Roger Kamm and colleagues from the Massachusetts Institute of Technology have taken us one step closer to understanding how cancer cells are sneaking into secondary invasion sites.
In their recent paper 1 published in Integrative Biology, Kamm et al produce a microfluidics-based platform for the study of tumour cell movement, which they use to analyse the process through which cancer cells spread throughout our body as they execute a complex invasion strategy.
Through this platform, Kamm and team showed that more aggressive tumour cells are better at getting out of our blood stream and into our tissues, and that within a group of tumour cells, subpopulations exist which differ in their tissue invasion capability. But what makes these cells good at moving through our bodies?
Metastasis is a step in malignancy in which tumour cells move from their initial development site, enter the blood stream, and move through the vascular system to secondary invasion sites. Extravasation is the final step in metastasis: tumour cells work their way out of the vascular network by latching onto the endothelial cells lining our blood vessels, squeezing out through small pores and entering adjacent tissue.
As such an important step in metastasis, finding drug targets within the extravasation mechanism of tumour cells has potential to allow for a huge development in cancer therapy. But in order to do this, we must understand the key molecular players in extravasation.
In the past, studies have been low resolution in vivo and have not allowed for the elucidation of the molecular details of the process. Developments in the field of microfluidics have provided advancements. However, there are limitations both in the unknown effect of microfluidic components on extravasation mechanisms and in the physiological relevance. 3D microvascular networks are now being more widely used to study cell migration as they allow for more physiologically representative studies due to their formation through angio- and vasculogenesis (growth of new blood vessels).
In Kamm’s paper, the team combined these microvascular networks with microfluidic technology to study the entire process of extravasation in vitro; the model is high-resolution, high throughput and has increased physiological relevance over previous models.
First of all, human umbilical vein endothelial cells were used to ‘grow’ microvascular networks through vasculogenesis. Cell culturing within two gel-filled channels lead to spreading and organisation of endothelial cells into tubes, providing a micro-scale blood vessel network.
Once this model system was set up, changes in pressure were used to draw a suspension of tumour cells into the vascular network, in a process called seeding. Seeded tumour cells are shown below (green), in amongst the vascular network (red), in an image taken from Fig. 1 of Kamm’s paper. After seeding, tumour cells were left to their own devices for 30min before the channel was washed. After this, cells that had begun the extravasation process remained within the channel through mechanical or adhesive interactions; they had completed the ‘latching on’ step of extravasation.
Kamm found that sub-populations of tumour cells exist, which had varying extravasation capabilities. His research team also showed positive correlation between the metastatic potentials of different cells lines and their extravasation capabilities. This tells us that the more aggressive tumour cells are better at getting out of our blood vessels and into our tissues.
In addition to this, Kamm et al showed that elevated levels of TNF-α, a pro-inflammatory molecule, were associated with both an increase in endothelial permeability and extravasation rate, suggesting a correlation between the two.
In this work, Kamm and colleagues have made an excellent contribution to the study of tumour metastasis, and their microfluidic-based research platform is sure to continue to elucidate the molecular signatures behind the process. We look forward to future work by this research team!
This article by Kamm et al will be free to download* for the next two weeks, so pick it up for a thorough read.
- Mechanisms of tumour cell extravasation in an in vitro microvascular network platform. Roger D. Kamm, Michelle B. Chen, Jordan A. Whisler and Jessie S. Jeon. DOI: 10.1039/C3IB40149A.
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