Analysis of the Internal Hypoxic Environment in Solid Tumor Tissue Using a Folding Paper System

Abstract

Hypoxia is a nonphysiological oxygen tension which is common in most malignant tumors. Hypoxia stimulates complicated cell signaling networks in cancer cells, e.g., the HIF, PI3K, MAPK, and NFκB pathways. Then, cells release a number of cytokines such as VEGFA to promote the growth of peripheral blood vessels and lead to metastasis. In the current work, understanding of the internal hypoxic environment in solid tumor tissue was attempted by developing a folding paper system. A paper-based solid tumor was constructed by folding a filter paper cultured with cancer cells. The cellular response in each layer could be analyzed by disassembling the folded paper after the culture course. The result showed that an internal hypoxic environment was successfully reproduced in the paper-based solid tumor. The cells in the inner layer expressed high levels of HIF1-α and VEGFA. Hence, proliferation and migration of endothelial cells were shown to be induced by the cells located in the internal hypoxic environment. Moreover, the paper-based solid tumor was transplanted into nude mice for the study of hypoxic response and angiogenesis. The crosstalk between internal and external parts of solid tumor tissue could be analyzed by sectioning each layer of the paper-based solid tumor. This approach provides a favorable analytical method for the discovery of the interaction between cancer cells, hypoxia, and peripheral angiogenesis.

XBP1s promotes the development of lung adenocarcinoma via the p‑JNK MAPK pathway

“…2A ). Since tumor cells survive in a hypoxic microenvironment ( 29 ), the A549 cell line was cultured under 2% O 2 hypoxia to further investigate the expression level of XBP1s. The protein expression level of XBP1s in the A549 cell line was increased under hypoxic conditions.…”

Bionanotechnology and bioMEMS (BNM): state-of-the-art applications, opportunities, and challenges

“…Furthermore, a paper-based gel-free cell culture model was further demonstrated in the construction of a folding paper system. 225 The system was developed to simulate the internal hypoxic environment of solid tumor tissue and analyze the protein expression of each sectioning layer of the tumor. HIF1-α and VEGF were highly expressed by the cells in the inner layer of the system, as shown in Fig.…”

Exploring New Dimensions of Tumor Heterogeneity: The Application of Single Cell Analysis to Organoid‐Based 3D In Vitro Models

“…Our group [142][143][144][145][146][147] and others [148][149][150][151][152][153][154][155] have created papersupported models where thin paper scaffolds infiltrated with cells embedded in hydrogels are assembled to create a tissue construct with one or more layers (Figure 2Ciii). Single-layer systems offer quick and inexpensive fabrication and a mechanically reinforced platform for applications where low hydrogel volumes are desired to facilitate live imaging but a 3D structure is still required and where repeated media changes could degrade softer hydrogel domes.…”