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Baring the bones
NASHVILLE—The American Cancer Society estimates that there will be some 3,300 new cases of bone cancer in 2016, with about 1,490 deaths attributable to this cancer type. While it is not one of the most frequently studied types of cancer—primary cancers of the bones comprise less than 0.2 percent of all cancers, according to the American Cancer Society—new work is underway into the nature of this cancer, with some promising results.
Some of that work was detailed recently in Rome at ECTS 2016, the 43rd annual meeting of the European Calcified Tissue Society, by Dr. Julie Sterling of the Department of Veterans Affairs and Vanderbilt University.
The study in question, “3D Tissue Engineered Constructs for Modeling Tumor-Induced Bone Disease,” was conducted in Nashville by researchers from the Department of Veterans Affairs and Vanderbilt University. (It was completed on an earlier version of 3D tissue engineered constructs [TECs] that has since been superseded.)
The 3D TECs in question were created using imaging together with inkjet 3D printing technology to capture the mechanical and morphometric properties of trabecular bone, allowing them to present with no significant differences in bone morphometric parameters compared to the human bones they were modeled on.
The culture of rat MSCs on the bone-like TECs resulted in a significant 1.7-fold increase in mineralization compared to collagen-like TECs. The culture of bone-metastatic MDA-MB-231 breast cancer cells on bone-like TECs in a perfusion bioreactor demonstrated a significant more than fivefold increase in the expression of integrin beta 3, Gli2 and PTHrP as compared to collagen-like TECs.
“Until now, it has not been possible to study the progress and treatment of bone cancers in the microenvironments of bones themselves or truly bone-like models. Instead, we have continued to grow cell cultures for study on tissue culture plates, essentially the modern answer to the Petri dish,” Sterling explained in a press release. “So we used a combination of imaging and inkjet 3D printing technology to create 3D tissue engineered constructs that reproduce the form and mechanics of trabecular bone, the bone tissue found at the ends of long bones as well as in the vertebrae of the spinal column and other places.”
Specifically, the bone replicas were based on three different human bone areas: the head of the femur, the tibial plateau (the flatter part of the tibia that connects with the femur) and lumbar vertebra. The 3D TECs were used in studies of cell cultures, including stem cell cultures and bone-based breast cancer cell cultures.
“When bone-based breast cancer cells (bone-metastatic MDA-MB-231) cultured on the 3D TECs were treated with the inhibitor drugs Cilengitide or SD208 (intended to inhibit the growth and invasiveness of tumor cells), the apparent benefits that had been found in the tissue culture plates environment were not there,” said Sterling. “But when the treatment was the Gli2 inhibitor GANT58 (which inhibits signaling en route to the cell receptors), the treatment had a similar and significant effect whether in the 3D TEC environment or the tissue culture plate environment.
“This suggests that an effective way of blocking the establishment of tumors in bone may be to target factors downstream of cell receptors rather than targeting the cells directly. It also shows how important it can be to have a physical bone-like environment for the study of tumors and treatments.”
Finding a potential new approach for treating bone cancer is encouraging. While primary bone cancers are rare, it is very common for cancer originating at another part of the body to metastasize to the bones. As the authors of the study noted in the abstract, “While the importance of interactions between bone and tumors is well-established, the mechanism by which the physical bone microenvironment regulates disease progression is limited by the lack of suitable in-vitro models.” These 3D TECs offer a new way to more closely track cancer progression with more accurate models.