Abstract
Tumor metastasis with resistance to anticancer therapies is the main cause of death in cancer patients. It is necessary to develop reliable tumor metastasis models that can closely recapitulate the pathophysiological features of the native tumor tissue. In this study, chondroitin sulfate (CS)-modified alginate hydrogel beads (ALG-CS) are developed to mimic the in vivo tumor microenvironment with an abnormally increased expression of CS for the promotion of tumor cell metastasis. The modification mechanism of CS on alginate hydrogel is due to the cross-linking between CS and alginate molecules via coordination of calcium ions, which enables ALG-CS to possess significantly different physical characteristics than the traditional alginate beads (ALG). And quantum chemistry calculations show that in addition to the traditional egg-box structure, novel asymmetric egg-box-like structures based on the interaction between these two kinds of polymers are also formed within ALG-CS. Moreover, tumor cell metastasis is significantly enhanced in ALG-CS compared with that in ALG, as confirmed by the increased expression of MMP genes and proteins and greater in vitro invasion ability. Therefore, ALG-CS could be a convenient and effective 3D biomimetic scaffold that would be used to construct standardized tumor metastasis models for tumor research and anticancer drug screening.
Highlights
A three-dimensional (3D) model based on a 3D scaffold is the subject of recently increasing attention because it recapitulates certain features of solid tumor tissues, such as cell-ECM interaction and tumor micro-architecture[3,4,5,6]
The diameter of alginate hydrogel beads (ALG)-Chondroitin sulfate (CS) was significantly smaller than that of ALG for freshly prepared beads (P = 3.93065E-9), beads soaked in CaCl2 solution (P = 1.05332E-8) or beads soaked in cell culture medium (P = 0) for 3 days (Fig. 2a)
Immersion in cell culture medium resulted in a significant increase in the size of both types of beads compared with that of freshly prepared beads (Fig. 2a), which might be due to the calcium-sodium ion exchange in the cell culture medium
Summary
A three-dimensional (3D) model based on a 3D scaffold is the subject of recently increasing attention because it recapitulates certain features of solid tumor tissues, such as cell-ECM interaction and tumor micro-architecture[3,4,5,6]. Compared with corresponding healthy tissues, the CS expression level is significantly increased within the ECM of many human solid tumors[25], such as hepatocellular carcinoma (HCC) and head and neck squamous cell carcinoma (HNSCC)[26,27,28], which indicates that CS is closely related to tumor occurrence, progression and metastasis[12,29]. This abnormal increase of CS expression in the in vivo tumor microenvironment inspired us to modify the alginate hydrogel using CS. We aimed to develop a convenient and effective 3D biomimetic scaffold that could be used to construct standardized tumor metastasis models for tumor research and anticancer drug screening
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