3D microtumors in vitro supported by perfused vascular networks

Abstract

There is a growing interest in developing microphysiological systems that can be used to model both normal and pathological human organs in vitro. This “organs-on-chips” approach aims to capture key structural and physiological characteristics of the target tissue. Here we describe in vitro vascularized microtumors (VMTs). This “tumor-on-a-chip” platform incorporates human tumor and stromal cells that grow in a 3D extracellular matrix and that depend for survival on nutrient delivery through living, perfused microvessels. Both colorectal and breast cancer cells grow vigorously in the platform and respond to standard-of-care therapies, showing reduced growth and/or regression. Vascular-targeting agents with different mechanisms of action can also be distinguished, and we find that drugs targeting only VEGFRs (Apatinib and Vandetanib) are not effective, whereas drugs that target VEGFRs, PDGFR and Tie2 (Linifanib and Cabozantinib) do regress the vasculature. Tumors in the VMT show strong metabolic heterogeneity when imaged using NADH Fluorescent Lifetime Imaging Microscopy and, compared to their surrounding stroma, many show a higher free/bound NADH ratio consistent with their known preference for aerobic glycolysis. The VMT platform provides a unique model for studying vascularized solid tumors in vitro.

Tumour-on-a-chip: microfluidic models of tumour morphology, growth and microenvironment

“…This device can create chemical gradients of multiple anti-tumour drugs and generate multiplicates of sample data on a single chip to specifically monitor mesenchymal migration and survival of tumour cells upon exposure to drugs that inhibit cell migration, including axitinib [189]. In a study by Sobrino et al [124], vascularized microtumours were created on a PDMS membrane to study the effects of vascular targeting agents, such as apatinib and linifanib (figure 7a). A key drawback to this approach is the absorption of the agents in question by the PDMS membrane.…”

“…An in vitro model recapitulating the cancer cells as well as their microenvironment can enable more biomimetic and clinically relevant outcomes to accelerate our knowledge in tumour biology and improve cancer therapeutic development. In this section, we briefly review the microdevices developed in the past few decades to study different TMEs, including the peri-necrotic niche, peri-vascular niche and metastatic niche [122,124,132].…”

“…The TME is complex and dynamic in cell -cell interactions and biophysical as well as biochemical interactions between the tumour and the stroma. Adapted from [123,124].…”

Cancer metabolism gets physical

“…These tools can be used to readily manipulate and measure real-time, single-cell dynamics by using endogenous or genetically encoded fluorescent sensors. For example, a vascularized microtumor (VMT) model was used to map metabolic activity within different regions of hybrid microfluidic organoids via fluorescence lifetime imaging of NAD + (nicotinamide adenine dinucleotide) and NADH (reduced form of NAD + ) (40). The VMT platform mimicked stromal composition, matrix structure, and vascular function, and it simulated metabolic responses to pharmacologic agents (40).…”

Towards personalized computational oncology: from spatial models of tumour spheroids, to organoids, to tissues

“…These microphysiological systems are capable of maintaining live cultures for weeks and even months and can replicate complex organ environments, including 3D multicellular organ structures, nutrient supply and waste removal, oxygenation states, interstitial flows and a variety of microenvironmental gradients [163,165]. These systems are composed of individually addressable micro-compartments to permit precise regulation of a specific organ layer or tissue area and individualized tissue perfusion [166,167]. As such, they hold promise as attractive platforms for future drug development.…”