Scientists at the University of California, San Diego (UCSD), have shown how the extracellular environment surrounding a tumor can affect the ease with which cancer cells can metastasize to other sites. The studies, headed by Stephanie Fraley, Ph.D., professor of bioengineering at UCSD’s department of bioengineering, showed that cancer cells placed in a 3D matrix of high-density collagen, but not low-density collagen, develop structures that resemble blood vessels and express a characteristic gene module, which in a number of different human cancers was found to be predictive of metastasis and patient survival. 

The researchers hope that their findings will help inform the development of new approaches to predicting the likelihood of metastasis and indicate which patients are likely to need more aggressive therapy. “Profiling additional cancer cell types and patient-derived tumor cells could also help to refine the gene module’s prognostic value in the nine tumor types already identified or define additional cancer-specific versions of the CINP,” the researchers write in their published paper in Nature Communications. “Validation of the prognostic value of this gene module could help patients avoid the long-term side effects of aggressive radiation and chemotherapy if the likelihood of metastasis is very low.”  The UCSD team’s paper is entitled “3D Collagen Architecture Induces a Conserved Migratory and Transcriptional Response Linked to Vasculogenic Mimicry.”

The vast majority of cancer deaths are caused by metastatic tumors, which occur when cancer cells from the primary tumor break away and migrate to other body tissues. In order to metastasize, the migrating tumor cells must first push through the extracellular matrix surrounding the primary tumor and reach either the lymph or blood vessels. What hasn’t been clear to date is how the structure of this extracellular matrix—and particularly the organization of collagen within it—may help or hinder tumor cell migration.

To investigate this relationship, the UCSD team placed cancer cells in a 3D collagen matrix and observed their reactions. They found that when placed in a dense collagen matrix, characterized by short fibers and small pores, the migrating cells first appeared trapped. However, after a single round of cell division, the cells switched to “a highly invasive motility behavior,” which wasn’t seen in cells embedded in a low-density collagen matrix. “We thought that putting cells into this more constrained environment would prevent their spread,” said Daniel Ortiz Velez, lead study author and a Ph.D. student in Fraley's lab. “But the opposite happened.”

In the high-density collagen matrix, the migrating cancer cells also switched on a specific set of genes, or gene module, and started to form interconnected network structures that resemble blood vessels. This is similar to a phenomenon known as vascular mimicry, which is seen in some patients’ tumors, and can be associated with aggressive forms of cancer. The gene module, which they called collagen-induced network phenotype, or CINP, was “enriched for migration and vasculogenesis-associated genes,” the authors note. Importantly, the behavior of cancer cells in the 3D collagen matrix isn't mirrored when they are grown in a petri dish. “It's critical to have the cells surrounded by a 3D environment that mimics what happens in the human body,” Fraley added.

Searching through clinical tumor gene expression and histology databases, the researchers also found that the same cancer cell gene module that was switched on by the migrating cancer cells in their 3D matrix studies was predictive of patient survival and metastasis across nine different types of cancers, and was also linked with a vasculogenic mimicry phenotype.

“…we show that the associated transcriptional response is conserved among cancer types in vitro and is predictive of patient survival in multiple clinical datasets for various tumor types,” the authors conclude. “Our integrative study suggests that a collagen-induced migration phenotype and gene expression program are linked to a metastatic clinical tumor cell phenotype and potentiates future work to identify mechanistic strategies capable of limiting metastasis in several cancers.”

It's not unreasonable to suggest that the channels built by the malignant cells aid blood flow to tumors. Researchers have speculated that this may make it easier for cancer cells to spread to distant sites. One of the next steps will be to look for targets that can prevent cell transformation.

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