Methods for monitoring tumour cells in living animals are transforming our view of cancer.
Mikala Egeblad was blown away when she made her first action film of tumour cells inside live mice. Until then, she had studied samples on microscope slides, where the cells sat still, frozen in time. But seeing them in a living animal brought the cells to life. “You turn on the microscope and look in the live mouse and suddenly these same cells are running around like crazy,” says Egeblad, a cancer researcher at Cold Spring Harbor Laboratory in New York. “It really changed my thinking.”
Increasingly, cancer researchers are embracing the chance to spy on individual tumour cells in their native environment. In studies of static tissue cultures, investigators have to infer what cancer and other cells surrounding the tumour might be doing, and how they might be interacting. Tracking cancer in live animals over time — an approach called intravital imaging — puts those interactions on display, and allows biologists to zoom in on the small number of dangerous cells within a tumour that drive the disease or resist treatment.
The technique is young, and labs are still working out how best to analyse the gigabytes of video data it generates. But the increasing use of intravital imaging over the past decade has already helped researchers to piece together timelines for key cellular and molecular events, such as the process by which tumour cells sneak into blood vessels. Such clues have yielded new hypotheses about how cancers grow, spread and resist treatment — information that could, for example, eventually enable drug developers to understand why some cancer cells do not succumb to therapy.
And in a video-obsessed culture, the imaging technique holds instant appeal. “When we show our movies, people fall out of their seats when they see how dynamic a tumour lesion can be,” says Peter Friedl at Radboud University Nijmegen in the Netherlands. “It's a change in perception.”
First used by cancer biologists in the late 1990s, intravital imaging involves focusing powerful microscopes directly onto exposed tissue in a live, anaesthetized mouse. More labs have adopted intravital imaging as technological improvements have made it possible to peer further into tissue — now as many as 20 cells deep — and to tease out fainter signals. A growing library of molecular markers has given researchers the ability to visualize up to eight different kinds of cells and structures, including various immune-system cells and the endothelial cells that line blood vessels. “The markers and the microscopy technology make this a powerful combination,” says Frederic de Sauvage, vice-president of molecular oncology at the biotechnology company Genentech in South San Francisco, California, who has seen the technology in action.
Putting these components together creates a comprehensive picture of cancer as a complex ecosystem of cells that migrate, proliferate and interact. Although cancer researchers have long understood that cells in a tumour are genetically heterogeneous, intravital imaging is revealing how the behaviour of individual cells can also differ. For example, cancer cells may march in single file or collectively as a tight-knit group, depending on the type of tumour and its environment.
One mysterious cellular behaviour that has landed in the sights of these microscopes is that of the macrophage, a type of immune cell that normally engulfs pathogens, removes dead cells and stimulates immune responses. Macrophages can incite immune cells to fight cancer, but more often they boost a tumour's growth and spread.
Intravital imaging studies showed that macrophages, along with tumour cells and endothelial cells, form a structure that pumps tumour cells into the bloodstream — a key step in metastasis. Working with rodents, researchers led by John Condeelis at Albert Einstein College of Medicine in New York found that when macrophages come into contact with mammary tumour cells, the tumour cells become more invasive, degrading the protein-rich matrix around blood vessels and squeezing between the endothelial cells. Macrophages cause the endothelial cells to lose contact with each other, opening a hole in the vessel wall and allowing tumour cells to stream out of the tissue and into the bloodstream1, 2.
Condeelis's team has shown that this 'pump' is present in human breast cancer. The group has also identified three molecular markers, one for each cell type in the structure, that indicate its presence in tumours. In a study3 of 60 people with breast cancer, individuals with a higher density of these pumps in their tumours were more likely to develop metastases in other organs. A start-up company, MetaStat in Montclair, New Jersey, has licensed this prognostic technology and is developing a test that predicts metastatic risk in people with breast cancer. The company hopes to have the test in clinical trials by the end of this year. Condeelis's group is also working on a probe to identify the pumps using magnetic resonance imaging, avoiding the need to take tissue biopsies from patients.
Written By: Corie Lok
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