The geometric shape of the outside edge of a cancerous tumor plays a significant role in activating tumor-seeding cells that lead to metastasis.1
“The most dangerous part of cancer is metastasis,” said Kristopher Kilian, PhD, a professor of materials science and engineering at the University of Illinois at Urbana-Champaign.
“Some cells that we call cancer stem cells adopt deadly characteristics where they can travel through the bloodstream to other tissue and form new tumors. There’s a need for ways to find these cells and to study them, and importantly, to develop drugs that target them, because these cancer stem cells are resistant to chemotherapy drugs that target the main tumor. This causes recurrence: The cancer comes back.”
In this study, engineered tissue environments in various shapes and patterns were used to better understand skin cancer. The more curved the cell cultures were, the more likely the cancer cells at the edges of the tumor were to display markers of stem cell characteristics. These characteristics are key to metastasis.
The researchers cultured mouse skin-cancer colonies on various 2-D and 3-D environments of different shapes and patterns to see if the tumor shape contributes to activation of cancer stem cells, and to see where in the tumor the stem cells appeared.
The stem cells seemed to appear in the highest numbers along the edges of the engineered tumor environments, particularly where there were corners and convex curves.
“It was actually quite surprising,” Kilian said. “Normal stem cells prefer a soft, squishy, internal position. So for cancer, everyone had assumed that the cancer stem cells were in the middle of the tumor. We found that geometric constraints, like you would have where a tumor touches healthy tissue, seem to activate these cancer stem cells at the perimeter.”
Further tests on other cancer cell lines, including human cervical, lung, and prostate cancers, determined that they also responded to the patterned tumor environments in the same way.
Next, tests on the skin-cancer stem cells in live mice found that the cells taken from the patterned environments were much more likely to cause tumors than cells taken from a conventional flat dish.
“We found that many more mice developed tumors when given the cells that we had engineered to have these stem cell characteristics, and they had a much higher incidence of metastasis in the lungs,” Kilian said. “In a tumor, similarly, regions that develop these kinds of shapes may activate cells that can then escape and form more tumors. This may allow surgeons to look at the perimeter of a growing tumor and use the shape to guide their assessment of which regions could be more problematic – where they need to take out more tissue around the tumor and where they may not need to take as much.”
The hope is for the patterned, engineered tissue environments to allow researchers to find and culture cancer stem cells, which are very elusive in conventional cultures, at less than 1% of cells. Further, these tissue environments may eventually allow testing of personalized treatments for patients.
1. Lee J, Abdeen AA, Wycislo KL, et al. Interfacial geometry dictates cancer cell tumorigenicity [published online ahead of print April 4, 2016]. Nat Mater. doi:10.1038/nmat4610.