Kosuke Hiramatsu

The value of vaginal cytology for postoperative surveillance of endometrial cancer

The value of conducting vaginal cytology surveillance after endometrial cancer (EC) surgery has not been fully established, yet in Japan it is still performed routinely in many institutions. We have retrospectively examined its diagnostic and prognostic values. We studied 759 EC cases that underwent hysterectomy at our hospital in Osaka, Japan from January 2010 to December 2019. Information on the clinicopathological factors at the time of initial and postoperative treatments, and the sites and diagnostic timing of recurrences were extracted from medical records and analyzed. Recurrences from primary EC were observed in 11.2% of the patients (85/759). In 23.5% of the cases (20/85), the recurrence included a vaginal component. The two most common single-sites of recurrence were vagina (14.1%, 12/85) and lung (12.9%, 11/85). The diagnosis of vaginal recurrence was made from symptoms and gynecological examination in 14 of the 20 cases. Only one was diagnosed solely by vaginal cytology; in that case, macroscopic lesions appeared two months after obtaining the abnormal cytology. We found that, in postoperative follow-up surveillance for EC, most cases of vaginal recurrence were first diagnosed by a careful pelvic examination. For current routine postoperative practice, monitoring critical symptoms and conducting careful gynecological examinations has been shown to be more important than cytological examinations.

Anti-lipolysis-stimulated lipoprotein receptor monoclonal antibody as a novel therapeutic agent for endometrial cancer

Abstract Background Endometrial cancer (EC) is a common gynecologic malignancy and patients with advanced and recurrent EC have a poor prognosis. Although chemotherapy is administered for those patients, the efficacy of current chemotherapy is limited. Therefore, it is necessary to develop novel therapeutic agents for EC. In this study, we focused on lipolysis-stimulated lipoprotein receptor (LSR), a membrane protein highly expressed in EC cells, and developed a chimeric chicken–mouse anti-LSR monoclonal antibody (mAb). This study investigated the antitumor effect of an anti-LSR mAb and the function of LSR in EC. Methods We examined the expression of LSR in 228 patients with EC using immunohistochemistry and divided them into two groups: high-LSR (n = 153) and low-LSR groups (n = 75). We developed a novel anti-LSR mAb and assessed its antitumor activity in an EC cell xenograft mouse model. Pathway enrichment analysis was performed using protein expression data of EC samples. LSR-knockdown EC cell lines (HEC1 and HEC116) were generated by transfected with small interfering RNA and used for assays in vitro. Results High expression of LSR was associated with poor overall survival (hazard ratio: 3.53, 95% confidence interval: 1.35–9.24, p = 0.01), advanced stage disease (p = 0.045), deep myometrial invasion (p = 0.045), and distant metastasis (p < 0.01). In EC with deep myometrial invasion, matrix metalloproteinase (MMP) 2 was highly expressed along with LSR. Anti-LSR mAb significantly inhibited the tumor growth in EC cell xenograft mouse model (tumor volume, 407.1 mm3versus 726.3 mm3, p = 0.019). Pathway enrichment analysis identified the mitogen-activated protein kinase (MAPK) pathway as a signaling pathway associated with LSR expression. Anti-LSR mAb suppressed the activity of MAPK in vivo. In vitro assays using EC cell lines demonstrated that LSR regulated cell proliferation, invasion, and migration through MAPK signaling, particularly MEK/ERK signaling and membrane-type 1 MMP (MT1-MMP) and MMP2. Moreover, ERK1/2-knockdown suppressed cell proliferation, invasion, migration, and the expression of MT1-MMP and MMP2. Conclusions Our results suggest that LSR contributes to tumor growth, invasion, metastasis, and poor prognosis of EC through MAPK signaling. Anti-LSR mAb is a potential therapeutic agent for EC.

VRK1 Is a Novel Therapeutic Target for Small Cell Neuroendocrine Carcinoma of the Cervix

ABSTRACT Small cell neuroendocrine carcinoma of the cervix (SCNEC) is classified as a high‐grade neuroendocrine carcinoma with a worse prognosis than other major histological types of cervical cancer. Identifying novel therapeutic targets based on its molecular characteristics is highly desirable but challenging due to the rarity of SCNEC and the resulting lack of research resources. In this study, we identified vaccinia‐related kinase 1 (VRK1) as a potential therapeutic target for SCNEC. VRK1 was prioritized based on our previously reported proteomic analysis of patient‐derived organoids. Immunohistochemistry of patient samples consistently revealed high VRK1 expression in SCNEC, as opposed to its variable expression in other cervical carcinomas. Although VRK1 knockdown in SCNEC had only a limited effect on cell proliferation in two‐dimensional cultures, it significantly suppressed cell proliferation in three‐dimensional cultures and inhibited xenograft tumor growth in vivo. Gene set enrichment analysis of RNA‐sequencing data from mouse xenograft models demonstrated that VRK1 is associated with mitochondrial‐related pathways. Furthermore, under oxidative stress conditions, VRK1 knockdown resulted in a reduction of mitochondrial membrane potential, an indicator of mitochondrial integrity, and decreased expression of cytochrome c oxidase subunit IV (COX IV), a nuclear‐encoded subunit of cytochrome c oxidase, the terminal enzyme complex of the mitochondrial respiratory chain. These findings suggest that VRK1 knockdown indirectly impaired mitochondrial function. Collectively, these anti‐tumor effects highlight VRK1 as a promising therapeutic target for SCNEC.