Koshiro Obata

Common genetic changes between endometriosis and ovarian cancer.

We analyzed 81 ovarian cancers for loss of heterozygosity (LOH) on 10q23 and for mutations in PTEN. LOH was common among the endometrioid (43%) and serous (28%) cancers, but was infrequent among the other histological subtypes. Somatic PTEN mutations were detected in seven (21%) endometrioid cancers and the mutation in all informative cases was accompanied by loss of the wild-type allele. One mucinous cancer without 10q23 LOH was shown to harbor two somatic PTEN mutations. Frequent LOH was observed on chromosome 6q (60.0%) and chromosome 10q (40.0%) in ovarian atypical endometriosis, but no PTEN mutations were observed. These findings support the hypothesis that endometrioid and clear cell ovarian carcinomas may arise through malignant transformation of endometriotic lesions.

Clinicopathologic and immunohistochemical features and microsatellite status of endometrial cancer of the uterine isthmus.

To clarify the clinicopathologic, molecular, and immunohistochemical characteristics of uterine isthmic endometrial cancer (UIE), we examined 13 cases of UIE and compared them with 33 cases of endometrial cancer of the uterine corpus (UCE) with respect to clinicopathologic factors, the expression of p53, the estrogen receptor (ER) and the progesterone receptor (PR) status, DNA ploidy, and microsatellite instability (MSI). Five (38.4%) of the UIE patients had stage I, two (15.4%) had stage II, and six (46.2%) had stage III disease (FIGO 1988). Myometrial invasion was confirmed in 92.3% of the UIE patients, and these patients had a higher (p<0.05) frequency of >50% myometrial invasion (46.2%) than the patients with UCE (15.2%). Moreover, the UIE patients had a higher frequency of positive peritoneal cytology (p<0.05) and pelvic lymph node metastases (p<0.05). No UIE tumors exhibited MSI, and the tumors in these patients had a higher expression of p53 (p<0.01), a lower expression of ER (p<0.05) and PR (p<0.05), and a higher frequency of DNA aneuploidy (p<0.01) than the UCE tumors. These findings suggest that the UIE is clearly different from UCE in the clinicopathologic, immunohistochemical features, and microsatellite status.

Clear cell adenocarcinoma arising from umbilical endometriosis.

Umbilical endometriosis is a very rare condition, and as far as we are aware, there have been no reported cases of its malignant transformation. Here, we report a case of clear cell adenocarcinoma arising from umbilical endometriosis in a 60‐year‐old woman who underwent hysterectomy for a uterine myoma at the age of 38, and who denied cyclic bleeding at the site of an umbilical cutaneous nodule correlating with menses until the age of 48. An umbilical tumor (3 cm diameter) was identified by magnetic resonance imaging and an abnormal accumulation was found only at the umbilical lesion by positron emission tomography examination. We observed endometriosis adjacent to the clear cell adenocarcinoma and transformation to carcinoma from endometriosis at the umbilical lesion histopathologically. Clear cell adenocarcinoma of the umbilicus was thought to have arisen from endometriosis; it expressed HER‐2 protein and showed strong mesothelial characteristics immunohistochemically.

Erythropoietin Receptor Antagonist Suppressed Ectopic Hemoglobin Synthesis in Xenografts of HeLa Cells to Promote Their Destruction

The aim of this study is to explore a cause-oriented therapy for patients with uterine cervical cancer that expresses erythropoietin (Epo) and its receptor (EpoR). Epo, by binding to EpoR, stimulates the proliferation and differentiation of erythroid progenitor cells into hemoglobin-containing red blood cells. In this study, we report that the HeLa cells in the xenografts expressed ε, γ, and α globins as well as myoglobin (Mb) to produce tetrameric α2ε2 and α2γ2 and monomeric Mb, most of which were significantly suppressed with an EpoR antagonist EMP9. Western blotting revealed that the EMP9 treatment inhibited the AKT-pAKT, MAPKs-pMAPKs, and STAT5-pSTAT5 signaling pathways. Moreover, the treatment induced apoptosis and suppression of the growth and inhibited the survival through disruption of the harmonized hemoprotein syntheses in the tumor cells concomitant with destruction of vascular nets in the xenografts. Furthermore, macrophages and natural killer (NK) cells with intense HIF-1α expression recruited significantly more in the degenerating foci of the xenografts. These findings were associated with the enhanced expressions of nNOS in the tumor cells and iNOS in macrophages and NK cells in the tumor sites. The treated tumor cells exhibited a substantial number of perforations on the cell surface, which indicates that the tumors were damaged by both the nNOS-induced nitric oxide (NO) production in the tumor cells as well as the iNOS-induced NO production in the innate immune cells. Taken together, these data suggest that HeLa cells constitutively acquire ε, γ and Mb synthetic capacity for their survival. Therefore, EMP9 treatment might be a cause-oriented and effective therapy for patients with squamous cell carcinoma of the uterine cervix.

Immunohistochemical Studies concerning Cathepsin D in Endometrial Carcinomas

Objectives: To study the prognostic value of immunohistochemical detection of cathepsin D and laminin in endometrial carcinomas.

Mutational analysis of the estrogen receptor-α gene in familial ovarian cancer

Aim: The genetic region of 6q25 containing the estrogen receptor‐α (ER‐α) gene is lost in a significant number of ovarian tumors. The aim of this study was to identify how inherited variation in the ER‐α gene contributes to susceptibility to familial ovarian cancer.