Cancer-on-a-Chip: Models for Studying Metastasis

Abstract

The microfluidic-based cancer-on-a-chip models work as a powerful tool to study the tumor microenvironment and its role in metastasis. The models recapitulate and systematically simplify the in vitro tumor microenvironment. This enables the study of a metastatic process in unprecedented detail. This review examines the development of cancer-on-a-chip microfluidic platforms at the invasion/intravasation, extravasation, and angiogenesis steps over the last three years. The on-chip modeling of mechanical cues involved in the metastasis cascade are also discussed. Finally, the popular design of microfluidic chip models for each step are discussed along with the challenges and perspectives of cancer-on-a-chip models.

Keywords: cancer cell migration; cancer-on-a-chip; metastasis-on-a-chip; metastatic microenvironment; microfluidic chip.

Figure 1

Microfluidic models involving metastatic steps described in this paper. (A,B) Invasion/intravasation process and (C) extravasation process.

Figure 2

Simple representative microfluidic-based cancer-on-a-chip models show the movement of cancer cells from its site of origin to the distant organs. Microfluidic-based cancer-chips models are grossly classified into two types: horizontal and vertical chips. In horizontal cancer chip models (such as microvascular network (MVN) chip), the chambers are walled off by micron-sized pillars, which creates separate compartments for growing different cell types in their own zone without mixing with each other during the initial seeding but allow cellular interactions via paracrine, juxtracrine, or mechanical fashion. In vertical chips, the channels are separated by a membrane that may represent both cancer intravasation and extravasation process. In some cases (such as ovarian TME organ-on-a-chip (OTME)), a vertical layer can be integrated with the horizontal chips to mimic a more complex tumor pathophysiology.

Figure 3

Tumor endothelial cells vascularize in different mechanisms: During sprouting angiogenesis, endothelial cells respond to proangiogenic factors to form a dynamic of stalk and migrating tip cells that control and guide the sprouts. Intussusceptive angiogenesis forms hollow transcapillary pillars and splits into 2 parallel vessels. In vessel co-option, cancer cells collaborate with adjacent normal tissue vasculatures and thus, incorporate the vessels into the tumor. In some cancers, a non-endothelial blood irrigation system is developed where cancer cells eventually transdifferentiate into endothelial cells, a process known as vascular mimicry. Cancer-on-chip models are heavily concentrated on articulating the process of sprouting angiogenesis in tumors.