Dr Ranjana Srivastava
How are you?

Patient
I'm very good.

Dr Ranjana Srivastava
Here's the rest of our team. Lots of faces today. I'll just check... As long as he's sitting up and alert. How's your hand doing?

Patient
Yeah…

Dr Ranjana Srivastava
My name is Dr Ranjana Srivastava. I'm an oncologist.

Dr Ranjana Srivastava
How's chemo going today?

NARRATION
Every day in Australia, 360 people learn they have cancer. It goes without saying, it's a very stressful time. I often think about how stress affects my patient's prognosis. And it's an issue the medical community has long debated.

Dr Ranjana Srivastava
How are you going?

Patient
No, good.

Dr Ranjana Srivastava
Is this your first lot?

Patient
Yeah. This is the first one.

NARRATION
From my own clinical experience, it does seem that stress has a negative effect on cancer outcomes. But to date, we haven't had good science to know how this happens.

Dr Ranjana Srivastava
New Australian research has identified pathways caused by stress that facilitate the movement of cancer cells around the body.

Dr Erica Sloane
The stress is sort of acting like a fertiliser and helping the tumour cell take hold and colonise those other organs.

NARRATION
What's more important, the researchers may have found a way to prevent it.

Dr Ranjana Srivastava
My hands are cold. I apologise in advance. I'm sorry. Don't jump.

NARRATION
My patient, Robert Denny, was diagnosed with bowel cancer in December 2014.

Dr Ranjana Srivastava
Just have a feel of your liver. Big breath in. And out.

NARRATION
Robert's been having chemotherapy and it has been a difficult time.

Dr Ranjana Srivastava
How does Mary think you're travelling now?

Robert Denny
She's quite happy with me. She says I get a bit bad-tempered. As they say, it's just part of the treatment.

Dr Ranjana Srivastava
No, you can't blame the chemo for being bad-tempered.

NARRATION
Robert's making light of it, but stress is now proving a real factor in cancer spread. Challenging circumstances activate our body's fight or flight response. In times of threat, this allows us to respond quickly. But if it becomes chronic, stress can have damaging effects on our health. It's associated with greater risk for depression, heart disease, and infectious diseases. When it comes to cancer, stress as a cause has not been convincingly proven. But over the last 10 years, Dr Erica Sloane's lab has been looking at how stress drives metastases - that is, the spread of an existing cancer from the original tumour.

Dr Erica Sloane
At the time that I started this research, we had an understanding of how stress affected cancer patients at a psychological level, but we really didn't understand how stress got into the body of a cancer patient and how it could affect the cancer cells. And what we found was that when a mouse has cancer, when they're stressed, the cancer hears that and it sends a signal into the cancer that allows tumour cells to escape from the cancer and spread through the body. The stress is sort of acting like a fertiliser and helping the tumour cell take hold and colonise those other organs.

NARRATION
But they didn't know how this was happening.

Dr Erica Sloane
So, we've got a picture here of the lymphatic system. You can see it's an amazingly vast network that goes right through the body.

Dr Ranjana Srivastava
And we've known for quite some time that cancers spread through the lymphatic system, haven't we?

Dr Erica Sloane
Yeah, we have. We can see how close it is to the circulatory system, and for a tumour cell that's sitting here in the breast, it's really just a short jump into the lymphatic system, and from there it's got a pathway to track right through the body.

NARRATION
Very recently, Erica's lab discovered that stress co-opts this lymphatic network to create new, faster pathways of escape for cancer cells from a primary tumour. This research by Erica's colleague, Dr Caroline Lee, has been looking specifically at human breast cancer, but in mice.

Dr Ranjana Srivastava
Human stress is so multifactorial. Explain to me how you stress mice.

Dr Caroline Lee
What happens when you're stressed is you get a release of these stress hormones that then prepare your body for threat. So, the way that we mimic this in mice is through a method we call restraint stress, which is essentially just putting them into a confined space. And this activates the same pathways as humans have activated when they're in stressful situations.

Dr Ranjana Srivastava
Alright, so, I can understand that that's a physiological stress that you are imposing on the mice. How do you measure psychological stress, which, as I see every day, is such an important component of cancer?

Dr Caroline Le
Mice actually do like being in small, confined spaces. The part that they don't like is not being able to escape, and so when we stress them in these confined spaces, this activates the psychological fear factor, or the coping mechanism that we see in humans, which then leads to these physiological responses that we then can measure later.

NARRATION
Stressed and unstressed mice are injected with human tumour cells. These cells are tagged with a protein extracted from nature, from fireflies, so they emit light.

Dr Caroline Le
So, what that enables us to do is then track the tumour cells once they're in the mouse and track where they move throughout the mouse.

NARRATION
The mouse is anaesthetised and injected with a substance that triggers the luminescence in the tumour cells. It's then placed in an imager.

Dr Caroline Le
So, what we have here is the primary tumour. These tumour cells have spread from the primary tumour and moved up to the lymph nodes here under the arm and then here into the chest.

NARRATION
Using this, and other imaging techniques, Caroline has found that stress increases the number and size of lymphatic vessels leading out of a primary tumour.

Dr Caroline Le
So, what you can see is that the flow in the mouse under stress conditions flows much faster than that in the mouse under control conditions.

Dr Ranjana Srivastava
It's just flying through, isn't it?

Dr Caroline Le
Right.

NARRATION
These stress-induced superhighways dramatically increase the number and size of metastases.

Dr Caroline Le
So, you see six times more spread of cancer in stress mice compared to control mice.

NARRATION
Given that metastasis is behind the vast majority of cancer deaths and that stress is an inevitable part of having cancer, it's cruel news.

Patient
It's hard not to think about, you know, that I do have cancer and at the end of the day, you know, what can you do?

