Cancer metastasis: issues and challenges

Metastasis is the major cause of treatment failure in cancer patients and of cancer?related deaths.This editorial discusses how cancer metastasis may be better perceived and controlled.Based on big?data analyses,a collection of150 important pro?metastatic genes was studied.Using The Cancer Genome Atlas datasets to re?analyze the effect of some previously reported metastatic genes—e.g.,JAM2,PPARGC1A,SIK2,and TRAF6—on overall survival of patients with renal and liver cancers,we found that these genes are actually protective factors for patients with cancer.The role of epithelial–mesenchymal transition(EMT)in single?cell metastasis has been well?documented.However,in metastasis caused by cancer cell clusters,EMT may not be necessary.A novel role of epithelial marker E?cadherin,as a sensitizer for chemoresistant prostate cancer cells by inhibiting Notch signaling,has been found.This editorial also discusses the obstacles for developing anti?metastatic drugs,including the lack of high?throughput technologies for identifying metastasis inhibitors,less application of animal models in the pre?clinical evaluation of the leading com?pounds,and the need for adjustments in clinical trial design to better reflect the anti?metastatic efficacy of new drugs.We are confident that by developing more effective high?throughput technologies to identify metastasis inhibitors,we can better predict,prevent,and treat cancer metastasis.

P-MSC-derived extracellular vesicles facilitate diabetic wound healing via miR-145-5p/CDKN1A-mediated functional improvements of high glucose-induced senescent fibroblasts

Background:Persistent hyperglycaemia in diabetes causes functional abnormalities of human dermal fibroblasts(HDFs),partially leading to delayed skin wound healing.Extracellular vesicles(EVs)containing multiple pro-healing microRNAs(miRNAs)have been shown to exert therapeutic effects on diabetic wound healing.The present study aimed to observe the effects of EVs derived from placental mesenchymal stem cells(P-MSC-EVs)on diabetic wound healing and high glucose(HG)-induced senescent fibroblasts and to explore the underlying mechanisms.Methods:P-MSC-EVs were isolated by differential ultracentrifugation and locally injected into the full-thickness skin wounds of diabetic mice,to observe the beneficial effects on wound healing in vivo by measuring wound closure rates and histological analysis.Next,a series of assays were conducted to evaluate the effects of low(2.28 x 1010 particles/ml)and high(4.56 x 1010 particles/ml)concentrations of P-MSC-EVs on the senescence,proliferation,migration,and apoptosis of HG-induced senescent HDFs in vitro.Then,miRNA microarrays and real-time quantitative PCR(RT-qPCR)were carried out to detect the differentially expressed miRNAs in HDFs after EVs treatment.Specific RNA inhibitors,miRNA mimics,and small interfering RNA(siRNA)were used to evaluate the role of a candidate miRNA and its target genes in P-MSC-EV-induced improvements in the function of HG-induced senescent HDFs.Results:Local injection of P-MSC-EVs into diabetic wounds accelerated wound closure and reduced scar widths,with better-organized collagen deposition and decreased p16INK4a expression.In vitro,P-MSC-EVs enhanced the antisenescence,proliferation,migration,and antiapoptotic abilities of HG-induced senescent fibroblasts in a dose-dependent manner.MiR-145-5p was found to be highly enriched in P-MSC-EVs.MiR-145-5p inhibitors effectively attenuated the P-MSC-EV-induced functional improvements of senescent fibroblasts.MiR-145-5p mimics simulated the effects of P-MSC-EVs on functional improvements of fibroblasts by suppressing the expression of cyclin-dependent kinase inhibitor 1A and activating the extracellular signal regulated kinase(Erk)/protein kinase B(Akt)signaling pathway.Furthermore,local application of miR-145-5p agomir mimicked the effects of P-MSC-EVs on wound healing.Conclusions:These results suggest that P-MSC-EVs accelerate diabetic wound healing by improv-ing the function of senescent fibroblasts through the transfer of miR-145-5p,which targets cyclin-dependent kinase inhibitor 1A to activate the Erk/Akt signaling pathway.P-MSC-EVs are promising therapeutic candidates for diabetic wound treatment.

