Rationale: In the bone marrow microenvironment (BMME), mesenchymal stem/stromal cells (MSCs) control the self-renewal of both healthy and cancerous hematopoietic stem/progenitor cells (HSPCs). We previously showed that in vivo leukemia-derived MSCs change neighbor MSCs into leukemia-permissive states and boost leukemia cell proliferation, survival, and chemotherapy resistance. But the mechanisms behind how the state changes are still not fully understood. Methods: Here, we took a reverse engineering approach to determine BCR-ABL1+ leukemia cells activated transcriptional factor C/EBPβ, resulting in miR130a/b-3p production. Then, we back-tracked from clinical specimen transcriptome sequencing to cell co-culture, molecular and cellular assays, flow cytometry, single-cell transcriptome, and transcriptional regulation to determine the molecular mechanisms of BCR-ABL1-driven exosome-miR130b-3p-mediated gap-junction Cx43 MSC intercellular communications. Results: BCR-ABL1-driven exosome-miR130a/b-3p mediated gap-junction Cx43 (a.k.a., GJA1) BMSC intercellular communications for subclonal evolution in leukemic microenvironment by targeting BMSCs-expressed HLAs, thereby potentially maintaining BMSCs with self-renewal properties and reduced BMSC immunogenicity. The Cx43 low and miR-130a/b high subclonal MSCs subsets of differentiation state could be reversed to Cx43 high and miR-130a/b low subclones of the higher stemness state in Cx43-overexpressed subclonal MSCs. Both miR-130a and miR-130b might only inhibit Cx43 translation or degrade Cx43 proteins and did not affect Cx43 mRNA stability. The subclonal evolution was further confirmed by single-cell transcriptome profiling of MSCs, which suggested that Cx43 regulated their stemness and played normal roles in immunomodulation antigen processing. Thus, upregulated miR-130a/b promoted osteogenesis and adipogenesis from BMSCs, thereby decreasing cancer progression. Our clinical data validated that the expression of many genes in human major histocompatibility was negatively associated with the stemness of MSCs, and several immune checkpoint proteins contributing to immune escape in tumors were overexpressed after either miR-130a or miR-130b overexpression, such as CD274, LAG3, PDCD1, and TNFRSF4. Not only did immune response-related cytokine-cytokine receptor interactions and PI3K-AKT pathways, including EGR3, TNFRSF1B, but also NDRG2 leukemic-associated inflammatory factors, such as IFNB1, CXCL1, CXCL10, and CCL7 manifest upon miR-130a/b overexpression. Either BCR siRNAs or ABL1 siRNAs assay showed significantly decreased miR-130a and miR-130b expression, and chromatin immunoprecipitation sequencing confirmed that the regulation of miR-130a and miR-130b expression is BCR-ABL1-dependent. BCR-ABL1 induces miR-130a/b expression through the upregulation of transcriptional factor C/EBPβ. C/EBPβ could...
To confirmed the pharmacokinetics and pharmacodynamics of sodium glycididazole (CMNa) in different cancer xenografts, and evaluate whether tumor hypoxia status is correlated with its radiosensitizing effects Materials/Methods: Human esophageal cancer (EC109), head and neck cancer (FaDu) and lung cancer (A549) nude mice xenografts were used. Tissue and plasma were collected at different time after i.v. injection of 171.9mg/kg, 57.3mg/kg or 19.1mg/kg CMNa. The concentrations of CMNa and its metabolites in the tumors and normal tissues were determined by HPLC and compared. The tumors were locally irradiated to 30 Gy in 6 fractions as given 171.9mg/kg, 57.3mg/kg or 19.1mg/kg CMNa before each irradiation. Mice received radiation alone or without treatment were used as the control. Tumor volume was monitored and the tumor growth delay were calculated and compared among groups Tumor sections were also prepared and IHC staining for HIF-1a. Pre-treatment plasma concentration of osteopontin (OPN) was tested by ELSA and its correlation with tumor growth delay was analyzed. Results: CMNa was rapidly eliminated from the blood and the distribution half-life at three doses of CMNa were 0.765, 0.613, and 0.293 minutes, respectively. Twenty minutes after CMNa administration, the drug concentration significantly decreased and could barely be detected in the kidney, spleen, heart, lung and brain. The drug concentration in the tumor was 1.6w2.8 times higher than the muscle, especially at the high and medium dose. CMNa could sensitize tumors to irradiation for all three cancer type at different dose. For EC109 and FaDu xenografts, Vt/V0 in high CMNa dose group was significantly lower than those in the irradiation alone group (EC109: PZ0.038, FaDu: PZ0.048). However, these was no statistical difference between middle, low dose and irradiation groups (P>0.05). Significant more HIF1-aexpression were detected in FaDu (3+, 70%) and EC109 (2+w3+, 50%) xenografts as comparison of A549 tumors (1+, 40%). The median plasma concentration of OPN before the irradiation was 62.87 ng/ml (23.09w111.04 ng/ml), 66.96 pg/ml (25.69w113.01 pg/ml) and 47.73 pg/ml (16.99w93.72 pg/ml) for EC109, FaDu and A549 tumor-bearing mice, respectively. Conclusion: This pre-clinical study demonstrated that CMNa rapidly distributed into and eliminated from main normal organs. Higher tumor drug concentrations were also detected. Significant radiation-enhancing effects were found, especially at high does for head & neck and esophageal cancers. Meanwhile, the level of serum OPN concentration might be the predictor of radiosensitizing effects. These pharmacokinetics and pharmacodynamics findings might be useful for future translational studies.
a little more noticeable tendency in NPS group. AI increase was relatively higher in early, NPS, high dose groups (pZ0.076). The recovery tendency in late phase (14 weeks) was a little bit more in pancreatic shield (PS), high dose group (pZ0.067). Crypt atrophy was determined by the ratio of area occupied by connective tissue in mucosa. This tended to be high in low dose, NPS group (pZ0.062). It also showed an increasing trend in late phase especially in PS group (pZ0.032 in low dose group) (pZ0.012 in high dose group). IL-6 reflected the change with radiation dose escalation (pZ0.020). HIF-1a (pZ0.002 in low dose group, pZ0.001 in high dose group), NF-kB (pZ0.003 in low dose group, pZ0.038 in high dose group), and VEGF (pZ0.016 in low dose group, pZ0.006 in high dose group) were generally associated with tissue recovery at late phase. Conclusion: CDIA technique may provide the proper irradiation method free from volume effect deviation. Radiation-induced GIT toxicity was related to dose escalation with differential recovery over time. PS seems to be advantageous in terms of toxicity inhibition compared to NPS. These results can be a theoretical basis for reducing the radiation toxicity by confirming the relationship between the local irradiation and multi-organic impact with future studies.
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