Alcohol promotes epithelial mesenchymal transformation-mediated premetastatic niche formation of colorectal cancer by activating interaction between laminin-γ2 and integrin-β1

BACKGROUND Colorectal cancer(CRC) is a common malignant tumor. Alcohol consumption is positively correlated with CRC malignant metastasis;however, the mechanism is unclear. The interaction between laminin-γ2(LAMC2) and integrin-β1(ITGB1) plays a role in premetastatic niche signaling, which may induce epithelial mesenchymal transformation(EMT) and lead to metastasis.AIM To investigate the effects of alcohol on CRC metastasis from the molecular mechanism of the premetastatic niche.METHODS The interaction between LAMC2 and ITGB1 was measured by Duolink assay, and the expression levels of LAMC2, ITGB1 and focal adhesion kinase(FAK), snail, fibronectin, N-cadherin and special AT-rich sequence binding protein 1(SATB1) were measured by quantitative real-time polymerase chain reaction, immunohistochemistry and western blotting. Interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α) and IL-6 levels were measured via enzyme-linked immunosorbent assay, histopathological assessment via hematoxylin eosin staining, and determination of aberrant crypt foci via methylene blue.RESULTS The lymph node metastasis rate was higher in the alcohol group than non-alcohol group. There was a significant increase in interaction signals between LAMC2 and ITGB1, and an increase in phosphorylate-FAK/FAK, snail, fibronectin, N-cadherin and SATB1, whereas E-cadherin was reduced in the alcohol group compared to the non-alcohol group in both animal and clinical samples. Serum IL-1β, TNF-α and IL-6 were higher in alcohol group than in non-alcohol group. Alcohol may promote CRC metastasis by influencing the molecular mechanism of the premetastatic niche.CONCLUSION Our study suggests that alcohol promotes EMT-mediated premetastatic niche formation of CRC by activating the early interaction between LAMC2 and ITGB1 and lead to CRC metastasis.

Cellular and molecular characteristics of the premetastatic niches

The premetastatic niches(PMN)formed by primary tumor-derived molecules regulate distant organs and tissues to further favor tumor colonization.Targeted PMN therapy may prevent tumor metastasis in the early stages,which is becoming increasingly important.At present,there is a lack of in-depth understanding of the cellular and molecular characteristics of the PMN.Here,we summarize current research advances on the cellular and molecular characteristics of the PMN.We emphasize that PMN intervention is a potential therapeutic strategy for early prevention of tumor metastasis,which provides a promising basis for future research and clinical application.

Colorectal cancer and dormant metastases:Put to sleep or destroy?

After reading the review by An et al“Biological factors driving colorectal cancer metastasis”,which covers the problem of the metastasis of colorectal cancer(CRC),I had a desire to discuss with readers one of the exciting problems associated with dormant metastases.Most deaths from CRCs are caused by metastases,which can be detected both at diagnosis of the primary tumor and several years or even decades after treatment.This is because tumor cells that enter the bloodstream can be destroyed by the immune system,cause metastatic growth,or remain dormant for a long time.Dormant tumor cells may not manifest themselves throughout a person’s life or,after some time and under appropriate conditions,may give rise to the growth of metastases.In this editorial,we will discuss the most important features of dormant metastases and the mechanisms of premetastatic niche formation,as well as factors that contribute to the activation of dormant metastases in CRCs.We will pay special attention to the possible mechanisms involved in the formation of circulating tumor cell complexes and the choice of therapeutic strategies that promote the dormancy or destruction of tumor cells in CRCs.

Emerging nanomedicine-based therapeutics for hematogenous metastatic cascade inhibition:Interfering with the crosstalk between “seed and soil”

Despite considerable progresses in cancer treatment,tumor metastasis is still a thorny issue,which leads to majority of cancer-related deaths.In hematogenous metastasis,the concept of"seed and soil"suggests that the crosstalk between cancer cells(seeds)and premetastatic niche(soil)facilitates tumor metastasis.Considerable efforts have been dedicated to inhibit the tumor metastatic cascade,which is a highly complicated process involving various pathways and biological events.Nonetheless,satisfactory therapeutic outcomes are rarely observed,since it is a great challenge to thwart this multi-phase process.Recent advances in nanotechnology-based drug delivery systems have shown great potential in the field of anti-metastasis,especially compared with conventional treatment methods,which are limited by serious side effects and poor efficacy.In this review,we summarized various factors involved in each phase of the metastatic cascade ranging from the metastasis initiation to colonization.Then we reviewed current approaches of targeting these factors to stifle the metastatic cascade,including modulating primary tumor microenvironment,targeting circulating tumor cells,regulating premetastatic niche and eliminating established metastasis.Additionally,we highlighted the multiphase targeted drug delivery systems,which hold a better chance to inhibit metastasis.Besides,we demonstrated the limitation and future perspectives of nanomedicine-based anti-metastasis strategies.

Jiedu recipe,a compound Chinese herbal medicine,suppresses hepatocellular carcinoma metastasis by inhibiting the release of tumor-derived exosomes in a hypoxic microenvironment

Objective:Tumor-derived exosomes(TDEs)play crucial roles in intercellular communication.Hypoxia in the tumor microenvironment enhances secretion of TDEs and accelerates tumor metastasis.Jiedu recipe(JR),a traditional Chinese medicinal formula,has demonstrated efficacy in preventing the metastasis of hepatocellular carcinoma(HCC).However,the underlying mechanism remains largely unknown.Methods:Animal experiments were performed to investigate the metastasis-preventing effects of JR.Bioinformatics analysis and in vitro assays were conducted to explore the potential targets and active components of JR.TDEs were assessed using nanoparticle tracking analysis(NTA)and Western blotting(WB).Exosomes derived from normoxic or hypoxic HCC cells(H-TDEs)were collected to establish premetastatic mouse models.JR was intragastrically administered to evaluate its metastasis-preventive effects.WB and lysosomal staining were performed to investigate the effects of JR on lysosomal function and autophagy.Bioinformatics analysis,WB,NTA,and immunofluorescence staining were used to identify the active components and potential targets of JR.Results:JR effectively inhibited subcutaneous-tumor-promoted lung premetastatic niche development and tumor metastasis.It inhibited the release of exosomes from tumor cells under hypoxic condition.JR treatment promoted both lysosomal acidification and suppressed secretory autophagy,which were dysregulated in hypoxic tumor cells.Quercetin was identified as the active component in JR,and the epidermal growth factor receptor(EGFR)was identified as a potential target.Quercetin inhibited EGFR phosphorylation and promoted the nuclear translocation of transcription factor EB(TFEB).Hypoxia-impaired lysosomal function was restored,and secretory autophagy was alleviated by quercetin treatment.Conclusion:JR suppressed HCC metastasis by inhibiting hypoxia-stimulated exosome release,restoring lysosomal function,and suppressing secretory autophagy.Quercetin acted as a key component of JR and regulated TDE release through EGFR-TFEB signaling.Our study provides a potential strategy for retarding tumor metastasis by targeting H-TDE secretion.