in check.

But not kill them? You could exhaust them?

Hopefully exhaust them or, by a combination of approaches, by curing the stem cells on the one hand and preventing the conversion of non-stem cells into stem cells on the other hand, by combining these two different approaches.

Tell us about the pathway, the slug?

These are two transcription factors, so basically these are genes inducing the other gene expression. Essentially they are as a switch for different gene programmes. We found these two key transcription factors, slug and sox9, so they need to act together in the mammary system, they can convert the differential mammary cells back into mammary stem cells. Also we are starting to accumulate evidence showing this kind of phenomenon also occurs in breast cancer and can drive more differential tumour cells back into less differential tumour cells.

So what controls the slug and the sox9?

That’s one thing we are studying right now. We hope to find that, the control, the key signalling pathways that we’re mediating is two gene expression, the expression of these two transcription factors. That could give us a target to intervene. So one can imagine in cancer, in an experimental setting we can express a gene by using experimental approaches but what’s happening in cancer is actually the signals in the tumour could activate these two genes, induce the expression of these two genes. So if we can find those signals, we can prevent those signals, therefore we could presumably inhibit the expression of the two factors and therefore prevent the cancer stem cells, inhibit cancer stem cells.

Good, thank you very much, that’s very clear. You’ve done a lot of this work at Bob Weinberg’s lab but you’re starting shortly in Einstein in New York?

Exactly.

Good luck, and I hope everything goes well.

Thank you very much.

Thank you.