NARRATION
Fortunately, the researchers have something positive to report, too. They're hoping an age-old class of medication, beta-blockers, might have a brand-new role in tackling cancer. Beta-blockers are commonly used for high blood pressure and cardiac arrhythmia, but they're also known to control the effects of stress.

Dr Erica Sloane
They work by blocking the stress response. And so if you have a beta-blocker present, then the beta-blocker will get in the way of adrenaline and stop it binding, and so heart rate doesn't go up as much, blood pressure won't go as high.

NARRATION
When the beta-blocker propranolol was given to stressed mice, the effects of stress were totally negated.

Dr Caroline Le
What we then see is that stress no longer restructures the lymphatic system and we don't get this increase in spread of cancer in response to stress.

NARRATION
Although generally a safe medication, beta-blockers are not without side effects. Drawing on their knowledge of how stress acts on cancer cells, the researchers hope to develop a cancer-specific beta-blocker.

Dr Erica Sloane
This gives us an opportunity to design even newer generation beta-blockers that we can use to target the tumour rather than targeting the heart.

NARRATION
All this work has been done in mice, but the data is so interesting and the implications so important that it merits human study. That's what anaesthetist Dr Jonathan Hiller is doing here, at the Peter MacCallum Cancer Centre in Melbourne. He's conducting a pilot trial in women recently diagnosed with breast cancer and who are about to undergo surgery.

Dr Jonathan Hiller
We've chosen the perioperative period, 'cause as an anaesthetist we often see women have a state of increased stress and anxiety at the time of surgery. And the build-up to surgery following their diagnosis can be incredibly anxiety-provoking.

NARRATION
That's exactly how it was for trial participant Angela O'Regan.

Angela O'Regan
Good boy.

NARRATION
In January this year, Angela was diagnosed with breast cancer and told she needed surgery.

Angela O'Regan
I was just so absolutely petrified of having a general anaesthetic, 'cause I'd never had anything like it before. I would even ask my friend in Scotland, "Have you had an anaesthetic? What happened? What did you feel like?"

NARRATION
Trial participants like Angela are given either the active drug - the beta-blocker propranolol - or a placebo.

Angela O'Regan
Because it's propranolol and it's a beta-blocker, you have to check your blood pressure every day.

Angela O'Regan
I'll relax.

Declan O'Regan
Yeah.

Angela O'Regan
So, I used to get Declan to check my blood pressure every day. You have to watch it doesn't go too low, 'cause you can end up with different side effects - like you can end up, you know, being dizzy and feeling faint. Yeah, different things like that.

NARRATION
It's a double-blind trial, so neither the participant nor Jonathan knows who has got what.

Angela O'Regan
In my mind, I think I did have the right tablet. I definitely felt less stressed. I definitely...I definitely did feel less stressed. But I don't know if that was that, or if it was in my mind.

Professor Michael Henderson
It's about 12:30. We'll see you in about an hour. You'll be fine. We will take good care of you.

NARRATION
Angela is one of 60 women the trial is planning to recruit.

Professor Michael Henderson
About 20% overall will have lymph node involvement. But in most cases, it's low-burden disease.


NARRATION
Before they remove the tumour, the team injects radioactive blue dye into the patient's breast to locate the key lymph node.

Professor Michael Henderson
If you look in there now, you can see the blue stain mark. So, you can see the little lymphatic running down through there.

Dr Ranjana Srivastava
Mm-hm.

Professor Michael Henderson
Straight into the node. And if you put the probe on top of it, it will go berserk. Watch this.

Dr Ranjana Srivastava
And why does it do that?

Professor Michael Henderson
Well, the blue dye's been injected under the nipple and it's got into the breast's lymphatic system. And we know that if cancer cells are going to spread from a breast cancer, the place it goes to is to that first lymph node, or the sentinel node.

NARRATION
Surgery is often the first stage of treatment for breast cancer. And despite all their care, surgery is an assault on the body, inducing a stress response that is similar to that caused by traumatic injury.

Dr Jonathan Hiller
Patients are exposed to a lot of stress through the surgery and not just their anxiety. They're exposed to pain through to hypothermia, a number of medications related to their anaesthetic. So we often see states of stress and what we call inflammatory stress - inflammatory response is a direct result from surgery and well known to exist.

Dr Ranjana Srivastava
Participants' stress levels are analysed through blood samples taken before and after surgery.

Dr Jonathan Hiller
There are markers in the white cells that circulate in our body that reflect our overall state of stress and anxiety. We want to see whether using beta-blockers changes that signature at the time of surgery. We're very keen to see whether the medication changes the behaviour of the tumour with its propensity to metastasise. We look at specific genes and specific changes in the tumour and the tumour micro-environment to see whether these changes that occurred in mice also occur as a result of the medication in women. At this stage, we're looking at very specific biological features of the cancer. We're not looking at the impact overall to women's cancer outcome.

NARRATION
The trial is ongoing, but I'll certainly be very interested in the results. Angela's own surgery went well. She's having chemotherapy and, in the meantime, trying to keep her stress levels under control without medication.

Story Contacts

Dr Ranjana Srivastava
Oncologist
Monash Health

Dr Erica Sloan
Cancer Biologist
Monash Institute of Pharmaceutical
Sciences

Dr Caroline Le
Cancer Biologist
Monash Institute of Pharmaceutical
Sciences

Professor Michael Henderson
Surgeon
Peter MacCallum Cancer Centre

Related Info

Recent published research study by Drs Caroline Le and Erica Sloan on stress and cancer

Dr Erica Sloan’s lab at MIPS

Report on new research by Drs Caroline Le and Erica Sloan

Fairfax media report on the breast cancer pilot trial at Peter MacCallum Cancer Centre

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