Cancer Cell Dissemination and Homing to the Bone Marrow in a Zebrafish Model

Abstract

Advancement of many solid tumors and hematologic malignancies is frequently characterized by dissemination and homing of cancer cells to the bone marrow (BM). Methods to quantitatively characterize these key steps of the metastatic cascade in mammalian models are currently limited and do not offer opportunities to perform rapid, large-scale genomic, or drug screening. Because of their optical clarity, we used zebrafish to develop an in vivo model of cancer cell dissemination and homing to the BM. We performed intracardiac injection of multiple myeloma (MM) cells derived from human BM or cell lines and monitored their migration to the caudal hematopoietic tissue (CHT), the region where hematopoiesis occurs in the zebrafish embryo, which recapitulates a BM-like niche. Transcriptomic analyses confirmed that MM cells homing to the CHT displayed gene-expression differences compared with MM cells outside of the CHT, including significant enrichment for genes known to regulate interleukin-6 (IL6) signaling, cell adhesion, and angiogenesis. Collectively, our findings point to the zebrafish as a valuable model in which to study cancer cell homing to the hematopoietic niche and to establish a screening platform for the identification of factors and mechanisms contributing to the early steps of bone metastasis. Cancer Res; 76(2); 463-71. Ó2016 AACR.

Development of a Patient-Derived Xenograft (PDX) of Breast Cancer Bone Metastasis in a Zebrafish Model

“…Despite the histological and molecular similarities, i.e., tissue of origin and hormone receptor pattern of MCF7 cells, respectively, the patient-derived cells showed a specific grafting pattern with cells mainly colonizing the CHT of the ZF, suggesting that the in vivo behavior of these cells may be due to an adaptation process to the bone tissue of the patient. As the CHT is the first homing and expansion site for hematopoietic stem cells in the ZF embryo [27], the experimental phenotype can be considered as an expression of bone marrow tropism [28]. A more detailed and mechanistic description of the process of dissemination and colonization of the CHT by cancer cells can be found in the study by He et al [29].…”

Engineering Hematopoietic Stem Cells: Lessons from Development

“…Zebrafish adult whole KM transplants rescue impaired multilineage hematopoiesis and lethality that occurs in day 2 hpf gata1 −/− mutant embryos (Traver et al, 2003), showing that KM HSCs can rescue hematopoietic defects at the earlier CHT stage. CD41 + HSCs isolated from zebrafish KM home to the CHT niche upon injection into 48 hour-old embryos, (Sacco et al, 2016), indicating that the developmental stage of transplant recipients regulates homing of donor KM HSCs, and more mature HSCs can engraft in hematopoietic organs that arise at earlier developmental time points.…”

“…Other model organisms can be used to mechanistically dissect aspects of HSC function. Human CD34 + or CD138 + cell xenotransplants into 48 hpf zebrafish embryos enable the in vivo visualization of cell homing to hematopoietic organs (Sacco et al, 2016; Staal et al, 2016), taking advantage of the high level of conservation of hematopoiesis across species (Figure 1), and may provide novel models of heterochronic HSC transplantation.…”

Disseminated tumour cells in bone marrow are the source of cancer relapse after therapy

“…The mechanism underlying the process of DTCs localizing to and colonizing the bone marrow is complex, and the homing and survival of DTCs are more like a selective process. In one study, intracardiac injection of tumour cells was performed to study late stage of metastasis . These DTCs may transform into more aggressive variants and grow out to overt metastasis .…”