Background: Advanced breast cancer metastasizes to many organs including bone, but few effective treatments are available. Here we report that induced tumor-suppressing (iTS) MSCs protected bone from metastases while un-induced MSCs did not. Methods: iTS MSCs were generated by overexpressing Lrp5, β-catenin, Snail, or Akt. Their tumor-suppressing capability was tested using a mouse model of mammary tumors and bone metastasis, human breast cancer tissues and cancer cell lines. Results: In a mouse model, the induced MSC-derived conditioned medium (MSC CM) reduced mammary tumors and suppressed tumor-induced osteolysis. Tumor-promoting genes such as CXCL2 and LIF, as well as PDL1, a blocker of T-cell-based immune responses were downregulated. Proteomics analysis revealed that heat shock protein 90 (Hsp90ab1), calreticulin (Calr) and peptidylprolyl isomerase B (Ppib), which are highly expressed intracellular proteins in many cancers, were enriched in MSC CM as atypical tumor suppressors. Thus, overexpressing selected genes that were otherwise tumorigenic rendered MSCs the tumor-suppressing capability through the atypical suppressors, as well as p53 and Trail. Notably, the inhibitory effect of Lrp5- and Akt-overexpressing MSC CMs, Hsp90ab1 and Calr presented selective inhibition to tumor cells than non-tumor cells. The development of bone-resorbing osteoclasts was also suppressed by MSC CMs. Conclusion: Collectively, the results showed an anti-tumor effect of iTS MSCs and suggested novel therapeutic approaches to suppress the progression of tumors into the bone.

Rationale : The progression of cancer cells depends on the soil and building an inhibitory soil might be a therapeutic option. We previously created tumor-suppressive secretomes by activating Wnt signaling in MSCs. Here, we examined whether the anti-tumor secretomes can be produced from tumor cells. Methods: Wnt signaling was activated in tumor cells by overexpressing β-catenin or administering BML284, a Wnt activator. Their conditioned medium (CM) was applied to cancer cells or tissues, and the effects of CM were evaluated. Tumor growth in the mammary fat pad and tibia in C57BL/6 female mice was also evaluated through μCT imaging and histology. Whole-genome proteomics analysis was conducted to determine and characterize novel tumor-suppressing proteins, which were enriched in CM. Results: The overexpression of β-catenin or the administration of BML284 generated tumor-suppressive secretomes from breast, prostate and pancreatic cancer cells. In the mouse model, β-catenin-overexpressing CM reduced tumor growth and tumor-driven bone destruction. This inhibition was also observed with BML284-treated CM. Besides p53 and Trail, proteomics analysis revealed that CM was enriched with enolase 1 (Eno1) and ubiquitin C (Ubc) that presented notable tumor-suppressing actions. Importantly, Eno1 immunoprecipitated CD44, a cell-surface adhesion receptor, and its silencing suppressed Eno1-driven tumor inhibition. A pan-cancer survival analysis revealed that the downregulation of MMP9, Runx2 and Snail by CM had a significant impact on survival outcomes ( p < 0.00001). CM presented a selective inhibition of tumor cells compared to non-tumor cells, and it downregulated PD-L1, an immune escape modulator. Conclusions: The tumor-suppressive secretome can be generated from tumor cells, in which β-catenin presented two opposing roles, as an intracellular tumor promoter in tumor cells and a generator of extracellular tumor suppressor in CM. Eno1 was enriched in CM and its interaction with CD44 was involved in Eno1's anti-tumor action. Besides presenting a potential option for treating primary cancers and metastases, the result indicates that aggressive tumors may inhibit the growth of less aggressive tumors via tumor-suppressive secretomes.

Acute respiratory distress syndrome virus-2 (SARS-CoV-2) responsible for coronavirus disease 2019 (COVID-19) infection, which causes global public health emergencies, has sped widely for more than 5 months and has the risk of long-term transmission. No effective treatment has been discovered to date. In the cases we report, the patient continued to deteriorate even after administration of antiviral drugs such as lopinavir/ritonavir, interferon-α, and ribavirin, as well as intravenous injection of meropenem, methylprednisolone, and immunoglobulin. So, we infused the patient with convalescent plasma (CP), and the absolute lymphocyte count increased the next day and returned to normal on the fourth day. Followed by intravenous infusion of mesenchymal stem cells (MSCs), bilateral infiltrates were absorbed and the pulmonary function was significantly improved. We note that the intravenous infusion of CP and MSCs for the treatment of severe COVID-19 patients may have synergistic characteristics in inhibiting cytokine storm, promoting the repair of lung injury, and recovering pulmonary function. We hope to provide a reference for the research direction of COVID-19 clinical strategies.

Colorectal neoplasia differentially expressed (CRNDE) is a long non-coding RNA which has been proved upregulated in various cancers. Meanwhile, CRNDE has been demonstrated to be involved in multiple biological processes of different cancers according to previous study. Moreover, recent studies suggested CRNDE might be a potential diagnostic biomarker and prognostic predictor due to its high sensitivity and specificity in cancer tissues and plasma. In this review, we summarize the biological function of CRNDE and the relevant mechanisms in cancers to establish a molecular basis for the clinical use of CRNDE in the future.