The role of the tumor microenvironment in tumor progression and metastasis has been the subject of extensive research, but little has been known about how the metastatic process is initiated. Now researchers from the University of California San Diego say they have uncovered how the microenvironment triggers metastatic behavior in cancer cells.
According to research published yesterday in Nature Communications, when tumor cells are confined in a dense environment, they turn on a specific set of genes and begin to form structures that resemble blood vessels.
The set of genes, or gene module, that causes the cells' behavior was named collagen-induced network phenotype (CINP) by the researchers. Putting these cells into a constrained environment essentially rewrites their gene expression. "It's almost like the matrix is encoding the gene module," explained Stephanie Fraley, a professor of bioengineering at UCSD and the leader of the study.
The team built a custom 3D collagen matrix to facilitate their research. They placed the malignant cells in the matrix and found that the cells turned into structures that mimic blood vessels when surrounded by the matrix made of short fibers and small pores (as opposed to long fibers and large pores) and that this phenomenon was independent of other physical features of the matrix such as stiffness.
"We thought that putting cells into this more constrained environment would prevent their spread," said Daniel Ortiz Velez, the study's first author and a Ph.D. student in Fraley's lab. "But the opposite happened."
The cells do not exhibit this behavior in traditional petri dishes. "It's critical to have the cells surrounded by a 3D environment that mimics what happens in the human body," Fraley added.
CINP was able to predict patient life expectancy and whether tumors will metastasize across nine types of cancer, including breast, lung, pancreatic, and kidney cancers. It could also be used to help determine whether patients are suffering from an aggressive type of cancer and inform the decisions patients and their physicians make when choosing specific therapies.
Image: Breast cancer cells are grown in a highly dense 3-D collagen matrix. After 7 days the cells form networks that resemble the early stages of blood vessel development. Images show representative structures observed in these environments after satining for cells nuclei (blue) and the cell's cytoskeleton (green). Similar structures have been observed in tumor patient samples and have been referred to as vasculogenic mimicry. Image courtesy of UCSD.