Eriko Sato

Coexpression of EphB4 and ephrinB2 in tumour advancement of ovarian cancers.

EphB4 and ephrinB2 expressions in ovarian cancers were studied to analyse EphB4/ephrinB2 functions against clinical backgrounds. EphB4 and ephrinB2 were dominantly localised in ovarian cancer cells of all cases studied. Both the histoscores and mRNA levels of EphB4 and ephrinB2 significantly increased with clinical stages (I<II<III<IV, P<0.001) in ovarian cancers, although there was no significant difference in EphB4 and ephrinB2 histoscores or in mRNA levels according to histopathological types. EphB4 as well as ephrinB2 histoscores in cancer cells correlated with the corresponding mRNA levels in each case (EphB4, P<0.001; ephrinB2, P<0.001). The 24-month survival rates of the 36 patients with high EphB4 and ephrinB2 expression were poor (25 and 27%, respectively), while for the other 36 patients with low EphB4 and ephrinB2 expression, they were significantly higher (68 and 64%, respectively). Therefore, EphB4/ephrinB2 may function in tumour advancement and coexpression of the Eph/ephrin system may potentiate tumour progression leading to poor survival. Thus, EphB4/ephrinB2 can be recognised as a novel prognostic indicator in the primary tumours of ovarian cancers.

Expression of IP-10 related to angiogenesis in uterine cervical cancers.

Angiogenesis is essential for development, growth and advancement of solid tumours. Interferon-γ-inducible protein 10 (IP-10) regulates lymphocyte chemotaxis, mediates vascular pericyte proliferation and acts as an angiostatic agent, thus inhibiting tumour growth. This prompted us to study the clinical implications of IP-10 expression related to angiogenesis in uterine cervical cancers. The levels of IP-10 decreased with advancement, and the prognosis of the 30 patients with low IP-10 expression in uterine cervical cancers was poor (66%), whereas the 24-month survival rate of the other patients with high IP-10 expression was 90%. Furthermore, IP-10 levels significantly reverse-correlated with vascular endothelial growth factor (VEGF) levels in uterine cervical cancers. Interferon-γ-inducible protein 10 might work on suppression of angiogenesis associated with VEGF in advancement, and can be recognised as a prognostic indicator. Furthermore, IP-10 activation might be effective on the suppression of regrowth or recurrence after intensive treatment for advanced cervical cancers.

Clinical implication of expression of vascular endothelial growth factor-C in metastatic lymph nodes of uterine cervical cancers

Vascular endothelial cell growth factor (VEGF)-C levels were significantly (P<0.05) increased in 24 out of 40 metastatic lymph node lesions of uterine cervical cancers. The prognosis of the 24 patients with increased VEGF-C level in metastatic lymph node lesions was poor and the 24-month survival rate was 38%, while the rate of the 16 patients with no change in VEGF-C level in metastatic lymph node lesions was 81%. There was a significant (P<0.01) difference in the 24-month survival rates between the two groups. This is novel, direct evidence that VEGF-C might contribute to the aggressive lymphangitic metastasis in uterine cervical cancers, and that the increase in VEGF-C level from primary tumour to metastatic lymph node might be a prognostic indicator.

Clinical Implications of Expression of ETS-1 Related to Angiogenesis in Metastatic Lesions of Ovarian Cancers

Objective: ETS-1 has been identified as a proto-oncogene and a transcription factor for tumor angiogenesis, which is essential for the growth, invasion and metastasis of solid tumors. The aim is to investigate the clinical implications of ETS-1 expression in peritoneal metastatic lesions of ovarian cancers. Methods: In primary tumors and peritoneal metastatic lesions from 30 patients with stage III ovarian cancers, ETS-1 histoscores and ets-1 mRNA levels were determined by immunohistochemistry and competitive RT-PCR-Southern blot analysis using recombinant RNA, respectively. Results: Immunohistochemical staining revealed that ETS-1 was expressed in the cancer cells and vascular endothelial cells. ETS-1 histoscores in the endothelial cells and ets-1 mRNA levels were significantly (p < 0.05) increased in 20 of 30 peritoneal metastatic lesions of ovarian cancers. There was a significant correlation between microvessel counts (MVCs) and ETS-1 histoscores in the endothelial cells (p < 0.001) and between MVCs and ets-1 mRNA levels in the primary tumor and the peritoneal metastatic lesion of ovarian cancers (p < 0.001). Furthermore, the 24-month survival rate of patients with significantly increased ets-1 mRNA level (2/20, 10%) was significantly (p < 0.01) lower than that of patients with no change in the level (6/10, 60%) from the primary tumor to the peritoneal metastatic lesion. Conclusions: ETS-1 might be associated with peritoneal metastasis dominantly as an angiogenic mediator and additionally as an oncogene product to activate tumor invasion in ovarian cancers.

Clinical implication of estrogen-related receptor (ERR) expression in ovarian cancers☆

The expression of estrogen receptor (ER)alpha and ERbeta mRNAs did not show any specific manner according to clinical backgrounds in ovarian cancers. On the other hand, the levels of estrogen-related receptor (ERR)alpha mRNA increased with clinical stages regardless of histopathological types in ovarian cancers. However, ERRbeta and ERRgamma mRNA levels were extremely low to determine reliably. ERRalpha can bind to the steroid receptor coactivator family without any ligands, and drive transcription activity of the target genes. The manner of ERR and ER gene expressions might show an independent usage of common cofactors. It is speculated that the up regulation of ERRalpha might be related to advancement of ovarian cancers regardless of plausible interaction via cofactors regulated by ERs. Although ERRalpha is not directly related to growth of ovarian cancer, ERRalpha is a candidate for prognostic factors for ovarian cancer.

