Background: The chemokine stromal derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 have been demonstrated to be crucial for the homing of stem cells and prostate cancers to the marrow. While screening prostate cancers for CXCL12-responsive adhesion molecules, we identified CD164 (MGC-24) as a potential regulator of homing. CD164 is known to function as a receptor that regulates stem cell localization to the bone marrow.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency leads to lower cholesterol and is associated with reduced vascular complications in the general population. Cholesterol lowering may also have beneficial effects in sickle cell disease (SCD). The objective of this study was to determine effects of PCSK9 deficiency in a mouse model of SCD. Bone marrow transplantation (BMT) was performed from donor SCD mice to wild-type, PCSK9-deficient, and LDLR-deficient recipients to generate SCD controls (Pcsk9+/+, SCDbmt) with preserved PCSK9 status, SCD mice with deficiency of PCSK9 (Pcsk9−/−, SCDbmt), and SCD mice with deficiency of LDLR (Ldlr−/−, SCDbmt). Although cholesterol levels were lower in Pcsk9−/−, SCDbmt mice compared to Pcsk9+/+, SCDbmt mice, anemia was more severe in Pcsk9−/−, SCDbmt mice. Increased reticulocytosis, enhanced ex vivo erythrocyte sickling, and increased erythrocyte phosphatidylserine exposure was also observed. Livers, spleens, and kidneys contained increased iron in Pcsk9−/−, SCDbmt mice compared to Pcsk9+/+, SCDbmt mice consistent with greater hemolysis. SCD mice with deficiency of LDLR (Ldlr−/−, SCDbmt mice) had similar anemia as Ldlr+/+, SCDbmt mice despite higher serum cholesterol. In conclusion, deficiency of PCSK9 is associated with worsened anemia in SCD mice due to increased hemolysis. These findings may have implications for lipid-lowering strategies in patients with SCD, as well as for potential novel modifiers of anemia severity.
14Pre-metastatic niches in distant tissue facilitate metastasis from the primary tumor. Cargo-free 15 porous polymer scaffolds implanted in tumor-bearing mice act as synthetic metastatic niches 16 recruiting metastasizing cancer cells. Herein, we investigated the mechanisms by which these 17 implants attract cancer cells from circulation. Scaffolds attract cancer cells in part via 18 S100A8/A9 secreted by Gr1 + myeloid cells in a mechanism that mimics lung metastasis. Further, 19 cancer cells attracted to the scaffold have a lung-tropic gene expression signature regardless of 20 their tissue of origin. The scaffold implant reduces metastasis to the lung suggesting otherwise 21 lung-tropic cancer cells are diverted to the scaffold. The suppression of metastatic spread by the 22 scaffold suggests this mechanism may be exploited for novel therapies, and may broadly 23 influence the design of scaffold-based drug delivery system for anti-cancer therapy. 24 25 30 metastasizing cancer cells before they are detectable in native organs 5, 6 , show potential as a 31 therapeutic by reducing metastatic tumor burden in native organs 6 , and can be engineered and 32 humanized to uniquely study human pathways in native pre-metastatic niche progression 6-9 . 33Previous work has shown that the detection of cancer cells at the synthetic pre-metastatic niche 34 occurs soon after the arrival of myeloid cells 5, 6 , and identifying the mechanism governing 35 2 recruitment would improve their application as models 8, 9 for study of native pre-metastatic 36 niches and as local delivery systems for immunotherapy 10, 11 . 37 Here, we dissected the contribution of different cell subsets at the synthetic pre-metastatic 38 niche-a cargo-free microporous poly(ε-caprolactone) (PCL) scaffold implant-to cancer cell 39 recruitment. Further, we investigated the common myeloid cell secreted S100A8/A9 recruitment 40 axis between the synthetic pre-metastatic niche and pre-metastatic lung, which may divert 41 metastasis of lung-tropic cancer cells to the implant. These studies will determine the extent to 42 which cargo-free synthetic pre-metastatic niches mimic the organotropic metastasis observed in 43 native tissues where cancer cells originating in a given organ will preferentially metastasize to 44 metastatic niches in a particular organ 12, 13 . 45 Results and discussion 46 Diseased conditioning enhances breast cancer cell recruitment from the blood to scaffold 47 65 cells from diseased and healthy scaffolds and lungs, with quantification of 4T1 cell 66 transmigration towards the conditioned media in an in vitro extravasation model (Fig. 1C). The 67 diseased conditioned media of both the scaffold and lung stimulated more 4T1 cells 68 transmigration than the conditioned media produced from healthy tissue (Fig. 1C). 69Expanded granulocytic myeloid cells at the diseased scaffold implant secrete S100A8/A9 to 70 recruit breast cancer cells. We next sought to determine which cell populations at the scaffold 71 secreted the soluble factor...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.