Metabolic response of lung cancer cells to radiation in a paper-based 3D cell culture system

Abstract

(100-200 word limit)This work demonstrates the application of a 3D culture system, which is known as Cells-in-Gels-in-Paper or CiGiP, in evaluating the response of lung cancer cells to ionizing radiation. This system has four attributes: (i) multiple layers of paper, containing cell-embedded hydrogels, are assembled into a stack to form a thick (~800 µm) tissue-like construct, (ii) the metabolism of the cells, coupled with the boundary conditions imposed by an impermeable holder, generate a gradient of oxygen and nutrients that decreases monotonically in the stack, (iii) the construct has no peripheral components (e.g., pumps, tubing), that fits easily in an irradiator, and (iv) the construct can be disassembled into individual layers, allowing for the quantification of cellular phenotypes based on their position within the stack. With increased distance from the source of oxygenated media, cells show increased levels of hypoxia-inducible factor, decreased proliferation, and reduced sensitivity to ionizing radiation. The multi-layer culture setup for CiGiP also distinguished differences in the radiosensitivity of three isogenic variants of A549 cancer cells, which have known differences in their metastatic behavior in vivo. The CiGiP system can, therefore, capture aspects of radiosensitivity of populations of cancer cells related to mass-transport phenomenon inaccessible in traditional culture systems.

Three‑dimensional cell culture: A powerful tool in tumor research and drug discovery (Review)

“…Thus, 3D culture may be a powerful tool in tumor and relevant drug research. Marked advances have been made in the basic development of 3D tumor models so far, and prominent studies using 3D tumor cell models to simulate the tumor microenvironment or assess drug delivery in the past 5 years are summarized in Table I (6,8,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Considering the advantages of 3D tumor models, the present review provides an overview of the methods and techniques successfully devised for practicing 3D tumor cell culture.…”

Microphysiological Systems as Enabling Tools for Modeling Complexity in the Tumor Microenvironment and Accelerating Cancer Drug Development

“…As cells can migrate through the layer interface, they demonstrated chemotaxis of cancer following the oxygen concentration gradient . Furthermore, with a hypoxia‐inducible multilayer stack model, they demonstrated that an increased level of HIF‐1α was related to an increased radiation resistance ( Figure ) . In terms of the cancer–stromal cell interaction, Camci‐Unal et al demonstrated that the primary human lung tumor cells migrated toward the tumor fibroblasts by using multilayered paper scaffolds .…”

Microsensor systems for cell metabolism – from 2D culture to organ-on-chip

“…[123][124][125][126][127] Paper has also been used for both fluidic compartments and cell scaffold. 128,129 Supernatants and perfusion media are then transferred to external readers or analysed in situ. Measurement is often limited to viability testing by optical methods such as fluorimetric live/ dead staining.…”