Metastasis-on-a-chip mimicking the progression of kidney cancer in the liver for predicting treatment efficacy

Abstract

Metastasis is one of the most important factors that lead to poor prognosis in cancer patients, and effective suppression of the growth of primary cancer cells in a metastatic site is paramount in averting cancer progression. However, there is a lack of biomimetic three-dimensional (3D) in vitro models that can closely mimic the continuous growth of metastatic cancer cells in an organ-specific extracellular microenvironment (ECM) for assessing effective therapeutic strategies.Methods: In this metastatic tumor progression model, kidney cancer cells (Caki-1) and hepatocytes (i.e., HepLL cells) were co-cultured at an increasing ratio from 1:9 to 9:1 in a decellularized liver matrix (DLM)/gelatin methacryloyl (GelMA)-based biomimetic liver microtissue in a microfluidic device.Results: Via this model, we successfully demonstrated a linear anti-cancer relationship between the concentration of anti-cancer drug 5-Fluorouracil (5-FU) and the percentage of Caki-1 cells in the co-culture system (R2 = 0.89). Furthermore, the Poly(lactide-co-glycolide) (PLGA)-poly(ethylene glycol) (PEG)-based delivery system showed superior efficacy to free 5-FU in killing Caki-1 cells.Conclusions: In this study, we present a novel 3D metastasis-on-a-chip model mimicking the progression of kidney cancer cells metastasized to the liver for predicting treatment efficacy. Taken together, our study proved that the tumor progression model based on metastasis-on-a-chip with organ-specific ECM would provide a valuable tool for rapidly assessing treatment regimens and developing new chemotherapeutic agents.

Is It Time to Start Transitioning From 2D to 3D Cell Culture?

“…Another idea that has gained immense popularity amongst organ chip researchers is the idea of a human-on-a-chip (Wang et al, 2020). This model aims to examine normal human physiology within a microfluidic system by combining single organ chip designs into a multi-organ chip design that allows the organs to work in conjunction with each other much like organs in the human body do (Wang et al, 2020). MOC and a complete human-on-a-chip design would allow for cheaper and more effective drug testing and thus would greatly benefit biomedical sectors (Wang et al, 2020).…”

“…A scrupulous investigation was conducted that aimed to mimic the progression of kidney cancer via a novel 3D metastatic cancer cell model (Wang et al, 2020). Previous metastatic cancer models have been created culturing cells in 3D but lacked the ability to interact with the correct physiopathological conditions as well as accurately reflect the effect of anticancer drugs in vivo (Wang et al, 2020). A 3D biomimetic liver microtissue modeled in DLM/GelMA hydrogel and subjected to continuous perfusion was used to culture the kidney cancer cells (Caki-1) (Wang et al, 2020).…”

“…Previous metastatic cancer models have been created culturing cells in 3D but lacked the ability to interact with the correct physiopathological conditions as well as accurately reflect the effect of anticancer drugs in vivo (Wang et al, 2020). A 3D biomimetic liver microtissue modeled in DLM/GelMA hydrogel and subjected to continuous perfusion was used to culture the kidney cancer cells (Caki-1) (Wang et al, 2020). This served as an effective model to mimic kidney cancer metastasis and discovered a linear anti-cancer correlation between the concentration of Caki-1 cells and the concentration of the drug 5-Fluorouracil.…”

Modeling of Nanotherapy Response as a Function of the Tumor Microenvironment: Focus on Liver Metastasis

“…To model liver metastasis, gelatin methacryloyl was combined with decellularized liver matrix components including bioactive factors derived from liver matrix, in a dynamic culture system to assess drug-dose responses to acetaminophen and sorafenib ( Lu et al, 2018 ). In a similar metastasis-on-a-chip model of kidney cancer metastasized to the liver, NP-conjugated 5-fluorouracil was shown to be more efficacious than free drug ( Wang et al, 2020 ).…”

Applications of Gelatin Methacryloyl (GelMA) Hydrogels in Microfluidic Technique-Assisted Tissue Engineering

“…Therefore, this platform was considered to be a promising tool for cardiac pathophysiological study and drug screening [95]. Wang et al [96] reported a microfluidic tumor progression model based on metastasis-on-a-chip. Decellularized liver matrix (DLM)/GelMA (ratio 2:3) hydrogel was assembled on the chip to serve as a 3-D biomimetic liver microenvironment to culture kidney cancer cells (Caki-1) to mimic the progression of metastatic kidney cancer, as shown in Figure 7.…”