Abstract
While microfluidic systems model aspects of metastasis, they are limited to artificially created tissues of limited complexity. We set out to develop an in vitro model of tumor cell migration from a primary tumor to a distant site that allows use of tissue. Accordingly, we created a macrofluidic model using culture plate wells connected with type I collagen-coated large bore tubing and has recirculating media. Green fluorescent protein-positive prostate carcinoma cells in a hydrogel or excised tumor xenografts from mice were placed into primary tumor sites and either human bone stromal cells (HS-5) in a hydrogel or human-derived bone chips were seeded into metastatic sites. Cells from the primary sites migrated to and grew in metastatic sites. Bone enhanced growth at metastatic sites and established a CXCL12 gradient that was higher in metastatic versus primary sites. AMD3100-mediated inhibition of CXCL12 function reduced the number of cells targeting the bone at the metastatic sites. In summary, we have developed a macrofluidic metastasis model that allows incorporation of tumor and metastatic microenvironment tissues and models chemotaxis. This system allows for incorporation of tumor heterogeneity and inclusion of an intact microenvironment. These features will facilitate identification of mechanisms and therapeutics for bone metastasis.
Highlights
While microfluidic systems model aspects of metastasis, they are limited to artificially created tissues of limited complexity
In an approach to complement microfluidic models, we develop here a novel in vitro model that is capable of using ex vivo tumor tissue and tissued derived from the microenvironment in a recirculating system to recapitulate the in vivo microenvironment to investigate prostate carcinoma metastasis
The outlet in the well designated as the “primary site” was connected via a PE tube that was coated with collagen I to the inlet connected to the well designated as the “metastatic site.”
Summary
While microfluidic systems model aspects of metastasis, they are limited to artificially created tissues of limited complexity. Murine in vivo models have been developed to research the extravasation process and bone metastasis[15,16,17], they do not replicate human-specific characteristics relating to tumors, stem cell differentiation, and their responses to therapeutic drugs. An in vitro 3D microfluidic model of the tumor vascular interface was designed to integrate live imaging, precise control of microenvironmental factors, and endothelial barrier measurement[21] While these microfluidic models have several advantages for research of tumor biology, they are only capable of evaluating small cell numbers in artificially constructed microenvironments
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