Abstract
Molecular crosstalk between intra-tumor blood vessels and tumor cells plays many critical roles in tumorigenesis and cancer metastasis. However, it has been very difficult to investigate the biochemical mechanisms underlying the overlapping, multifactorial processes that occur at the tumor-vascular interface using conventional murine models alone. Moreover, traditional two-dimensional (2D) culture models used in cancer research do not recapitulate aspects of the 3D tumor microenvironment. In the present study, we introduce a microfluidic model of the solid tumor-vascular interface composed of a human umbilical vein endothelial cell (HUVEC)-lined, perfusable, bioengineered blood vessel and tumor spheroids embedded in an extracellular matrix (ECM). We sought to optimize our model by varying the composition of the tumor spheroids (MDA-MB-231 breast tumor cells + mesenchymal stem cells (MSCs)/human lung fibroblasts (HLFs)/HUVECs) and the extracellular matrix (ECM: collagen, Matrigel, and fibrin gels with or without free HLFs) that we used. Our results indicate that culturing tumor spheroids containing MDA-MB-231 cells + HUVECs in an HLF-laden, fibrin-based ECM within our microfluidic device optimally (1) enhances the sprouting and migration of tumor spheroids, (2) promotes angiogenesis, (3) facilitates vascular invasion, and (4) preserves the structural integrity and functionality of HUVEC-lined microfluidic channels. This model may provide a platform for drug screening and mechanism studies on solid tumor interactions with functional blood vessels.
Highlights
Plastic, making them useful in studying drug-induced changes in the behavior of tumor cells[13]
We found that while Matrigel-based culture conditions facilitated the migration of monoculture (MDA-MB-231 cells) and mixed (MDA-MB-231 cells + mesenchymal stem cells (MSCs)) tumor spheroids in our 3D model, they significantly disrupted the structural integrity of the microfluidic Human umbilical vein endothelial cells (HUVECs) channel (Fig. S1)
We found that culturing our tumor spheroids in a fibrin ECM preserved the integrity of our model’s HUVEC channels while simultaneously promoting more active patterns of angiogenesis and tumor cell migration than those observed in other ECM cultures (Figs. 4 and 5)
Summary
Plastic, making them useful in studying drug-induced changes in the behavior of tumor cells[13]. Another study demonstrated that the bioengineered blood vessels in such microfluidic models closely mimic the in vivo architecture They observed that the differentiation and migration of vascular endothelial cells treated with pro-angiogenic growth factors, as well as the permeability of angiogenic sprouts within the device’s collagen matrix, are comparable to those of endogenous blood vessels[18]. Despite these exciting developments, it is still challenging to reproduce all aspects of the solid tumor microenvironment (e.g., ECM, stromal cells, growth factors, vascular crosstalk) in microfluidic model systems. We compared the optimization status of each system by observing (1) the structural integrity of the HUVEC vascular lumen, (2) the sprouting behaviors of tumor spheroids, (3) spheroidinduced angiogenesis, and (4) vascular invasion patterns
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