The formation of distant metastasis marks the stage of cancer progression when the disease becomes lethal. A major limitation in developing life-preserving timely interventions is the striking lack of robust technologies capable of early detection of metastatic disease as well as model systems that allow systematic screening and examination of factors contributing to breast cancer metastasis in a controlled setting. To this end, we developed implantable micro-porous poly(ε-caprolactone) (PCL) scaffolds to create a defined site in vivo to recruit and detect tumor cells and demonstrated its utility for early detection and management of metastatic disease in a translational setting. Here, we examine their potential in studying the role of immune-modulatory factors in immune cell and subsequent metastatic cell recruitment in an immune-competent mouse model of breast cancer metastasis.
PCL scaffolds were fabricated using gas-foaming and particulate leaching techniques. Scaffolds were implanted in the subcutaneous space of female BALB/c mice one month prior to inoculation with 4T1-tom-luc2 cells. We first characterized the relative abundance of leukocyte populations within the PCL scaffold in tumor free mice. The local inflammatory microenvironment enabled recruitment of tumor cells to the PCL scaffold site as evidenced by flow cytometric analysis of scaffolds retrieved at day 15 post tumor inoculation. In addition, the dynamics of immune cell populations at the scaffold site was significantly altered post tumor inoculation (e.g., significant up-regulation of myeloid derived suppressor cells (MDSCs)) and reflected the dynamics observed in the spleen. This indicates that such an engineered microenvironment could be used to identify and modulate key components of the metastatic niche in the context of immune cells. We are currently examining the influence of localized expression of anti-inflammatory cytokines (e.g., IL-10) and pro-inflammatory cytokines (e.g., CCL2) by combining gene delivery tools with micro-porous PCL scaffolds. Modulating the immune microenvironment at a defined site will help establish the relative contributions of immune cells and their correlation with subsequent metastatic cell recruitment. Such tools provide a user defined platform to probe the role of niche components on metastatic cell homing and colonization, thereby providing a strong foundation to advance fundamental studies of the pre-metastatic niche and tumor metastasis.