Calcium carbonate nanoparticles stimulate cancer cell reprogramming to suppress tumor growth and invasion in an organ-on-a-chip system

Abstract

The acidic microenvironment of solid tumors induces the propagation of highly invasive and metastatic phenotypes. However, simulating these conditions in animal models present challenges that confound the effects of pH modulators on tumor progression. To recapitulate the tumor microenvironment and isolate the effect of pH on tumor viability, we developed a bifurcated microfluidic device that supports two different cell environments for direct comparison. RFP-expressing breast cancer cells (MDA-MB-231) were cultured in treatment and control chambers surrounded by fibrin, which received acid-neutralizing CaCO3 nanoparticles (nanoCaCO3) and cell culture media, respectively. Data analysis revealed that nanoCaCO3 buffered the pH within the normal physiological range and inhibited tumor cell proliferation compared to the untreated control (p < 0.05). Co-incubation of cancer cells and fibroblasts, followed by nanoCaCO3 treatment showed that the nanoparticles selectively inhibited the growth of the MDA-MB-231 cells and reduced cellular migration of these cells with no impact on the fibroblasts. Sustainable decrease in the intracellular pH of cancer cells treated with nanoCaCO3 indicates that the extracellular pH induced cellular metabolic reprogramming. These results suggest that the nanoCaCO3 can restrict the aggressiveness of tumor cells without affecting the growth and behavior of the surrounding stromal cells.

Revolutionizing drug development: harnessing the potential of organ-on-chip technology for disease modeling and drug discovery

“…Problems arise when cells are forced to co-exist and develop with non-biological components or methods. As engineers develop organ on chip platform, several aspects of the development phases and designs should be taken into account ( Mastrangeli et al, 2019 ; Semertzidou et al, 2020 ; Fritschen and Blaeser, 2021 ; Lam et al, 2021 ).…”

Application of Microfluidic Systems for Breast Cancer Research

“…Moreover, the arrayed microchannel-based model provided a cost-effective test bed for identifying inhibitors of pathways involved in DCIS progression to IDC and for screening potential therapeutic targets. Calcium carbonate nanoparticles were found to stimulate cancer cell reprogramming to suppress tumor growth and invasion in an organ-on-a-chip system, which was developed to create a tumor microenvironment for isolating the effect of pH on tumor viability [47]. The results suggested that treating breast cancer cells (MDA-MB-231) cocultured with fibroblasts using CaCO 3 nanoparticles can restrict the aggressiveness of tumor cells without affecting the growth and behavior of the surrounding stromal cells.…”

Going with the Flow: Modeling the Tumor Microenvironment Using Microfluidic Technology

“…They found that fibroblasts promoted cancer cell growth and induced more migration by increasing the level of metalloproteinases (MMPs) in media [ 99 ]. To investigate the effect of pH on tumor viability, Lam et al employed a bifurcated microfluidic device and compared cell proliferation capability between culturing MDA-MB-231 breast cancer cells in media with and without fibrin, which can interact with acid-neutralizing calcium carbonate (CaCO 3 ) nanoparticles [ 148 ]. The authors found that nanoCaCO 3 treatment inhibited tumor cell growth, whereby the media pH was increased from 7.14 to 7.25 and the intracellular pH was decreased from 7.6 to 7.05, suggesting that low pH promotes cell proliferation.…”