What might accelerate the development of cancer therapeutics? Three-dimensional scaffolds, according to researchers at Rice University, the University of Texas MD Anderson Cancer Center, and Mount Sinai Medical Center. Their porous polymer scaffolds were designed to support the growth of biological tissue for implantation, and were used to culture Ewing’s sarcoma cells. The researchers say the scaffolds were effective at mimicking the environment in which such tumors develop.
“The scaffolds better recapitulate the microenvironment in which tumors grow, as compared with two-dimensional plastic surfaces typically used in cancer research to test anticancer drugs,” says Rice bioengineer Antonios Mikos, Ph.D., who led the research team with Joseph Ludwig, M.D., an assistant professor and sarcoma medical oncologist at MD Anderson. They note that although monolayer cultures recapitulate some of the phenotypic traits observed clinically, they are limited in their ability to model the full range of microenvironmental cues, such as ones elicited by 3D cell–cell and cell–extracellular matrix interactions.
“We’ve been working to investigate how we can leverage our expertise in engineering normal tissues to cancerous tissues, which can potentially serve as a better predictor of anticancer drug response than standard drug-testing platforms,” Dr. Mikos says.
By growing cancer cells within a three-dimensional scaffold rather than on flat surfaces, the team of researchers found that the cells bore closer morphological and biochemical resemblance to tumors in the body. Additionally, engineering tumors that mimic those in vivo offers opportunities to more accurately evaluate such strategies as chemotherapy or radiation therapies, he says.
Scaffolds fabricated in Dr. Mikos’ lab facilitate the development and growth of new tissue outside the body for subsequent implantation to replace defective tissues. The team found 3D scaffolds to be a suitable environment for growing Ewing’s sarcoma, the second most common pediatric bone malignancy. The tumor growth profile and protein expression characteristics were “remarkably unlike” those in 2D, Dr. Mikos comments.
They observed that Ewing sarcoma cells cultured in porous 3D electrospun poly(ε-caprolactone) scaffolds not only were more resistant to traditional cytotoxic drugs than were cells in 2D monolayer culture, but also exhibited remarkable differences in the expression pattern of the insulin-like growth factor-1 receptor/mammalian target of rapamycin pathway.
2D cultures may mask the mechanisms by which tumors develop resistance to anticancer therapeutics, they hypothesized, and “may lead to erroneous scientific conclusions that complicate our understanding of cancer biology,” they write.
The researchers’ next challenge is to customize scaffolds to more accurately match the actual conditions in which these tumors are found. “Tumors in vivo exist within a complex microenvironment consisting of several other cell types and extracellular matrix components,” Dr. Mikos said. “By taking the bottom-up approach and incorporating more components to this current model, we can add layers of complexities to make it increasingly reliable.
“But we believe what we currently have is very promising,” he says. “If we can build upon these results, we can potentially develop an excellent predictor of drug efficacy in patients.”
Their research appears online this week in the Proceedings of the National Academy of Sciences in a paper titled “Modeling Ewing sarcoma tumors in vitro with 3D scaffolds”.