COMBINED EFFECTS OF METRONOMIC ZOLEDRONATE WITH CORIOLUS VERSICOLOR IN A METASTATIC BREAST TUMOR MOUSE MODEL

Incidence of breast cancer is high in women worldwide and mortality usually results from tumor metastasis.Adjuvant chemotherapeutic,such as zoledronate(ZOL),has been used in metastatic breast cancer mainly for skeletal protection.Our previous studies demonstrated that Coriolus versicolor(CV)aqueous extract exhibited anti-tumor

Rescue of p53 functions by in vitro-transcribed mRNA impedes the growth of high-grade serous ovarian cancer

Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human cancers.Among various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits the high-est prevalence of TP53 mutations,present in>96%of cases.Despite intensive efforts to reactivate p53,no clinical drug has been approved to rescue p53 func-tion.In this study,our primary objective was to administer in vitro-transcribed(IVT)wild-type(WT)p53-mRNA to HGSOC cell lines,primary cells,and ortho-topic mouse models,with the aim of exploring its impact on inhibiting tumor growth and dissemination,both in vitro and in vivo.Methods:To restore the activity of p53,WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector system.Moreover,IVT WT p53 mRNA was delivered into different HGSOC model systems(primary cells and patient-derived organoids)using liposomes and studied for proliferation,cell cycle progression,apoptosis,colony formation,and chromosomal instabil-ity.Transcriptomic alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells,followed by ingenuity path-way analysis.In vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse models.Results:Reactivation of the TP53 tumor suppressor gene was explored in differ-ent HGSOC model systems using newly designed IVT mRNA-based methods.The introduction of WT p53 mRNA triggered dose-dependent apoptosis,cell cycle arrest,and potent long-lasting inhibition of HGSOC cell proliferation.Transcriptome analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling,such as apoptosis,cell cycle regulation,and DNA damage.Restoring p53 function concurrently reduces chromosomal instability within the HGSOC cells,under-scoring its crucial contribution in safeguarding genomic integrity by moderating the baseline occurrence of double-strand breaks arising from replication stress.Furthermore,in various mouse models,treatment with p53 mRNA reduced tumor growth and inhibited tumor cell dissemination in the peritoneal cavity in a dose-dependent manner.Conclusions:The IVT mRNA-based reactivation of p53 holds promise as a potential therapeutic strategy for HGSOC,providing valuable insights into the molecular mechanisms underlying p53 function and its relevance in ovarian cancer treatment.

Surgical treatment of hepatocellular carcinoma and related basic research with special reference to recurrence and metastasis

To summarize the progress of surgical treatment of hepatocellular carcinoma (HCC) and related basic research at the Liver Cancer Institute of Shanghai Medical University in the recent years, with special reference to recurrence and metastasis Methods Published and unpublished update clinical and experimental data in the above mentioned areas are summarized Results Surgical resection has played an important role in improving prognosis of HCC, the 5 year survival were 63 4% for small HCC resection (n=806), 39 6% for large HCC resection (n=1061), 64 7% for cytoreduction (using hepatic artery cannulation and ligation) and sequential resection of initially unresectable HCC (n=93), 56 0% for cytoreduction using transcatheter arterial chemoembolization (TACE) and followed by resection (n=65), and 22 4% for hepatic resection with removal of tumor thrombi in portal vein (n=103) Unfortunately, the 5 year recurrent rate after curative resection of HCC was up to 61 5%, which was mainly a result of intrahepatic “metastasis” and multicentric origin of HCC Clinically, re resection of subclinical recurrence yielded 56% of 5 year survival (n=202); prevention of recurrence by transcatheter arterial chemoembolization (TACE)+Interferon, or LAK/IL 2 therapy have decreased 3 year recurrent rate from 33% to 11%-18% In experimental aspect, metastatic human HCC model in nude mice (LCI D20) and HCC cell line with metastatic potential (MHCC97) have been established; studies on HCC invasiveness in the molecular level revealed similar results that reported in other solid cancers, and small HCC showed slightly better biological characteristics as compared with large HCC; microvessel density (MVD) that reflecting angiogenesis adversely correlated with 5 year survival of small HCC; experimental interventions using antisense H ras, bispecific antibody, BB94, as well as anti angiogenic agents (TNP470, suramin, CAI, heparin, antisense VEGF, etc ) have been demonstrated to inhibit tumor growth and lung metastasis in nude mice model Conclusions Recurrence and metastasis are the major obstacle to further improve prognosis of HCC, studies should be conducted both in clinical and experimental aspects, “HCC invasiveness” will be the major target to be studied, particularly in the molecular level, and anti angiogenesis will be one of the important approach