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.

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.

Mutational analysis of TP53 and p21 in familial and sporadic ovarian cancer in Japan.

OBJECTIVE: To investigate whether somatic mutations in cell cycle checkpoint genes, TP53 and p21, are involved in the development of ovarian cancer with or without BRCA1 germline mutation. METHODS: We analyzed somatic genetic alterations of TP53 and p21 in 46 ovarian cancer patients with BRCA1 germline mutations and 93 sporadic patients, using direct sequencing for the entire coding sequences in TP53 and p21. RESULTS: TP53 somatic mutations were detected in 25 of the 46 BRCA1 cases and 40 of the 93 sporadic cases (54.3% vs. 43.0%). In contrast, p21 somatic mutations were detected in 1 of the 46 BRCA1 cases and 2 of the 93 sporadic cases (2.2% vs. 2.2%). TP53 mutations in sporadic cases more frequently occurred in exons 6-11 than those in cases with germline BRCA1 mutations (84.4% vs. 56.3%: P = 0.013). The proportion of sporadic cases with TP53 mutations in non-serous tumors (e.g. endometrioid, clear cell, or mucinous) was significantly lower than that in serous tumors (18.5% vs. 53.0%: P = 0.0038). However, there was no significant difference between the proportion of BRCA1 cases with TP53 mutation in non-serous and in serous tumors (37.5% vs. 57.9%). CONCLUSIONS: Our results suggest that somatic mutation of TP53 plays less of a role in the carcinogenesis of sporadic non-serous tumors than in that of sporadic serous tumors or BRCA1-related tumors. Furthermore, p21 somatic mutation appears to be less involved in the development of ovarian cancer than TP53 somatic mutation.

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

AIM: The genetic region of 6q25 containing the estrogen receptor-alpha (ER-alpha) gene is lost in a significant number of ovarian tumors. The aim of this study was to identify how inherited variation in the ER-alpha gene contributes to susceptibility to familial ovarian cancer. METHODS: DNA obtained from 18 cases of familial ovarian cancer without mutation of the BRCA1 and BRCA2 genes, 20 cases with BRCA1 mutation, 20 cases of sporadic ovarian cancer, and 19 controls were screened for mutations in the coding region of the ER-alpha gene using direct sequencing. RESULTS: Two germline missense variants at codons 307 [GCC(Ala)-->TCC(Ser)] and 347 [ACC(Thr)-->TCC(Ser)] were detected in two unrelated cases with BRCA1 mutation, but not in all other cases tested. Three polymorphisms in codon 10 [TCT-->TCC(Ser)], codon 325 [CCC-->CCG(Pro)], and codon 594 [ACA-->ACG(Thr)] were identified in this series, and a higher frequency of the allele TCC at codon 10 and a lower frequency of the allele CCG at codon 325 were observed in familial cases without BRCA1 mutation, compared with those in familial cases with BRCA1 mutation, in both the sporadic cases and in the controls. CONCLUSIONS: We could not detect pathogenic mutations of the ER-alpha gene in ovarian cancer cases without BRCA1 mutation. However, association analyses of two polymorphisms suggest that the ER-alpha gene or a gene located close to the ER-alpha locus might be related to susceptibility of familial ovarian cancer without BRCA1 mutation.