Contemporary synthesis of bioactive cyclobutane natural products

Many cyclobutane natural products have intriguing biological properties that arise from their fascinating chemical structures.Cyclobutane natural products feature a cyclobutane scaffold as the core or as a part of the spirocyclic or fused cyclic core.However,the highly functionalized nature and the inherent stereochemistry of these cyclobutane natural products,which are associated with their biological activities,pose tremendous challenges to their preparation.In this perspective,we present contemporary advancements in synthetic methods and/or strategies en route to the bioactive cyclobutane natural products.We begin by describing the representative bioactive cyclobutane natural products and then focus on illustrative examples of their syntheses reported from 2018 to 2021.These advances will enable efficient syntheses of cyclobutanes of structural and biological importance.

Prostate cancer tends to metastasize in the bone-mimicking microenvironment via activating NF-κB signaling

Prostate cancer preferentially metastasizes to the bone. However, the underlying molecular mechanisms are still unclear. To explore the effects of a bone-mimicking microenvironment on PC3 prostate cancer cell growth and metastasis, we used osteoblast differentiation medium（ODM; minimal essential medium alpha supplemented with L-ascorbic acid） to mimic the bone microenvironment. PC3 cells grown in ODM underwent epithelial-mesenchymal transition and showed enhanced colony formation, migration, and invasion abilities compared to the cells grown in normal medium. PC3 cells grown in ODM showed enhanced metastasis when injected in mice. A screening of signaling pathways related to invasion and metastasis revealed that the NF-κB pathway was activated, which could be reversed by Bay 11-7082, a NF-κB pathway inhibitor. These results indicate that the cells in different culture conditions manifested significantly different biological behaviors and the NF-κB pathway is a potential therapeutic target for prostate cancer bone metastasis.

Interruption of Klf5 acetylation in basal progenitor cells promotes luminal commitment by activating Notch signaling

Prostate homeostasis and regeneration rely on the proper function of adult stem/progenitor cells(Ousset et al., 2012), which have also been considered as potential cells of origin for prostate cancer(Visvader, 2011) given their key positions in the lineage hierarchy and self-renewal capability. Accumulating evidence reveals the existence of multipotent progenitor cells in both basal and luminal cells.

Novel neutrophil extracellular trap-related mechanisms in diabetic wounds inspire a promising treatment strategy with hypoxia-challenged small extracellular vesicles

Neutrophil extracellular traps(NETs)have been considered a significant unfavorable factor for wound healing in diabetes,but the mechanisms remain unclear.The therapeutic application of small extracellular vesicles(sEVs)derived from mesenchymal stem cells(MSCs)has received considerable attention for their properties.Hypoxic preconditioning is reported to enhance the therapeutic potential of MSC-derived sEVs in regenerative medicine.Therefore,the aim of this study is to illustrate the detailed mechanism of NETs in impairment of diabetic wound healing and develop a promising NET-targeting treatment based on hypoxic pretreated MSC-derived sEVs(Hypo-sEVs).Excessive NETs were found in diabetic wounds and in high glucose(HG)-induced neutrophils.Further research showed that high concentration of NETs impaired the function of fibroblasts through activating endoplasmic reticulum(ER)stress.Hypo-sEVs efficiently promoted diabetic wound healing and reduced the excessive NET formation by transferring miR-17-5p.Bioinformatic analysis and RNA interference experiment revealed that miR-17-5p in Hypo-sEVs obstructed the NET formation by targeting TLR4/ROS/MAPK pathway.Additionally,miR-17-5p overexpression decreased NET formation and overcame NET-induced impairment in fibroblasts,similar to the effects of Hypo-sEVs.Overall,we identify a previously unrecognized NET-related mechanism in diabetic wounds and provide a promising NET-targeting strategy for wound treatment.

Molecular editing in natural product synthesis

Many natural products have remarkable biological functions due to their fascinating molecular architectures.Despite many advances in synthetic method development,the efficient synthesis of highly functionalized and structurally intricate natural products to meet the demand for biological investigations remains a daunting challenge.Molecular editing encompassing insertion,deletion,or exchange of atoms of highly functionalized compounds has emerged as a hotspot in new method development and has been applied in complex natural product synthesis.In this highlight,the latest developments in molecular editing in natural product synthesis are discussed.