Enhanced tumor targeting and timely viral release of mesenchymal stem cells/oncolytic virus complex due to GRP78 and inducible E1B55K expressions greatly increase the antitumor effect of systemic treatment.

Systemic delivery of oncolytic viruses has been widely regarded as an impractical option for antitumor treatment. Here, we selected two target genes as leading components, and significant therapeutic effects were obtained by simultaneously reducing the expression of transforming growth factor ß 1 (TGF-ß1) and heat shock protein 27 (HSP27) in various cancer cell types. Downregulation of HSP27 reduced the cellular levels of tumor progression-related proteins, and the simultaneous downregulation of HSP27 and TGF-ß1 increased tumor cell death beyond that observed with TGF-ß1 downregulation alone. To increase the potential for systemic administration, we generated modified mesenchymal stem cells (MSCs) to act as oncolytic adenovirus factories and carriers and assessed bioavailability in tumors after MSC injection. The MSCs were modified to express 78-kDa glucose-regulated protein (GRP78) and adenovirus early-region 1B 55 kDa (E1B55K). The tightly controlled inducible system permitted selective timing of viral release from carrier MSCs within the tumor. This approach significantly improved viral production, tumor targeting, timely viral release at the tumor site, and antitumor efficacy of the oncolytic adenovirus. These combined results demonstrate that engineered MSCs can significantly enhance the antitumor effects of oncolytic viruses without adverse safety issues, which may greatly extend the clinical applicability of oncolytic adenoviruses.

Enhanced oncolytic adenoviral production by downregulation of death-domain associated protein and overexpression of precursor terminal protein.

Adequate viral replication in tumor cells is the key to improving the anti-cancer effects of oncolytic adenovirus therapy. In this study, we introduced short hairpin RNAs against death-domain associated protein (Daxx), a repressor of adenoviral replication, and precursor terminal protein (pTP), an initiator of adenoviral genome replication, into adenoviral constructs to determine their contributions to viral replication. Both Daxx downregulation and pTP overexpression increased viral production in variety of human cancer cell lines, and the enhanced production of virus progeny resulted in more cell lysis in vitro, and tumor regression in vivo. We confirmed that increased virus production by Daxx silencing, or pTP overexpression, occurred using different mechanisms by analyzing levels of adenoviral protein expression and virus production. Specifically, Daxx downregulation promoted both virus replication and oncolysis in a consecutive manner by optimizing IVa2-based packaging efficiency, while pTP overexpression by increasing both infectious and total virus particles but their contribution to increased viral production may have been damaged to some extent by their another contribution to apoptosis and autophagy. Therefore, introducing both Daxx shRNA and pTP in virotherapy may be a suitable strategy to increase apoptotic tumor-cell death and to overcome poor viral replication, leading to meaningful reductions in tumor growth in vivo.

High levels of Daxx due to low cellular levels of HSP25 in murine cancer cells result in inefficient adenovirus replication.

When the adenoviral protein E1B55K binds death domain-associated protein (Daxx), the proteasome-dependent degradation of Daxx is initiated, and adenoviral replication is effectively maintained. Here, we show that the cellular levels of Daxx differ between human and mouse cancer cell lines. Specifically, we observed higher cellular Daxx levels and the diminished replication of oncolytic adenovirus in mouse cancer cell lines, suggesting that cellular Daxx levels limit the replication of oncolytic adenoviruses that lack E1B55K in murine cells. Indeed, the replication of oncolytic adenoviruses that lack E1B55K was significantly increased following infection with oncolytic adenovirus expressing Daxx-specific shRNA. Cellular Daxx levels were decreased in mouse cells expressing heat shock protein 25 (HSP25; homolog of human HSP27) following heat shock or stable transfection with HSP25-bearing plasmids. Furthermore, Daxx expression in murine cell lines was primarily regulated at the transcriptional level via HSP25-mediated inhibition of the nuclear translocation of the signal transducer and activator of transcription 3 (stat3) protein, which typically upregulates Daxx transcription. Conversely, human HSP27 enhanced stat3 activity to increase Daxx transcription. Interestingly, human Daxx, but not mouse Daxx, was degraded as normal by ubiquitin-dependent lysosomal degradation; however, HSP27 downregulation induced the ubiquitin-independent proteasomal degradation of Daxx.

A case report of angioleiomyoma of uterus.

Angioleiomyoma (AL) is a very rare benign tumor that originates from smooth muscle cells and has thick walled vessels. It may be found throughout the body but more frequently occurs in the lower extremities and rarely develops in the head and other parts of the body. This paper presents a case report of giant AL detected in a 33-year-old woman who complained of severe anemia, menorrhagia, and palpable lower abdominal mass. The patient underwent myomectomy and was diagnosed with AL based on the pathological report of mass. The effective treatment for AL is either simple hysterectomy or angiomyomectomy depending on the patient's desire to preserve fertility and symptom.

Uterine Serous Adenocarcinoma in an Elderly Postmenopausal Woman: Clinically Misdiagnosed as Uterine Cervix Cancer.

Uterine serous adenocarcinoma (USC) is rare and invasive cancer. This cancer is more often reported in the ovary, the fallopian tube, and the endometrium than uterine cervix. No matter where the tumor is located, the tumor exhibits similar histological characteristics. So when uterine cancer is proven to be serous adenocarcinoma, it is necessary to see if the tumor originated from ovary or endometrium and invaded the cervix. We report a case of a 73-year-old postmenopausal woman with USC arising near the internal os of endocervical canal, clinically misdiagnosed as uterine cervix cancer.

Sclerosing stromal tumor in an elderly postmenopausal woman.

Sclerosing stromal tumor (SST) of the ovary is a rare tumor derived from the sex cord stroma. This tumor was first described by Chalvaridjian and Scully in 1973. SST of the ovary is prevalence of 1.5% to 6% of ovarian stromal tumors. Patients are most commonly diagnosed in their 20s and 30s. There have been reports of SST postmenopausal women aged 65-, 67-, and 71 in the Republic of Korea; however, no report of this disease has been reported in women older than 80. In this study, we would like to report an 80-year-old postmenopausal woman who did not previously complain of any symptoms, and was finally diagnosed with SST. She was involved in a traffic accident, and huge pelvic mass was found during the evaluation of intra-abdominal hemorrhage. Total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed ; a final pathologic diagnosis reported SST.