Estrogen-related receptor expression in placenta throughout gestation

Estrogen receptor (ER) alpha and beta mRNA levels increased from the first to the second trimester and then decreased until normal term delivery. Estrogen-related receptor (ERR) alpha, beta and gamma mRNA levels gradually increased up to the second trimester and then comparatively rapidly increased until normal term delivery. ERRs can bind to the steroid receptor coactivator family without any ligands and drive transcription activity of the target genes. The manner of ERR and ER gene expressions might show a competitive interaction associated with the use of common cofactors. It is speculated that the up-regulation of ERRs is related to placental growth after the down-regulation of ERs because of the remarkably high concentration of estrogens for ERs from the second trimester until delivery.

Clinical implication of estrogen-related receptor (ERR) expression in uterine endometrial cancers

Estrogen receptor (ER)alpha and ERbeta mRNAs levels decreased with clinical stage, myometrial invasion and dedifferentiation. On the other hand, ERRalpha mRNA levels and histoscores increased with clinical stage and myometrial invasion, regardless of dedifferentiation. ERRalpha can bind to the steroid receptor coactivator family without any ligands, and drive transcription activity of the target genes. The competitive interaction of ERRalpha/ER expression associated with the use of common cofactors during loosing estrogen dependency might cause their expression manner. The up-regulation of ERRalpha might be related to tumor growth and advancement in uterine endometrial cancers. It is speculated that ERRalpha is a candidate for prognostic factors in uterine endometrial cancer, although ERRs are not directly related to growth of uterine endometrial cancer.

Coexpression of EphB4 and ephrinB2 in tumor advancement of uterine cervical cancers

OBJECTIVE Receptor EphB4 and the corresponding ligand ephrinB2 contribute to tumor growth in various human tumors. This prompted us to study the expression and localization of EphB4 and ephrinB2 in uterine cervical cancers to analyze the EphB4/ephrinB2 functions against clinical backgrounds. METHODS Immunohistochemistry and real-time RT-PCR have been done to determine the histoscores and mRNA levels of EphB4 and ephrinB2, respectively, in sixty-two uterine cervical cancer tissue samples. Patient prognoses were analyzed with a 36-month survival rate. RESULTS The localization of EphB4 and ephrinB2 was dominantly in the cancer cells of uterine cervical cancers of all cases given. Both the histoscores and mRNA levels of EphB4 and ephrinB2 significantly increased with clinical stages (I<II<III+IV, p<0.001) in uterine cervical cancers. The tumor sizes significantly correlated with the histoscore and mRNA levels of EphB4 and ephrinB2. There were significant differences in histoscores and mRNA levels of EphB4 and ephrinB2 in accordance with lymph node metastasis, but not according to histopathological types. The 36-month survival rates of the 31 patients with high EphB4 and ephrinB2 expression were poor (31% and 19%, respectively), while survival rates for the other 31 patients with low EphB4 and ephrinB2 expression were significantly higher (72% and 73%, respectively). CONCLUSION Coexpression of EphB4 and ephrinB2 increased with the disease advancement based on clinical stage, lymph node metastasis, tumor size and with poor patient prognoses. Therefore, EphB4/ephrinB2 expression might work on tumor advancement and coexpression of the Eph/ephrin system may potentiate tumor progression leading to poor survival, thus can be recognized as a novel prognostic indicator in the primary tumors of uterine cervical cancers.

Expression of ETS-1 Related to Angiogenesis in Uterine Endometrium during the Menstrual Cycle

ETS-1 has been identified as a transcription factor for angiogenesis, which is essential for the development and growth of the uterine endometrium. This characteristic prompted us to study whether ETS-1 functions as an angiogenic mediator in uterine endometrium. Immunohistochemical staining revealed that the localization of ETS-1 was similar to that of vascular endothelial cells. There was a significant correlation between microvessel counts and both ETS-1 histoscores and ets-1 mRNA levels in uterine endometrium. The ETS-1 histoscores and ets-1 mRNA levels increased in the proliferative phase, reached a peak during peri-ovulation and decreased in the secretory phase. Furthermore, the ETS-1 histoscores and ets-1 mRNA levels correlated with vascular endothelial growth factor (VEGF) levels in the proliferative phase. This indicates that ETS-1 might be an angiogenic mediator in uterine endometrium linked to VEGF in the proliferative phase.

Plausible linkage of hypoxia inducible factor-1α in uterine cervical cancer

Angiogenesis is essential for the development, growth and advancement of solid tumors. Angiogenesis is induced by hypoxia with angiogenic transcription factor hypoxia inducible factors (HIF). This prompted us to study the clinical implications of HIF relative to angiogenesis in uterine cervical cancers. Although there was no significant difference in HIF‐1α histoscores and mRNA levels according to histopathological type or lymph node metastasis, HIF‐1α histoscores and mRNA levels increased significantly with advancing cancer stages. The prognosis of 30 patients with high HIF‐1α in uterine cervical cancers was poor (73% survival), whereas the 24‐month survival rate of the other 30 patients with low HIF‐1α was 93%. HIF‐1α histoscores and mRNA levels were correlated with the levels of the angiogenic factors thymidine phosphorylase and interleukin‐8, and HIF‐1α might be linked with these factors in cervical cancer tissue. HIF‐1α is a candidate for prognostic indicator as an angiogenic mediator in uterine cervical cancer. (Cancer Sci 2006; 97: 861–867)