3-D model for cancer metastasis

August 6, 2012 § Leave a comment

Tumor cells (green) invading towards an endothelial monolayer (red). Image courtesy of Ioannis Zervantonakis.

Tumor cells bursting into blood vessels is an early and important step that causes a cancer to spread from one place to another.  In a paper out this week in the Proceedings of the National Academy of Sciences, researchers have created a 3-D tumor model in cell culture to better understand how this critical step in cancer metastasis actually happens.

The entry of tumor cells into the blood circulation is called tumor cell intravasation. It determines the number of cancer cells that spread from the primary tumor to distant organs. The mechanism of this rate-limiting step is a mystery, because it’s difficult to study the process inside animals and there aren’t any physiologically relevant tissue culture models.

Roger Kamm‘s group at the Massachusetts Institute of Technology has had a longstanding interest in making in-vitro models of blood vessels and studying how mechanical forces and cell–cell signaling affect the development of blood vessels. In this latest project, they turned their expertise to making a model that would allow them to see in real time how tumor cells interact with the endothelial layer of blood vessels and manage to break across the endothelial barrier.

To mimic the tumor microenvironment in solid tumors, Ioannis Zervantonakis, Kamm and colleagues designed the model to have a collagen type I matrix and macrophages that allowed cells to invade in three dimensions. They also developed a method to properly quantify the permeability of the endothelial barrier. The investigators used microfluidics, a technology based on a network of channels on the microscale, that mimicked the vessels and flows that tumor cells normally encounter inside the human body.

Using the model, the investigators observed that the macrophages induced endothelial barrier leakiness by secreting inflammatory cytokines, such as TNF-α, which facilitated higher tumor cell intravasation rates. The intravasation could be limited by antibodies that blocked the cytokines and restored endothelial barrier function. The investigators concluded that the endothelial cells acted as a barrier to tumor cell intravasation but were regulated by factors in the tumor microenvironment.

A major advantage of microfluidic technology is that it can work with microliter volumes, a highly attractive feature for experiments involving expensive or hard-to-get reagents or cells. For this reason, “our microfluidic model is a very attractive platform for drug discovery and screening,” explains Kamm. “Additionally, our microfluidic model may find applications in personalized medicine, incorporating clinical specimens inside the 3-D culture region to test the response of cancer cells from patients to cancer drugs.”

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