Kenzo Kosaka

PD-L1 on Tumor Cells Is Induced in Ascites and Promotes Peritoneal Dissemination of Ovarian Cancer through CTL Dysfunction

Purpose: Ovarian cancer often progresses by disseminating to the peritoneal cavity, but how the tumor cells evade host immunity during this process is poorly understood. Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be expressed in cancer cells. The purpose of this study is to elucidate the function of PD-L1 in peritoneal dissemination. Experimental Design: Ovarian cancer cases were studied by microarray and immunohistochemistry. PD-L1 expression in mouse ovarian cancer cell line in various conditions was assessed by flow cytometry. PD-L1–overexpression cell line and PD-L1–depleted cell line were generated, and cytolysis by CTLs was analyzed, and alterations in CTLs were studied by means of timelapse and microarray. These cell lines were injected intraperitoneally to syngeneic immunocompetent mice. Results: Microarray and immunohistochemistry in human ovarian cancer revealed significant correlation between PD-L1 expression and peritoneal positive cytology. PD-L1 expression in mouse ovarian cancer cells was induced upon encountering lymphocytes in the course of peritoneal spread in vivo and coculture with lymphocytes in vitro. Tumor cell lysis by CTLs was attenuated when PD-L1 was overexpressed and promoted when it was silenced. PD-L1 overexpression inhibited gathering and degranulation of CTLs. Gene expression profile of CTLs caused by PD-L1–overexpressing ovarian cancer was associated with CTLs exhaustion. In mouse models, PD-L1 depletion resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. Conclusion: PD-L1 expression in tumor cell promotes peritoneal dissemination by repressing CTL function. PD-L1–targeted therapy is a promising strategy for preventing and treating peritoneal dissemination. Clin Cancer Res; 19(6); 1363–74. ©2012 AACR.

Uterine peristalsis: comparison of transvaginal ultrasound and two different sequences of cine MR imaging.

To compare uterine peristalsis as seen on two different magnetic resonance (MR) imaging sequences and transvaginal ultrasound (TVUS), so as to better determine the best method for evaluating uterine peristalsis.

The comprehensive assessment of local immune status of ovarian cancer by the clustering of multiple immune factors

The aim of this study was to evaluate the local immune status of human ovarian cancers by the comprehensive analysis of tumor-infiltrating immune cells and immunosuppressive factors, and to elucidate the local immunity in clinical course. The numbers of CD1α+, CD4+, CD8+, CD57+, forkhead box P3+ and programmed cell death-1+ cells were counted, and the intensity of immunosuppressive factors, such as programmed cell death-1 ligand (PD-L)1, PD-L2, cyclooxygenase (COX)-1, COX-2 and transforming growth factor β1, were evaluated in 70 ovarian cancer specimens stained by immunohistochemistry. Then hierarchical clustering of these parameters showed the four clusters into ovarian cancer cases. Cluster 1, which had significantly better prognosis than the others, was characterized by high infiltration of CD4+ and CD8+ cells. In conclusion the comprehensive analysis of local immune status led to subdivide ovarian cancers into groups with better or worse prognoses and may guide precise understanding of the local immunity.

Eph-ephrin A system regulates murine blastocyst attachment and spreading.

Although numerous adhesion molecules are expressed on mammalian endometrial epithelial cells, there have not been any studies of a mechanism to prevent premature attachment of the embryo. In this study, we examined the possible involvement of Eph–ephrin interaction, which can induce repulsive forces. In mice, Eph A1, A2, and A4 were expressed on endometrial epithelial cells and ephrin A1–4 on blastocysts. Reverse transcriptase‐polymerase chain reaction showed that mRNA expression of ephrin A1–4 on embryos transiently decreased around the implantation period. Immunohistochemistry demonstrated that the expression of Eph A1 on endometrial epithelial cells and ephrin A1 and A3 expression on embryos decreased at implantation sites. Recombinant Eph A1 reacted with cell the surface of ephrin A‐bearing trophectoderm cells. Attachment assays using Eph A1‐coated dishes showed that blastocyst attachment was reversibly inhibited by Eph A1. These findings suggest an important role of the Eph–ephrin A system in regulating the initial embryo–maternal contact during the cross‐talk period that precedes embryo implantation. Developmental Dynamics 235:3250–3258, 2006.

Hepatocyte nuclear factor-1β (HNF-1β) promotes glucose uptake and glycolytic activity in ovarian clear cell carcinoma

Ovarian clear cell carcinoma (OCCC) is a morphologically and biologically distinct subtype of ovarian carcinomas that often arises in ovarian endometriosis. We previously reported that a unique carcinogenic environment, especially iron‐induced oxidative stress in endometriotic cysts may promote development of OCCC. We also identified a gene expression profile characteristic of OCCC (the “OCCC signature”). This 320‐gene OCCC signature is enriched in genes associated with stress response and sugar metabolism. However, the biological implication of this profile is unclear. In this study, we have focused on the biological role of the HNF‐1β gene within the OCCC signature, which was previously shown to be overexpressed in OCCC. Suppression of HNF‐1β in the HNF‐1β‐overexpressing human ovarian cancer cell line RMG2 using short hairpin RNA resulted in a significant increase in proliferation. It also facilitated glucose uptake, glycolytic activity, and lactate secretion along with increased expression of the glucose transporter‐1 (GLUT‐1) gene and several key enzymes in the glycolytic process. Conversely, forced expression of HNF‐1β in the serous ovarian cancer cell line, Hey, resulted in slowed cellular growth and repressed glycolytic activity. These data suggest that HNF‐1β represses cell growth, and at the same time, it promotes aerobic glycolysis which is known as the “Warburg effect.” As the Warburg effect is regarded as a characteristic metabolic process in cancer which may contribute to cell survival under hypoxic conditions or in a stressful environment, overexpression of HNF‐1β may play an inevitable role in the occurrence of OCCC in stressful environment.

