Higher levels of the structural proteins collagen and fibrin around a tumor counterintuitively make the tissue softer — the opposite of conventional thinking, a new study shows. Researchers at the University of Illinois Urbana-Champaign found that the interplay of these proteins can make a vast difference in tumor structure and growth as well as how drugs pass through the tissue, key considerations for developing lab-grown tumors for drug development and personalized medicine.
“Collagen and fibrin have been used in tissue engineering for a long time as two separate proteins. But in our bodies, they are continuously interacting with each other,” said Illinois mechanical science and engineering professor Bumsoo Han (M-CELS), the leader of the study published in the journal Acta Biomaterialia. “Because most engineered tumor models overlook this interaction, they may misrepresent how real tumors behave.”
Lab-grown tumor models are emerging as an alternative to animal models for cancer research. Based on human cells and proteins, they aim to reproduce a tumor and its tissue environment in a way that is closer to human physiology than animal models, Han said.
“Engineered tumor models have been used to study the biology of cancer, discover new drugs and predict the outcome of therapies in personalized medicine,” said Han, who also is a member of the Cancer Center at Illinois. “The intention is to capture the essence of human tumor pathology. However, most lab-grown tumors assume that adding more structural protein makes tissue stiffer. Our research shows that this assumption is often wrong.”
When tumors start to develop, they not only change the cellular composition of the surrounding tissue, but also change the protein composition. Requiring support as they form and grow, many cancers increase the amount of the protein collagen, which provides the main scaffolding connecting cells into tissue. The structure of the scaffolding determines how cells push or pull on their surroundings and how molecules, including drugs, are transported within the tissue. Developing tumors also promote the formation of new blood vessels, but because they’re immature, they start to leak, Han said. The leaky vessels deposit the protein fibrin, the coagulation protein that helps blood clot, which forms its own matrix in the tissue.
In the new study, Han’s group carefully analyzed the structure, properties and interactions of collagen and fibrin in cancer tissue and compared them with the hydrogels used as the tumor environment in engineered models.
“Many engineered tumor models treat collagen and fibrin as passive building materials. But we found that these proteins actively interact with each other and affect tumor growth and progression,” Han said.
The researchers saw two main counterintuitive properties that defy conventional thinking about structural proteins and tissue stiffness. First, they found that higher amounts of the scaffolding proteins made the tissue softer, rather than stiffer as is the common assumption. Second, they found that the timing, order and amount of collagen and fibrin deposited in the tissue creates different internal fiber networks.
“The reason is that these proteins have to occupy space. If you keep adding additional protein, it is competing for space with the matrix that is there. When fibrin is added to an already constructed collagen scaffold, it does not add up nicely due to the space constraint,” Han said. “Our study shows it is not only the only the amount, but how these two things interact, changing the mechanical property and eventually the tissue tumor physiology as well.”
The findings have implications not only for lab-grown human tumors, but also for research involving animal models, as the researchers observed that the distribution of fibrin differs between mouse and human tumors. The results also have especially important implications for research seeking to improve drug delivery to tumors, which is complicated by the protein matrix surrounding them. Researchers have been attempting approaches to remove some of the collagen, allowing freer drug transport, but are seeing that it also allows cancer cells broader movement, promoting growth and metastasis, Han said.
“Our findings have us asking, by targeting fibrin instead of collagen, could we change the tissue structure to improve drug delivery without making the tumor grow or spread?” Han said. His group is currently testing this question with improved tumor models based on their findings about how collagen and fibrin interact, as well as in animal models.
“Our study shows that, when making tumor models for study, we need to take into account not only the cellular composition and protein amounts, but also the structure of the proteins and their mechanical properties, to get a complete picture of the cancer,” Han said.
The U.S. National Institutes of Health supported this work, which also was partially supported by Virgil and Jan Cobb-Bourgon Endowment for Cancer Research Fund at the Cancer Center at Illinois. Han also is affiliated with the department of bioengineering, the Beckman Institute for Advanced Science and Technology, and the Materials Research Laboratory at the U. of I.