Inflammation and cancer: unravelling a 150-year-old mystery

Inflammation is one of the body’s most powerful weapons. It’s our reaction to bacteria and toxins, marked by an avalanche of immune cells and chemicals that take down the enemy and allow our wounds to heal.

But as well as preventing infections and repairing injuries, inflammation can also cause collateral damage. The masses of blood cells, antibodies, enzymes and other chemicals arriving at the scene cause a chain reaction, often affecting the tissues surrounding those they’re trying to protect.

And for people with long-term inflammatory conditions, a prolonged state of inflammation can sometimes cause irreparable damage, and sometimes leads to cancer.

Inflammation is a major culprit in cancer

The link between inflammation and cancer was first made more than 150 years ago. And it’s now thought that up to 1 in 4 cancers globally are linked to the condition.

Knowing that cancers linked to inflammation, such as oesophageal and lung cancer, are among those hardest to treat, we’ve dedicated £20 million as part of our Grand Challenge scheme to uncover the root cause. And the team of experts from the US, UK, Canada and Israel that are tackling this challenge, led by Professor Thea Tlsty, aim to ultimately find better ways to detect and treat these cancers.

“Understanding how inflammation can lead to cancer is the fundamental nature of this challenge,” says Dr Stuart McDonald, a lead researcher on the team from Barts Cancer Institute in London who studies an inflammatory condition of the food pipe, called Barrett’s oesophagus.

“The inflamed tissues don’t show any obvious signs that they’re going to develop into cancer, but a switch can occur, taking them towards cancer. And this is the part that we don’t understand,” explains McDonald.

But delving into these tissues, scientists think they might have uncovered some clues as to what’s going on.

The supporting environment could help cancers grow

According to McDonald and others working on the Grand Challenge project, the answers might not lie in the cancer cells themselves. Instead, the environment surrounding the tumour, and the supporting web of cells and proteins that hold this habitat together, called the stroma, could have a part to play.

Until now, McDonald’s work has focused on the lining of the oesophagus, where most cancers occur. But for this project, he’s now able to study the stroma too, enabling him to hear both sides of the conversation, and understand how each part contributes to cancer growth.

“There’s some nice evidence to suggest that when you target the stroma, you can revert an invasive cancer into a non-invasive one,” says McDonald.

So far, these results have only been seen in mice, but if scientists can translate this knowledge to people it may be possible to develop treatments that could revert tumours back to normal tissue.

New technology is uncovering cancer targets

One researcher who has played a key role in studying how the stroma affects cancer is Professor Donald Ingber from the Wyss Institute for Biologically Inspired Engineering at Harvard University in the US. His pioneering early work in the 1980s forms the basis for how mistakes in the development of normal stromal tissue can lead to cancer.

As part of the team taking on this Grand Challenge, Ingber’s role is to build on the foundations of his early work and use the latest technologies to bring about new discoveries.

This includes the so-called ‘organ-on-a-chip’ technology developed by Ingber’s team at the Wyss Institute.

Formed from a network of tiny channels housed in what looks like a clear computer memory stick, the chip allows researchers to recreate what goes on inside an organ in a controlled lab environment.

For example, they can take cells that line the human intestine or lungs, called epithelial cells, and grow them on one side of a porous membrane, with stromal cells grown on the other. They can then exert physical pressures on the chip to represent real life situations, such as the breathing motions of the lung. All the while, providing a liquid lifeline in the form of an artificial blood supply that flows across the cells as it would in the body.

Lung cancer cells (green) grow within healthy lung tissue (red) in the lung cancer chip, used to model and study how tumours grow. Credit: Wyss Institute at Harvard University

“We plan on taking pre-cancerous epithelial cells from patients and combining them with their own pre-cancerous stromal cells on the chip to recreate what tissues look like before they turn to cancer,” explains Ingber. “We can then replace the pre-cancerous stromal cells with normal stromal cells and see if that reverts the tissues back to normal.”

This meticulous approach will be mirrored across the team, with each group adding their expertise in the hunt for detection and treatment targets.

“This process is universal to all the team members, but each of us have our own particular specialities we can use to provide these targets,” says McDonald. So, while Ingber’s lab is focused on organs-on-chips, McDonald will be studying clinical samples.

This collaborative and convergent approach will generate a whole host of targets. The challenge then is to pick out the most important ones and work out how to attack them.

Sniffing out new cancer targets

Dr Kole Roybal, from the University of California, San Francisco, is leading a team that will be engineering human immune cells, called T cells, to ‘sniff out’ the signs of cancer.

According to Ingber, Roybal will be putting seeker molecules on the surface of these cells so that they find the targets identified by other team members, potentially helping them home in on cancerous cells. They could then “release signals that may help prevent progression or avert cancer entirely”, suggests Ingber.

McDonald hopes this will lead to new therapies using the targets he and others discover throughout the project.

But these developments will take time, and nothing is guaranteed. McDonald adds that some of the difficulties posed by these theoretical new therapies could take “more than the length of one Grand Challenge project” to solve. But there are other goals along the way that could ease the burden on cancer patients.

Changing the patient pathway

Desiree Basila, who in 2007 was diagnosed with a breast condition that can turn into cancer, called ductal carcinoma in situ (DCIS), is a patient advocate on the team from San Francisco.

“One of the big pieces of the project is trying to stratify risks,” she explains. “We’re trying to see which biological situations are going to lead to aggressive cancer and need to be treated. And then those which may be atypical but won’t lead to cancer.”

My great hope is that this project can help us know when treatment is really necessary, and if it is, provide treatment that improves both quantity and quality of life – Desiree Basila, patient advocate

This is critical for Basila, who turned down aggressive treatment for her condition, which is being studied in greater detail as part of another Grand Challenge project. She believes that softer approaches are needed to treat cancers.

“Scientists may be thrilled by their work when they can extend life by three months, but from a patient’s perspective, a lot of the time they spend three months suffering horrible side effects,” she says. “My great hope is that this project can help us know when treatment is really necessary, and if it is, provide treatment that improves both quantity and quality of life.”

McDonald shares this vision for cancer treatment, with one of his main goals being to identify who’s at risk and who doesn’t need to undergo therapy.

“I want to have the basis of a predictive model for how the stroma changes over time and what this means for cancer risk. That way we can get patients who are not at risk of cancer out of the clinic and free up resources for those that are at risk.”

This aspiration is shared by Ingber, who sees huge potential in the opportunity to prevent cancers through this work.

“If we can develop therapies that prevent progression, that’s an easier target to go after,” he says. “Once you have cancer, it’s really hard to reverse that, but if you stall it when it’s just at the inflammatory stage, maybe we can normalise it.

“By treating these patients early, you would be preventing cancer from ever forming, and that would be the goal.”

It’s ambitions like these that the Grand Challenge scientists are striving for.

Basila sees a world “where medicine is shared decision making and where patients have a voice in their own care – making decisions from a place of understanding, rather than fear”.

For patients with long-term inflammatory conditions, having the means to find out more about the risks associated with their condition would be a huge achievement to better manage their treatment. Now it’s down to the research to light the way.

Carl Alexander is a senior science media officer at Cancer Research UK