bims-miftum 2020-07-12 papers

Issue of 2020–07–12
three papers selected by
Nidhi Menon, Virginia Tech

Biotechnol Bioeng. 2020 Jul 10.

In Vitro Vascularized Tumor Platform for Modeling Tumor-Vasculature Interactions of Inflammatory Breast Cancer.

Manasa Gadde, Caleb Phillips, Neda Ghousifam, Anna G Sorace, Enoch Wong, Savitri Krishnamurthy, Anum Syed, Omar Rahal, Thomas E Yankeelov, Wendy A Woodward, Marissa Nichole Rylander.

Inflammatory breast cancer (IBC), a rare form of breast cancer associated with increased angiogenesis and metastasis, is largely driven by tumor-stromal interactions with the vasculature and the extracellular matrix (ECM). However, there is currently a lack of understanding of the role these interactions play in initiation and progression of the disease. In this study, we developed the first three-dimensional, in vitro, vascularized, microfluidic IBC platform to quantify the spatial and temporal dynamics of tumor-vasculature and tumor-ECM interactions specific to IBC. Platforms consisting of collagen type 1 ECM with an endothelialized blood vessel were cultured with IBC cells, MDA-IBC3 (HER2+) or SUM149 (triple negative), and for comparison to non-IBC cells, MDA-MB-231 (triple negative). Acellular collagen platforms with endothelialized blood vessels served as controls. SUM149 and MDA-MB-231 platforms exhibited a significantly (p<0.05) higher vessel permeability and decreased endothelial coverage of the vessel lumen compared to the control. Both IBC platforms, MDA-IBC3 and SUM149, expressed higher levels of VEGF (p<0.05) and increased collagen ECM porosity compared to non-IBC MDA-MB-231 (p<0.05) and control (p<0.01) platforms. Additionally, unique to the MDA-IBC3 platform, we observed progressive sprouting of the endothelium over time resulting in viable vessels with lumen. The newly sprouted vessels encircled clusters of MDA-IBC3 cells replicating a key feature of in vivo IBC. The IBC in vitro vascularized platforms introduced in this study model well-described in vivo and clinical IBC phenotypes and provide an adaptable, high throughput tool for systematically and quantitatively investigating tumor-stromal mechanisms and dynamics of tumor progression. This article is protected by copyright. All rights reserved.

Keywords: In Vitro ; Angiogenesis; Collagen; Endothelium; HER2+ Breast Cancer; Inflammatory Breast Cancer; Microfluidics; Sprouting; Triple Negative Breast Cancer; Vasculature

DOI: https://doi.org/10.1002/bit.27487

Adv Biosyst. 2019 Jan;3(1): e1800223

Epithelial-to-Mesenchymal Transition (EMT) and Drug Response in Dynamic Bioengineered Lung Cancer Microenvironment.

Vigneshwaran Mani, Zhonglin Lyu, Vineet Kumar, Baris Ercal, Hong Chen, Sanjay V Malhotra, Utkan Demirci.

Tumor microenvironment and the interplay of physical and mechanical forces are key determinants of cancer initiation, progression, and response to drug treatment. However, the impact of tumor microenvironment on cancer progression is poorly understood, in large due to the lack of in vitro models that recapitulate the physical aspects of tumor microenvironment. Herein, a simple, dynamic 3D nonsmall cell lung carcinoma culture using a multichannel microfluidic model platform is developed for evaluating the contribution of flow-induced hydrodynamic shear stress on epithelial-to-mesenchymal transition (EMT). It is found that flow induces changes in cellular morphology and EMT in 2D and 3D when lung cancer A549 cells are cultured on a microfluidic chip under laminar flow for 4-5 days compared to traditional static cultures. The role of dynamic cell culture on chemotherapeutic effects is monitored. Drug response with an existing anti-cancer drug, e.g., erlotinib and an investigational drug (NSC-750212), shows distinct cytotoxic effects in flow compared to static cultures, suggesting a potential influence of flow on drug efficacy in 2D and 3D models. The platform demonstrates the ability to create a dynamic microscale tumor model, which could be explored as a tool for early drug screening and treatment monitoring in cancer and other diseases.

Keywords: cancer microenvironment; drug response; epithelial-to-mesenchymal transition (EMT); microfluidics; tumoroids

DOI: https://doi.org/10.1002/adbi.201800223

J Funct Biomater. 2020 Jul 08. pii: E49. [Epub ahead of print]11(3):

Anti-Metastatic Effects of Plant Sap-Derived Extracellular Vesicles in a 3D Microfluidic Cancer Metastasis Model.

Kimin Kim, Jik-Han Jung, Hye Ju Yoo, Jae-Kyung Hyun, Ji-Ho Park, Dokyun Na, Ju Hun Yeon.

Natural medicinal plants have attracted considerable research attention for their potential as effective drugs. The roots, leaves and stems of the plant, Dendropanax morbifera, which is endemic to southern regions of Asia, have long been used as a folk medicine to treat variety of diseases. However, the sap of this plant has not been widely studied and its bioactive properties have yet to be clearly elucidated. Here, we isolated extracellular vesicles from D. morbifera sap with the goal of improving the intracellular delivery efficiency and clinical effectiveness of bioactive compounds in D. morbifera sap. We further investigated the anti-metastatic effects of D. morbifera sap-derived extracellular vesicles (DMS-EVs) using a cancer metastasis model based on 3D microfluidic system that closely mimics the in vivo tumor environment. We found that DMS-EVs exerted a concentration-dependent suppressive effect on cancer-associated fibroblasts (CAFs), which are important mediators of cancer metastasis. DMS-EVs also altered expression level of genes, especially growth factor and extracellular matrix (ECM)-related genes, including integrin and collagen. Our findings suggest that DMS-EVs can act as anti-CAF agents to reduce CAFs in the tumor microenvironment. They further indicate the utility of our 3D microfluidic model for various drug-screening assays as a potential alternative to animal testing for use in validating therapeutic effects on cancer metastasis.

Keywords: 3D microfluidics; anti-metastatic effects; cancer-associated fibroblasts; extracellular vesicles; plant sap

DOI: https://doi.org/10.3390/jfb11030049