Studying Tumor Angiogenesis and Cancer Invasion in a Three‐Dimensional Vascularized Breast Cancer Micro‐Environment

Abstract

Metastatic breast cancer is one of the deadliest forms of malignancy, primarily driven by its characteristic micro‐environment comprising cancer cells interacting with stromal components. These interactions induce genetic and metabolic alterations creating a conducive environment for tumor growth. In this study, a physiologically relevant 3D vascularized breast cancer micro‐environment is developed comprising of metastatic MDA‐MB‐231 cells and human umbilical vein endothelial cells loaded in human dermal fibroblasts laden fibrin, representing the tumor stroma. The matrix, as well as stromal cell density, impacts the transcriptional profile of genes involved in tumor angiogenesis and cancer invasion, which are hallmarks of cancer. Cancer‐specific canonical pathways and activated upstream regulators are also identified by the differential gene expression signatures of these composite cultures. Additionally, a tumor‐associated vascular bed of capillaries is established exhibiting dilated vessel diameters, representative of in vivo tumor physiology. Further, employing aspiration‐assisted bioprinting, cancer–endothelial crosstalk, in the form of collective angiogenesis of tumor spheroids bioprinted at close proximity, is identified. Overall, this bottom–up approach of tumor micro‐environment fabrication provides an insight into the potential of in vitro tumor models and enables the identification of novel therapeutic targets as a preclinical drug screening platform.

3D Bioprinted perfusable and vascularized breast tumor model for dynamic screening of chemotherapeutics and CAR-T cells

“…Collagen and fibrin, both being abundantly present at a native tumor site, were incorporated in our study as the bioprinting substrate. Building on our previous study (20) , we incorporated 2 mg/ml collagen along with 3 mg/ml fibrinogen in this study (C2F3), to build the tumor microenvironment. In order to precisely position H231F spheroids in the composite C2F3 hydrogel, it was essential to realize the entire bioprinting process prior to complete crosslinking of C2F3.…”

“…Fibrinogen and thrombin were purchased from Sigma Aldrich (Burlington, MA). Equal volumes of 4 mg/ml type I collagen and 6 mg/ml fibrin (20) was mixed together to obtain a final concentration of 2 mg/ml collagen and 3 mg/ml fibrin. This composite hydrogel will be referred to as 'C2F3'.…”

The Mechanisms of Ferroptosis and the Applications in Tumor Treatment: Enemies or Friends?

“…Tumor immunotherapy is an incredibly innovative treatment for cancer today, which has the advantages of stronger targeting and fewer side effects Lin et al, 2020;Tan et al, 2020;Xu et al, 2020;Wu et al, 2021;Xu et al, 2022). Although it has incomparable advantages compared with other traditional therapies, there are still problems of poor efficacy and drug resistance Dey et al, 2021;Repellin et al, 2021;Xiong et al, 2021) T cells and IFN-γ expression are positively correlated with the treatment prognosis of cancer patients. IFN-γ released by CD8 (+) T cells inhibits the expression of system Xc-, SLC3A2 and SLC7A11, thus blocking the uptake of cystine by tumor cells.…”

Diversity Models and Applications of 3D Breast Tumor-on-a-Chip

“…However, the cancer microenvironment could be vascularized in the body to gain oxygen and nutrition. For this reason, researchers attempted to explore tumor angiogenesis in a spheroid model to mimic the vascularized cancer microenvironment [ 4 , 5 ]. In breast tumor-on-a-chip, the microfluidic chip could be not only the application site of a previous spheroid, but also integrate the preparation process.…”

“…Marco P. Carvalho et al [ 28 ] obtained a heterotypic spheroid as the realistic model of breast tumors through co-culturing MCF-7 and human dermal fibroblasts with the ratio of 3:1 and 1:1. Madhuri Dey et al [ 4 ] developed a physiologically relevant 3D vascularized breast cancer micro-environment comprising of metastatic MDA-MB-231 cells and human umbilical vein endothelial cells. C. C Yang et al [ 29 ] combined heterocellular tumor spheroids with breast tumor cells and adipocyte cells to investigate the behavior of breast cancer cells in response to different environment stimuli in 3D microenvironment.…”