Tumor-on-a-chip for integrating a 3D tumor microenvironment: chemical and mechanical factors.

Tumor progression, including metastasis, is significantly influenced by factors in the tumor microenvironment (TME) such as mechanical force, shear stress, chemotaxis, and hypoxia. At present, most cancer studies investigate tumor metastasis by conventional cell culture methods and animal models, which are limited in data interpretation. Although patient tissue analysis, such as human patient-derived xenografts (PDX), can provide important clinical relevant information, they may not be feasible for functional studies as they are costly and time-consuming. Thus, in vitro three-dimensional (3D) models are rapidly being developed that mimic TME and allow functional investigations of metastatic mechanisms and drug responses. One of those new 3D models is tumor-on-a-chip technology that provides a powerful in vitro platform for cancer research, with the ability to mimic the complex physiological architecture and precise spatiotemporal control. Tumor-on-a-chip technology can provide integrated features including 3D scaffolding, multicellular culture, and a vasculature system to simulate dynamic flow in vivo. Here, we review a select set of recent achievements in tumor-on-a-chip approaches and present potential directions for tumor-on-a-chip systems in the future for areas including mechanical and chemical mimetic systems. We also discuss challenges and perspectives in both biological factors and engineering methods for tumor-on-a-chip progress. These approaches will allow in the future for the tumor-on-a-chip systems to test therapeutic approaches for individuals through using their cancerous cells gathered through approaches like biopsies, which then will contribute toward personalized medicine treatments for improving their outcomes.

Author Correction: Mimicking Embedded Vasculature Structure for 3D Cancer on a Chip Approaches through Micromilling.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Mimicking Embedded Vasculature Structure for 3D Cancer on a Chip Approaches through Micromilling.

The ability for cells to sense and respond to microenvironmental signals is influenced by their three dimensional (3D) surroundings, which includes the extracellular matrix (ECM). In the 3D environment, vascular structures supply cells with nutrients and oxygen thus affecting cell responses such as motility. Interpretation of cell motility studies though is often restricted by the applied approaches such as 2D conventional soft lithography methods that have rectangular channel cross-sectional morphology. To better simulate cell responses to vascular supply in 3D, we developed a cell on a chip system with microfluidic channels with curved cross-sections embedded within a 3D collagen matrix that emulates anatomical vasculature more closely than inorganic polymers, thus to mimic a more physiologically relevant 3D cellular environment. To accomplish this, we constructed perfusable microfluidic channels by embedding sacrificial circular gelatin vascular templates in collagen, which were removed through temperature control. Motile breast cancer cells were pre-seeded into the collagen matrix and when presented with a controlled chemical stimulation from the artificial vasculature, they migrated towards the vasculature structure. We believe this innovative vascular 3D ECM system can be used to provide novel insights into cellular dynamics during multidirectional chemokineses and chemotaxis that exist in cancer and other diseases.

Stress hormones reduce the efficacy of paclitaxel in triple negative breast cancer through induction of DNA damage.

BACKGROUND: The mechanisms by which stress hormones impact triple-negative breast cancer (TNBC) etiology and treatment are unclear. We have previously shown that stress hormones, cortisol, and catecholamines induce rapid DNA damage and impact DNA repair in NIH 3T3 fibroblasts. This study investigates whether stress hormones increase DNA damage in breast cancer cells and if this impacts drug efficacy. METHODS: We first screened a panel of 39 breast cancer cell lines for expression of adrenergic and glucocorticoid receptors and examined if stress hormones induce DNA damage and alter cell cycle regulation in vitro. A TNBC xenograft model was used to assess the impact of restraint stress on tumour growth and chemosensitivity to paclitaxel. RESULTS: We found that stress hormones induced DNA damage, phosphorylation of ATR, which was accompanied by an up-regulation of the G1 cell kinase inhibitor p21 and a cell cycle halt of TNBCs in the G1 phase. p21 knockdown abrogated G1 arrest by stress hormones. We also demonstrated that stress significantly decreased efficacy of paclitaxel. CONCLUSION: We describe a novel mechanism through which stress hormones can induce drug resistance to paclitaxel, which may have profound implications for treating drug resistance in patients with TNBC.

Role for Prdx1 as a specific sensor in redox-regulated senescence in breast cancer.

Recent studies suggest that Peroxiredoxin 1 (Prdx1), in addition to its known H2O2-scavenging function, mediates cell signaling through redox-specific protein-protein interactions. Our data illustrate how Prdx1 specifically coordinates p38MAPK-induced signaling through regulating p38MAPKα phosphatases in an H2O2 dose-dependent manner. MAPK phosphatases (MKP-1 and/or MKP-5), which are known to dephosphorylate and deactivate the senescence-inducing MAPK p38α, belong to a group of redox-sensitive phosphatases (protein tyrosine phosphatases) characterized by a low pKa cysteine in their active sites. We found that Prdx1 bound to both MKP-1 and MKP-5, but dissociated from MKP-1 when the Prdx1 peroxidatic cysteine Cys52 was over-oxidized to sulfonic acid, which in turn resulted in MKP-1 oxidation-induced oligomerization and inactivity toward p38MAPKα. Conversely, over-oxidation of Prdx1-Cys52 was enhancing in the Prdx1:MKP-5 complex with increasing amounts of H2O2 concentrations and correlated with a protection from oxidation-induced oligomerization and inactivation of MKP-5 so that activation toward p38MAPK was maintained. Further examination of this Prdx1-specific mechanism in a model of reactive oxygen species-induced senescence of human breast epithelial cells revealed the specific activation of MKP-5, resulting in decreased p38MAPKα activity. Taken together, our data suggest that Prdx1 orchestrates redox signaling in an H2O2 dose-dependent manner through the oxidation status of its peroxidatic cysteine Cys52.