Pancreatic cancer is one of the most insidious forms of the disease, in which an average of only 9% of patients are alive five years after diagnosis.
One of the reasons for such a dismal outcome is that pancreatic cancer cells are able to escape from tumors and enter the bloodstream very early in the disease.
This means that by the time the cancer is discovered, it has usually already spread.
Paradoxically, pancreatic tumors appear to almost lacking blood vessels altogether, which prevents cancer drugs from reaching and killing them and has puzzled scientists and clinicians trying to understand how the disease progresses.
Now, a recent study from Harvard University, Boston University, and the University of Pennsylvania has finally shed light on this mystery.
Using both in vitro and in vivo models of pancreatic cancer and vasculature, the study found that the tumor cells invade nearby blood vessels, destroy the endothelial cells that line them, and replace those cells with tumor-lined structures.
This process seems to be driven by the interaction between the protein receptor ALK7 and the protein Activin in pancreatic cancer cells, pointing to a possible target for future treatments.
Studying the interactions between pancreatic cancer and blood vessels has historically been very difficult.
It would require multiple, invasive tissue biopsies from human cancer patients, and imaging the disease over time in the internal organs of living mouse models is technically very challenging.
The researchers took a different approach by using organs-on-chips: clear, flexible, plastic chips about the size of a USB stick containing microfluidic channels embedded in a collagen matrix that can be lined with living cells kept alive via a constant flow of nutrient-rich media.
To replicate a pancreatic cancer tumor, the team seeded one channel with mouse pancreatic cancer cells and a neighboring channel with human endothelial cells.
They observed that after about four days, the pancreatic cancer cells began to invade the collagen matrix toward the blood vessel channel, and eventually wrapped themselves around the channel, spread along its length, and finally invaded it.
During the invasion process, the endothelial cells in direct contact with the cancer cells underwent apoptosis (cell death), leading to a blood vessel channel that was composed exclusively of cancer cells.
They saw the same pattern when using human pancreatic cancer cells in the organ-on-chip, and in living mouse models of pancreatic cancer, suggesting that this process may also occur in humans.
The researchers suspected that the mechanism by which pancreatic cancer cells ablate endothelial cells had something to do with the TGF-β signaling pathway, a cascade of molecular interactions that have been implicated in multiple types of cancers.
They introduced a TGF-β inhibitor into their organ-on-chip cancer model for seven days and saw that the ablation of endothelial cells was significantly reduced.
When pancreatic cancer cells were implanted into mice who were subsequently given the same inhibitor molecule, their tumors displayed a higher density of blood vessels, confirming that the inhibitor also reduced ablation in vivo.
The team says “not only has our study revealed a major insight into pancreatic cancer biology that could be used to drive the development of new treatments, our cancer-on-a-chip platform opens a new door to being able to more carefully study the interactions between blood vessels and other types of cancers, which could be extremely useful in teasing out these important but complex interactions.”
The team is actively looking into developing their platform to further understand additional cellular interactions in cancer, including between cancer and immune cells, and between cancer and the perivascular cells that surround and support blood vessels.
The research is published in Science Advances.
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