Abstract
Organ tropism of metastatic cells is not well understood. To determine the key factors involved in the selection of a specific organ upon metastasis, we established metastatic cell lines and analyzed their homing to specific tissues. Toward this, 143B osteosarcoma cells were injected intracardially until the kidney-metastasizing sub-cell line Bkid was established, which significantly differed from the parental 143B cells. The candidate genes responsible for kidney metastasis were validated, and SerpinF1/Pigment epithelium derived factor (PEDF) was identified as the primary target. Bkid cells with PEDF knockdown injected intracardially did not metastasize to the kidneys. In contrast, PEDF overexpressing 143B cells injected into femur metastasized to the lungs and kidneys. PEDF triggered mesenchymal-to-epithelial transition (MET) in vitro as well as in vivo. Based on these results, we hypothesized that the MET might be a potential barrier to extravasation. PEDF overexpression in various osteosarcoma cell lines increased their extravasation to the kidneys and lungs. Moreover, when cultured close to the renal endothelial cell line TKD2, Bkid cells disturbed the TKD2 layer and hindered wound healing via the PEDF-laminin receptor (lamR) axis. Furthermore, novel interactions were observed among PEDF, lamR, lysyl oxidase-like 1 (Loxl1), and SNAI3 (Snail-like transcription factor) during endothelial-to-mesenchymal transition (EndoMT). Collectively, our results show that PEDF induces cancer cell extravasation by increasing the permeability of kidney and lung vasculature acting via lamR and its downstream genes. We also speculate that PEDF promotes extravasation via inhibiting EndoMT, and this warrants investigation in future studies.
Highlights
Despite being a rare type of cancer, osteosarcoma (OS) is the most common bone cancer, and occurs mainly in children and young adults
Once 143B cells consistently metastasized into the liver, they were used for several repeated injections, following which the cells were suddenly biased to renal metastasis (Figure 1F) or lymph node metastasis (Figure 1G)
The initial metastasis in the specific organ was observed very weakly after four to five weeks from the cardiac injection, the repeated injections increased the aggressiveness of these sub-cell lines, and the luciferase signals could be observed within three weeks after the third time injection since the sub-population was detected in the specific organs
Summary
Despite being a rare type of cancer, osteosarcoma (OS) is the most common bone cancer, and occurs mainly in children and young adults. Most of the currently used surgical treatments that are combined with multiple-agent chemotherapy had been established during the 70s–80s. High-grade osteosarcomas have a high propensity for pulmonary metastasis; over 75% of metastatic OS cases involve the lung. Other organ metastases are extremely rare; the renal metastasis of OS is often found with pulmonary metastasis after death [3], and the hepatic metastasis of OS is found microscopically after chemotherapy [4]. The OS metastasize hematogeneously to lung and bones but rarely to lymph nodes [5]. It is crucial to determine the mechanism by which osteosarcomas prefer to metastasize to specific organs, as may be applicable to other cancers. Most established OS cell lines were found to be non-metastatic
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