In vivo capture and label-free detection of early metastatic cells

Abstract

Breast cancer is a leading cause of death for women, with mortality resulting from metastasis. Metastases are often detected once tumor cells affect the function of solid organs, with a high disease burden limiting effective treatment. Here we report a method for the early detection of metastasis using an implanted scaffold to recruit and capture metastatic cells in vivo, which achieves high cell densities and reduces the tumor burden within solid organs 10-fold. Recruitment is associated with infiltration of immune cells, which include Gr1hiCD11b+ cells. We identify metastatic cells in the scaffold through a label-free detection system using inverse-spectroscopic optical coherence tomography, which identifies changes to nanoscale tissue architecture associated with the presence of tumor cells. For patients at risk of recurrence, scaffold implantation following completion of primary therapy has the potential to identify metastatic disease at the earliest stage, enabling initiation of therapy while the disease burden is low.

Enhanced Survival with Implantable Scaffolds That Capture Metastatic Breast Cancer Cells In Vivo

“…An emerging approach for early detection lies with the implantation of a biomaterial scaffold that can capture metastatic cells (11). These scaffolds were modeled after the concept of the pre-metastatic niche (12, 13), echoing Paget’s “seed and soil” hypothesis proposed over a century ago (12, 14-17).…”

“…Importantly, these studies indicate that metastasis to specific organs is not random, but is influenced by the properties of the local environment (12, 13, 18). The initial translation of these principals led to the development and implementation of micro-porous poly(lactide-co-glycolide) (PLG) biomaterial scaffolds, which recruited metastatic breast cancer cells through the local immune response in vivo , resulting in decreased tumor burden at metastatic sites (11). However, PLG scaffolds were degradable over time scales considered too short for clinical translation.…”

Extracellular matrix mediators of metastatic cell colonization characterized using scaffold mimics of the pre-metastatic niche

“…ECM proteins present in the pre-metastatic niche were utilized to enhance tumor cell colonization to PCL scaffolds implanted subcutaneously, which is a location to which metastatic cells do not normally colonize in our breast cancer models [17]. The ability of ECM to promote colonization was investigated by preparing PCL scaffolds coated with fibronectin and collagen IV, two ECM proteins previously shown to accumulate at the niche.…”

“…A previous report by Azarin et al . demonstrates that implanted polymer scaffolds can be used for the early detection of circulating tumor cells in orthotopic breast cancer mouse models, prior to their arrival at target organs [17]. The potential for early detection may be improved due to the increased accumulation of tumor cells to our defined niche that could facilitate the application of imaging tools to identify cancer cells within the implant.…”

Linear-array-based photoacoustic tomography for label-free high-throughput detection and quantification of circulating melanoma tumor cell clusters

“…However, most of these existing technologies require blood to be drawn to isolate and capture CTCs ex vivo, reducing the effective CTC detection sensitivity. Optical imaging technologies, such as confocal microscopy, in vivo flow cytometry, and optical coherence tomography, have been applied to detect CTCs in vivo [8][9][10][11] . However, suffering from strong optical scattering in biological tissue, these techniques have shallow penetration, limiting them to imaging only small blood vessels, which results in low throughput for CTC detection.…”