Roger Kamm - Tumor cells go against the flow
Microfluidic model helps explain how fluidís flow in bodily tissue influences tumor cell migration.
Alissa Mallinson, Mechanical Engineering
July 22, 2011
Cancer's uncontrolled spread throughout the body is
what makes the disease so deadly. To shed some
light on the spreading process, mechanical
engineers at MIT have developed a microfluidic
model to better understand how cancer cells break
loose from their original tumor, make their way into
the body's vascular system and travel around the
Using that microfluidic device, Professor Roger
Kamm and mechanical engineering graduate student
William Polacheck, in collaboration with Joseph
Charest from the Charles Stark Draper Laboratory,
have discovered that the direction in which fluid
flows through bodily tissue determines how likely cancer cells are to spread, or metastasize. Armed with that
information, they say, it may be possible to limit the spread of cancer.
Almost as important as their discovery — described in a recent issue of Proceedings of the National Academy of
Sciences — is the 3-D microfluidic system they invented that led to it. Whereas previous insights were based
solely on visualizing individual cells in an artificial extracellular environment, Polacheck and Kamm's system
allows them to look at the way cells interact with tissue that mimics natural breast tissue.
"There isn't a single drug currently on the market that addresses how cancer cells break loose from a primary
tumor and get into the vascular system, migrate out, and form a secondary tumor. But those are processes that
we can actually simulate in our microfluidic system," says Kamm, the Cecil and Ida Green Distinguished
Professor of Biological and Mechanical Engineering at MIT.
It was the limitation of previous studies that fueled Polacheck, Charest and Kamm to develop this system and
investigate the migration of cancer cells, with the hope of discovering additional details that were previously
The basis of their experiments was the underlying knowledge that, due to their continual growth, tumors generate
high fluid pressure in surrounding tissues. This pressure, in turn, is known to generate a fluid flow away from thetumor. A former postdoc who worked with Kamm, Melody Swartz (now a professor at École Polytechnique
Fédérale de Lausanne in Switzerland), had previously discovered that due to this flow, ligands secreted by a
tumor cell selectively bind to receptors on the downstream side of the cell. She found that this process ultimately
results in an asymmetry that stimulates cells to migrate in the direction of the flow.
If this were the full story, it would be a discouraging result, because it would mean that when the cells start to
break loose from a tumor, they will preferentially move toward the vascular system, thus spreading the cancer.
But luckily, the story continues. With their new 3-D microfluidic platform — which consists of two channels
separated by a region of single cells in a gel, or matrix, across which a flow can be generated — Polacheck and
Kamm started experiments on breast-cancer cells. They aimed to simulate the process of migration in the body,
hoping to build on Swartz's findings.
To their surprise, they found just the opposite of her result: Instead of moving with the flow, as Swartz had found,
the cancer cells moved upstream. At first, they questioned their findings, but then Polacheck and Kamm realized
that the cause of the discrepancy is the existence of two competing mechanisms.
One is autologous chemotaxis, which occurs in low-cell-density situations or when the CCR7 receptor becomes
activated. Autologous chemotaxis produces downstream migration because the concentration of ligands is
increased on the downstream side of the cell, as Swartz had found.
The other, they discovered, happens in high-cell-density situations — like around a growing tumor — or when the
CCR7 receptor is blocked. This newly discovered mechanism kicks in when the pressure of a fluid flowing past a
cell leads to the activation of a class of receptors called integrins, ultimately prompting upstream migration. Both
mechanisms are due to asymmetry in a tumor cell's interactions with its environment.
"Acting on this might significantly improve cancer survival rates," Kamm says. "Pharmaceutical companies can
use this information to focus on creating drugs that would block the CCR7 receptor to prevent migration toward
the vascular system, and confine the tumors."
Because of its ability to mimic the interactions cells experience inside the body — using real human cells, in real
time — Polacheck and Kamm's system could be useful in myriad other biological studies as well, such as those
focused on inflammation, liver disease and liver toxicity, among others. "We're finding that the ability to visualize
the interactions between different cell types is critical to learning how the cells behave," Kamm says.
"The role of interstitial flow on cell migration in 3-D environments has been considered important, but the
mechanism and influence on migration and eventually metastasis has remained elusive for quite some time," says
Muhammad Zaman, assistant professor of biomedical engineering and medicine at Boston University, who was
not involved in this research. He adds that this study's comprehensive examination of cell migration speed and
direction "will significantly advance the field of both cell migration and tumor metastasis as well as provide
researchers with a robust platform to test novel hypotheses in cancer systems biology."