ABSTRACT
Blood vessels support tumours by providing nutrients and oxygen, while also acting as conduits for the dissemination of cancer1. Here we use mouse models of breast and lung cancer to investigate whether endothelial cells also have active 'instructive' roles in the dissemination of cancer. We purified genetically tagged endothelial ribosomes and their associated transcripts from highly and poorly metastatic tumours. Deep sequencing revealed that metastatic tumours induced expression of the axon-guidance gene Slit2 in endothelium, establishing differential expression between the endothelial (high Slit2 expression) and tumoural (low Slit2 expression) compartments. Endothelial-derived SLIT2 protein and its receptor ROBO1 promoted the migration of cancer cells towards endothelial cells and intravasation. Deleting endothelial Slit2 suppressed metastatic dissemination in mouse models of breast and lung cancer. Conversely, deletion of tumoural Slit2 enhanced metastatic progression. We identified double-stranded RNA derived from tumour cells as an upstream signal that induces expression of endothelial SLIT2 by acting on the RNA-sensing receptor TLR3. Accordingly, a set of endogenous retroviral element RNAs were upregulated in metastatic cells and detected extracellularly. Thus, cancer cells co-opt innate RNA sensing to induce a chemotactic signalling pathway in endothelium that drives intravasation and metastasis. These findings reveal that endothelial cells have a direct instructive role in driving metastatic dissemination, and demonstrate that a single gene (Slit2) can promote or suppress cancer progression depending on its cellular source.
Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Endothelium/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Neoplasm Metastasis , Nerve Tissue Proteins/metabolism , Toll-Like Receptor 3/metabolism , Animals , Chemotaxis , Disease Models, Animal , Disease Progression , Endothelial Cells/metabolism , Female , Humans , Intercellular Signaling Peptides and Proteins/genetics , Male , Mice , Neoplasm Metastasis/genetics , Nerve Tissue Proteins/genetics , RNA, Double-Stranded , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Signal Transduction , Toll-Like Receptor 3/deficiency , Toll-Like Receptor 3/genetics , Tumor Cells, Cultured , Roundabout ProteinsABSTRACT
BACKGROUND: Life expectancy of patients with multiple myeloma (MM) has increased over the past decades, underlining the importance of local tumor control and avoidance of dose-dependent side effects of palliative radiotherapy (RT). Virtual noncalcium (VNCa) imaging from dual-energy computed tomography (DECT) has been suggested to estimate cellularity and metabolic activity of lytic bone lesions (LBLs) in MM. OBJECTIVE: To explore the feasibility of RT response monitoring with DECT-derived VNCa attenuation measurements in MM. METHODS: Thirty-three patients with 85 LBLs that had been irradiated and 85 paired non-irradiated LBLs from the same patients were included in this retrospective study. Irradiated and non-irradiated LBLs were measured by circular regions of interest (ROIs) on conventional and VNCa images in a total of 216 follow-up measurements (48 before and 168 after RT). Follow-ups were rated as therapy response, stable disease, or local progression according to the MD Anderson criteria. Receiver operating characteristic (ROC) analysis was performed to discriminate irradiated vs. non-irradiated and locally progressive vs. stable/responsive LBLs using absolute attenuation post-irradiation and percentage attenuation change for patients with pre-irradiation DECT, if available. RESULTS: Attenuation of LBLs decreased after RT depending on the time that had passed after irradiation [absolute thresholds for identification of irradiated LBLs 30.5-70.0 HU [best area under the curve [AUC] 0.75 (0.59-0.91)] and -77.0 to -22.5 HU [best AUC 0.85 (0.65-1.00)]/-50% and -117% to -167% proportional change of attenuation on conventional and VNCa images, respectively]. VNCa CT was significantly superior for identification of RT effects in LBLs with higher calcium content [best VNCa AUC 0.96 (0.91-1.00), best conventional CT AUC 0.64 (0.45-0.83)]. Thresholds for early identification of local irradiation failure were >20.5 HU on conventional CT [AUC 0.78 (0.68-0.88)] and >-27 HU on VNCa CT [AUC 0.83 (0.70-0.96)]. CONCLUSION: Therapy response of LBLs after RT can be monitored by VNCa imaging based on regular myeloma scans, which yields potential for optimizing the lesion-specific radiation dose for local tumor control. Decreasing attenuation indicates RT response, while above threshold attenuation of LBLs precedes local irradiation failure.