Abstract
Understanding mechanisms mediating tumor metastasis is crucial for diagnostic and therapeutic targeting. Here, we take advantage of a transparent embryonic zebrafish xenograft model (eZXM) to visualize and track metastatic cells in real time using selective plane illumination microscopy (SPIM) for up to 30 h. Injected human leukemic and breast cancer cells exhibited cell-type specific patterns of intravascular distribution with leukemic cells moving faster than breast cancer cells. Tracking of tumor cells from high-resolution images revealed acute differences in intravascular speed and distance covered by cells. While the majority of injected breast cancer cells predominantly adhered to nearby vasculature, about 30% invaded the non-vascularized tissue, reminiscent of their metastatic phenotype. Survival of the injected tumor cells appeared to be partially inhibited and time-lapse imaging showed a possible role for host macrophages of the recipient embryos. Leukemic cell dissemination could be effectively blocked by pharmacological ROCK1 inhibition using Fasudil. These observations, and the ability to image several embryos simultaneously, support the use of eZXM and SPIM imaging as a functional screening platform to identify compounds that suppress cancer cell spread and invasion.
Highlights
Understanding mechanisms mediating tumor metastasis is crucial for diagnostic and therapeutic targeting
Higher magnification images revealed that solid tumor cells present at the dorsal longitudinal anastomotic vessels (DLAVs) showed an amoeboid type of migration to migrate to the caudal hematopoietic tissue via the intersegmental vessels (ISV)
Concurring with visual observations from selective plane illumination microscopy (SPIM) movies, we found that a leukemic cell covered a significantly longer maximum distance travelled in anterior–posterior and dorsal–ventral direction (459.0 ± 70.05 μm) compared to breast tumor cells (91.44 ± 6.08 μm; P < 0.0001) (Fig. 2c)
Summary
Understanding mechanisms mediating tumor metastasis is crucial for diagnostic and therapeutic targeting. Existing in vivo models and various in vivo imaging tools, such as intra-vital imaging[3,4,5,6,7,8], magnetic resonance imaging[9], two-photon/multiphoton laser scanning m icroscopy[10,11], and optical frequency domain imaging[12], have played a pivotal role in studying certain facets of metastatic spread, allowed short-term tracking of individual cells, provided unique insights into the mechanism of tumor invasion by capturing migration, plasticity of single cells and their microenvironments, and associated changes in gene expression These advances have enabled a better understanding of metastasis, existing models are not amenable to visualization and continuous monitoring of tumor cells in real time. These aspects, combined with the versatility in imaging techniques, make the zebrafish an ideal platform for direct and continuous in vivo observation of tumor cells to enable a better understanding of tumorigenesis
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