Spontaneous regression of congenital cystic adenomatoid malformation of the lung: Longitudinal examinations by magnetic resonance imaging

ABSTRACT  We report a case of large cystic adenomatoid malformation of the lung (CCAM), which occupied almost the entire left lung with a prominent mediastinal shift at 24 weeks of gestation. The volume of the lesion, determined by magnetic resonance imaging (MRI), was 27.0 cm3. Subsequent MRI and ultrasound examinations revealed a spontaneous resolution of the lesion at 32 and 36 weeks of gestation without a mediastinal shift, when the lesion volume was 12.8 cm3 and 5.6 cm3, respectively. At 37 weeks of gestation, a mature male baby weighing 2638 g with an Apgar score of 7 was delivered by elective cesarean section. A lobectomy of the left upper lobe of the lung was carried out at 3 days of age, due to an enlargement of the CCAM after birth.

New regulatory mechanisms for human extravillous trophoblast invasion

Human extravillous trophoblasts (EVT) invade maternal deciduas and reconstructed maternal spiral arteries during early placentation. However, the precise regulatory mechanisms to induce EVT invasion toward arteries and/or to protect EVT from further invasion have not been well understood. Recently, it was found that EVT that had already ceased their invasion, specifically expressed cluster of differentiation (CD9) and dipeptidyl peptidase IV (DPPIV) on their cell surface. In addition, EVT migrating to maternal spiral arteries expressed CC chemokine receptor type-1 (CCR-1), which is a chemokine receptor for regulated on activation normal T cell expressed and secreted (RANTES) and so on. CD9 is associated with integrin molecules on the cell surface and is considered to modulate integrin function. In contrast, DPPIV is a cell surface peptidase that can metabolize RANTES at extracellular sites before its accessing to the chemokine receptors. In vitro functional assay showed that CD9, DPPIV and RANTES are involved in the regulation for EVT invasion. From these findings, it can be proposed that CD9 and DPPIV, including chemokines, are new regulatory factors for human extravillous trophoblasts.

Adenoid cystic carcinoma of skene glands: a rare origin in the female genital tract and the characteristic clinical course.

Adenoid cystic carcinoma (ACC) is a relatively uncommon malignancy that most frequently arises in the salivary glands. In the genital tract, approximately 60 cases of ACC that originated from Bartholin glands have been reported to date. In this report, we describe a case of ACC that arose from Skene glands, a very rare origin for this disease. In this patient, the disease had an indolent clinical course, with few symptoms other than localized pain. During the surgical operation, the tumor was found to have invaded more extensively than had been estimated preoperatively, and it required pelvic exenteration with radical vulvectomy. Although the precise preoperative assessment and the preparation for an extended operation are difficult, they are necessary for the successful treatment of this rare disease.

Clinical Management of Ovarian Endometriotic Cyst (Chocolate Cyst): Diagnosis, Medical Treatment, and Minimally Invasive Surgery

In the clinical management of endometriotic cyst, three major clinical disruptions need to be addressed adequately: pain, infertility, and malignant transformation. Symptoms differ according to the patient’s age and her life stage, and they should be managed individually. This review discusses the role of medical treatment with currently available drug regimens as well as surgical interventions for endometriotic cyst in terms of each symptom. Endometriosis-associated ovarian cancer is an important issue in the management of endometriosis in relatively elderly women, although it is not yet widely recognized. The need for standard management of these patients is also discussed.

Cancer risk and management in a woman with Peutz-Jeghers syndrome

Peutz-Jeghers syndrome (PJS) is known to cause an elevated risk of cancer development. We present the case of a 41-year-old Japanese woman with PJS who had various lesions in the abdominal and pelvic organs. The preoperative diagnosis was a right ovarian tumor suspected to be a mucinous borderline tumor, a uterine cervical lesion suspected to be lobular endocervical glandular hyperplasia (LEGH), gastrointestinal hamartomatous polyps, and intestinal invagination. She underwent hysterectomy, right salpingo-oophorectomy, left salpingectomy, and partial resection of the jejunum. The pathological diagnosis was an endometriotic cyst of the right ovary, atypical LEGH of the cervix, gastric metaplasia of the fallopian tube, intestinal hamartomatous polyps, and adenocarcinoma in a polyp of the jejunum. This case is representative for women with PJS who may develop multifocal malignancies positively based on the germline mutation of the LKB1/STK11 gene. The cancer risk, surveillance guidelines, and management for women with PJS were discussed in this case conference.