Abstract
Bone metastasis is one of the most common complications of advanced breast cancer (BrCa) with a poor clinical prognosis, due to the lack of effective drugs and therapeutics. Traditional screening systems for anti-cancer drugs are not capable of exactly reflecting the efficacy of drugs in vivo, mainly because they cannot replicate the dynamic metastasis process involving primary tumor, blood circulation and bone microenvironment. To precisely simulate the behavior of native BrCa cells, herein, a biomimetic 3D co-culture metastatic model composed of tumor, hollow vascular, and bone tissues is fabricated by one-step 3D bioprinting method for effective drug testing. Gelatin methacryloyl-based photocrosslinkable bioinks containing breast cancer cells (MDA-MB-231), human umbilical vein endothelial cells (HUVECs) and osteoblasts (h-OB) are applied to highly imitate the native metastatic niches with the formation of blood vessels, vascularized tumors, as well as vascularized bone tissues. The dynamic invasion behavior of BrCa cells from original sites to bone tissues through blood vessels is reproduced, and the interactive effect of cancer, vascular and bone cells are investigated. Moreover, the 3D co-culture metastatic model allows for higher drug resistance of BrCa cells than 2D culture and 3D mono-culture models. These results demonstrate that the 3D bioprinted co-culture metastatic model facilitates in-depth understanding of the basic mechanisms of BrCa migration and provides a physiologically relevant platform for the development of new therapeutic drugs.
Published Version
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