On-Chip Replication of Extremely Early-Stage Tumor Behavior

Cancer is a multistep progressive disease that generally involves tumor growth, invasion, and metastasis. It is crucial to understand tumor progression for tumor diagnosis and therapy. However, tumor progression at an extremely early stage (EES) is barely demonstrated because EES tumors are too small to be detected by imaging. Herein, we, for the first time, replicated tumor progression at the EES on a microfluidic chip and uncovered the tumor behaviors affected by the tumor microenvironment. To mimic the progression of a single solid tumor at the EES, a HeLa cell spheroid was seeded and cultured on the chip, and a microvascular network was developed to integrate the microphysiological contexts around the tumor. We revealed not only the growth patterns and cell behaviors of tumor spheroids of different sizes under angiogenesis and fibroblast conditions but also the effect of tumor progression on peritumoral angiogenesis. We found that smaller tumors were more aggressive and that endotheliocytes and fibroblasts significantly accelerated both the proliferation and migration of tumor cells. In addition, we also first present the dynamic epithelial–mesenchymal transition process of tumor cells and the formation of vasculogenic mimicry at the EES. This work can provide insights for understanding tumor progression at the EES and offer new ideas for tumor therapy.