Xenograft and organoid models in developing precision medicine for gastric cancer (Review).

Gastric cancer (GC), a highly heterogeneous disease, has diverse histological and molecular subtypes. For precision medicine, well­characterized models encompassing the full spectrum of subtypes are necessary. Patient­derived tumor xenografts and organoids serve as important preclinical models in GC research. The main advantage of these models is the retention of phenotypic and genotypic heterogeneity present in parental tumor tissues. Utilizing diverse sequencing techniques and preclinical models for GC research facilitates accuracy in predicting personalized clinical responses to anti­cancer treatments. The present review summarizes the latest advances of these two preclinical models in GC treatment and drug response assessment.

Role of heat shock protein 70 in silibinin-induced apoptosis in bladder cancer.

Hsp70 (heat shock protein 70) plays critical roles in cancer cell proliferation and apoptosis. Recently, accumulating evidences have demonstrated the cancer promoting effects of Hsp70 in bladder cancer. The development of novel therapeutic approaches targeting Hsp70 thus received great attention from researchers. In this study, we demonstrated that silibinin, a natural polyphenolic flavonoid isolated from the milk thistle, targeted Hsp70 by inhibiting its transcription in bladder cancer cells. We also demonstrated that knockdown of endogenous Hsp70 enhanced silibinin-induced apoptosis, while overexpression of exogenous Hsp70 could partially reverse the effects of silibinin-induced cell apoptosis. Furthermore, we found that silibinin could activate HSF1/Hsp70-regulated mitochondrial apoptotic pathway. Mechanically, silibinin inhibited the interaction between Apaf-1 and Hsp70, thus increasing the recruitment of pro caspase-9. Results from in vivo study demonstrated that silibinin suppressed the growth of bladder cancer xenografts, which was accompanied with the activation of caspase-3 and downregulation of HSF1 and Hsp70. Taken together, our data indicates that silibinin induces mitochondrial apoptosis via inhibiting HSF1/Hsp70 pathway and also suggests the therapeutic potential of silibinin in the treatment of bladder cancer.

Gastric cancer patient-derived organoids model for the therapeutic drug screening.

BACKGROUND: Gastric cancer (GC) is a highly heterogeneous disease featuring many various histological and molecular subtypes. Therefore, it is imperative to have well-characterized in vitro models for personalized treatment development. Gastric cancer patient-derived organoids (PDOs), re-capitulating in vivo conditions, exhibit high clinical efficacy in predicting drug sensitivity to facilitate the development of cancer precision medicine. METHODS: PDOs were established from surgically resected GC tumor tissues. Histological and molecular characterization of PDOs and primary tissues were performed via IHC and sequencing analysis. We also conducted drug sensitivity tests using PDO cultures with five chemotherapeutic drugs and twenty-two targeted drugs. RESULTS: We have successfully constructed a PDOs biobank that included EBV+, intestinal/CIN, diffuse/GS, mixed and Her2+ GC subtypes, and these PDOs captured the pathological and genetic characteristics of corresponding tumors and exhibited different sensitivities to the tested agents. In a clinical case study, we performed an additional drug sensitivity test for a patient who reached an advanced progressive stage after surgery. We discovered that the combination of napabucasin and COTI-2 exhibited a stronger synergistic effect than either drug alone. CONCLUSION: PDOs maintained the histological and genetic characteristics of original cancer tissues. PDOs biobank opens up new perspectives for studying cancer cell biology and personalized medicine as a preclinical study platform.

ß-Ionone represses renal cell carcinoma progression through activating LKB1/AMPK-triggered autophagy.

ß-Ionone, the end ring analog of ß-carotenoids, has been proven to have an antitumor effect in a variety of cancers. In this study, we investigated the impact of ß-ionone on renal cell carcinoma (RCC) cell lines (786-O and ACHN) using colony formation assays, flow cytometry analysis, and western blot analysis. We found that ß-ionone effectively inhibited the proliferation of RCC cells in vitro, which was also confirmed in a xenograft model. Moreover, we found that ß-ionone could induce autophagy, as indicated by LC3 puncta in 786-O and ACHN cell lines and the expression of LC3 in ß-ionone-treated RCC cells. To further explore the underlying mechanism, we assessed liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) signaling pathway activity, and the results showed that ß-ionone inhibited the proliferation of RCC cells by inducing autophagy via the LKB1/AMPK signaling pathway. In summary, our findings provide a new therapeutic strategy of ß-ionone-induced autophagy in RCC.

Silibinin inhibits the migration, invasion and epithelial-mesenchymal transition of prostate cancer by activating the autophagic degradation of YAP.

Silibinin (SB), a flavonoid extracted from milk thistle seeds, has been found to exert antitumor effects in numerous tumor types. Our previous study reported that SB had anti-metastatic effects in prostate cancer (PCa). However, the exact underlying molecular mechanisms remain to be determined. The present study aimed to investigate the effects of SB on the migration, invasion and epithelial-mesenchymal transition (EMT) of castration-resistant PCa (CRPC) cells using wound healing, Transwell assays, and western blotting. The results revealed that SB treatment significantly inhibited the migration and invasion of CRPC cell lines. Moreover, SB was confirmed to activate autophagy, as determined using LC3 conversion, LC3 turnover and LC3 puncta assays. Further mechanistic studies indicated that the expression levels of Yes-associated protein (YAP) were downregulated in an autophagy-dependent manner after SB treatment. In addition, the SB-induced autophagic degradation of YAP was associated with the anti-metastatic effects of SB in CRPC. In conclusion, the findings of the present study suggested that SB might inhibit the migration, invasion and EMT of PCa cells by regulating the autophagic degradation of YAP, thus representing a potential novel treatment strategy for metastatic CRPC.

Exploration of the pathogenic factors of neonatal jaundice and the clinical effect of blue phototherapy.

OBJECTIVE: To study the pathogenic factors of neonatal jaundice and the clinical effect of blue light phototherapy. METHODS: We selected 240 children with neonatal jaundice admitted to our hospital from January 2018 to January 2019 as the research subjects, and divided them into a control group and experimental group by a random grouping method, with 120 cases in each group. The control group received conventional treatment, and the experimental group received blue phototherapy. We observed the therapeutic effect on the two groups and analyzed the onset factors, compared the transcutaneous bilirubin value, serum bilirubin level, the time for the jaundice to subside after treatment, lactate dehydrogenase (LDH), creatine kinase (CK) in the myocardial enzyme spectrum, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) to show liver function. RESULTS: Rate of effective treatment in the experimental group was higher than that in the control group. The transcutaneous bilirubin values and serum bilirubin levels of the two groups of children with jaundice were reduced after treatment (P<0.001), and the decrease in the experimental group after treatment was more notable (P<0.001). Jaundice subsided after treatment in the experimental group faster than in the control group (P<0.001). Children with jaundice in the experimental group had lower indexes of LDH, CK, ALT and AST compared with those of the control group (P<0.05). CONCLUSION: Phototherapy is a preferable method for neonatal jaundice and worthy of clinical application.