Macrofluidic recirculating model of skeletal metastasis

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.