bims-miftum 2020-08-30 papers

Issue of 2020–08–30
three papers selected by
Nidhi Menon, Virginia Tech

Analyst. 2020 Aug 27.

A multilayered cancer-on-a-chip model to analyze the effectiveness of new-generation photosensitizers.

Magdalena Flont, Elżbieta Jastrzębska, Zbigniew Brzózka.

Three-dimensional (3D) cellular models of cancer tissue are necessary tools to analyze new anticancer drugs under in vitro conditions. Diagnostics and treatment of ovarian cancer are major challenges for current medicine. In our report we propose a new three-dimensional (3D) cellular model of ovarian cancer which can mimic a fragment of heterogeneous cancer tissue. We used Lab-on-a-chip technology to create a microfluidic system that allows cellular multilayer to be cultured. Cellular multilayer mimics the structure of two important elements of cancer tissue: flesh and stroma. For this reason, it has an advantage over other in vitro cellular models. We used human ovarian fibroblasts (HOF) and human ovarian cancer cells in our research (A2780). In the first stage of the study, we proved that the presence of non-malignant fibroblasts in co-culture with ovarian cancer cells stimulates the proliferation of cancer cells, which is important in the progression of ovarian cancer. In the next stage of the research, we tested the usefulness of the newly-developed cellular model in the analysis of anticancer drugs and therapies under in vitro conditions. We tested two photosensitizers (PS): free and nanoencapsulated meso-tetrafenylporphyrin, and we evaluated the potential of these drugs in anticancer photodynamic therapy (PDT) of ovarian cancer. We also studied the mechanism of PDT based on the analysis of the level of reactive oxygen species (ROS) in cell cultures. Our research confirmed that the use of new-generation PS can significantly increase the efficacy of PDT in the treatment of ovarian cancer. We also proved that the newly-developed 3D cellular model is suitable for rapid screening of anticancer drugs and has the potential to be used clinically in the future, e.g. in the selection of treatment methods for anticancer personalized medicine.

DOI: https://doi.org/10.1039/d0an00911c

J Vis Exp. 2020 Aug 07.

A Biomimetic Model for Liver Cancer to Study Tumor-Stroma Interactions in a 3D Environment with Tunable Bio-Physical Properties.

Carlemi Calitz, Nataša Pavlović, Jenny Rosenquist, Claudia Zagami, Ayan Samanta, Femke Heindryckx.

Hepatocellular carcinoma (HCC) is a primary liver tumor developing in the wake of chronic liver disease. Chronic liver disease and inflammation leads to a fibrotic environment actively supporting and driving hepatocarcinogenesis. Insight into hepatocarcinogenesis in terms of the interplay between the tumor stroma micro-environment and tumor cells is thus of considerable importance. Three-dimensional (3D) cell culture models are proposed as the missing link between current in vitro 2D cell culture models and in vivo animal models. Our aim was to design a novel 3D biomimetic HCC model with accompanying fibrotic stromal compartment and vasculature. Physiologically relevant hydrogels such as collagen and fibrinogen were incorporated to mimic the bio-physical properties of the tumor ECM. In this model LX2 and HepG2 cells embedded in a hydrogel matrix were seeded onto the inverted transmembrane insert. HUVEC cells were then seeded onto the opposite side of the membrane. Three formulations consisting of ECM-hydrogels embedded with cells were prepared and the bio-physical properties were determined by rheology. Cell viability was determined by a cell viability assay over 21 days. The effect of the chemotherapeutic drug doxorubicin was evaluated in both 2D co-culture and our 3D model for a period of 72h. Rheology results show that bio-physical properties of a fibrotic, cirrhotic and HCC liver can be successfully mimicked. Overall, results indicate that this 3D model is more representative of the in vivo situation compared to traditional 2D cultures. Our 3D tumor model showed a decreased response to chemotherapeutics, mimicking drug resistance typically seen in HCC patients.

DOI: https://doi.org/10.3791/61606

Pharmacol Ther. 2020 Aug 24. pii: S0163-7258(20)30198-4. [Epub ahead of print] 107668

Tumor organoid models in precision medicine and investigating cancer-stromal interactions.

Ren Xu, Xiaotao Zhou, Shike Wang, Christine Trinkle.

Tumor development and progression require chemical and mechanical cues derived from cellular and non-cellular components in the tumor microenvironment, including the extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), endothelial cells, and immune cells. Therefore, it is crucial to develop tissue culture models that can mimic in vivo cancer cell-ECM and cancer-stromal cell interactions. Three-dimensional (3D) tumor culture models have been widely utilized to study cancer development and progression. A recent advance in 3D culture is the development of patient-derived tumor organoid (PDO) models from primary human cancer tissue. PDOs maintain the heterogeneity of the primary tumor, which makes them more relevant for identifying therapeutic targets and verifying drug response. Other significant advances include development of 3D co-culture assays to investigate cell-cell interactions and tissue/organ morphogenesis, and microfluidic technology that can be integrated into 3D culture to mimic vasculature and blood flow. These advances offer spatial and temporal insights into cancer cell-stromal interactions and represent novel techniques to study tumor progression and drug response. Here, we summarize the recent progress in 3D culture and tumor organoid models, and discuss future directions and the potential of utilizing these models to study cancer-stromal interactions and direct personalized treatment.

Keywords: Drug screening; Extracellular matrix; Patient-derived organoid; Personalized treatment; Three-dimensional tissue culture; Tumor microenvironment

DOI: https://doi.org/10.1016/j.pharmthera.2020.107668