Hiroshi Toyoki

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 Implications of the Expression of Estrogen Receptor-α and -β in Primary and Metastatic Lesions of Uterine Endometrial Cancers

Novel human estrogen receptor (ER)-β was identified in cDNA libraries from human testes. ER-β specifically expresses in the testis, ovary, thymus, spleen, osteoblasts, fetus and uterine endometrium. ER-β might not conserve the same physiological functions as does ER-α. Therefore, expressions of ER-α and ER-β mRNAs in primary and metastatic lesions of uterine endometrial cancers were investigated. The levels of ER-β mRNA were significantly lower than those of ER-α mRNA in uterine endometrial cancers and in normal uterine endometria. The ratio of ER-β to ER-α mRNA in most primary uterine endometrial cancers was similar to that in normal uterine endometria (<0.4% of ER-β mRNA to ER-α mRNA). On the other hand, in 14 of the 20 lymph node metastasis-positive cases of uterine endometrial cancers, the ratio in the metastatic lesion was significantly higher than that in the primary lesion of the corresponding case, and patient prognosis in these cases was extremely poor. Therefore, it is suggested that the intact synchronized expression of ER-β interacting with ER-α might be disrupted, especially in most metastases of uterine endometrial cancers, leading to poor patient prognosis related to estrogen refractoriness.

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.

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.

Postpartum hemorrhage in coagulopathic patients: preliminary experience with uterine arterial embolization with N-butyl cyanoacrylate.

The present report describes uterine artery embolization (UAE) with N-butyl cyanoacrylate (NBCA) in four patients with postpartum hemorrhage (PPH) in a coagulopathic condition. Initial UAE with gelatin sponge particles and/or fibered platinum microcoils had failed in these patients. Subsequently, a mixture of NBCA and iodinated poppy seed oil (Lipiodol) was used as embolic material, and hemostasis was achieved immediately in all patients. No vaginal bleeding recurred thereafter, and all patients were discharged within 3 weeks of UAE. One patient resumed menstruation in 6 months. NBCA may be a promising embolic material for emergent UAE in patients with PH, especially for patients with a coagulopathic condition.

Clinical implications of expression of ETS-1 in relation to angiogenesis in ovarian cancers

ETS‐1 has been identified as a transcription factor involved in tumor angiogenesis, which is essential for the growth, invasion, and metastasis of solid tumors. This result prompted us to study whether ETS‐1 works as an angiogenic mediator in ovarian cancers. Immunohistochemical staining revealed that ETS‐1 was expressed in vascular endothelial cells and in cancer cells of ovarian cancers. There was a significant correlation between microvessel counts and both ETS‐1 histoscores and ets‐1 mRNA levels in ovarian cancers. Both ETS‐1 histoscores and ets‐1 mRNA levels increased with the progression of ovarian cancers. Furthermore, the 24‐month survival rate of 30 patients with high ets‐1 (high ETS‐1 histoscores and high ets‐1 mRNA levels) was 30%, while that of 30 other patients with low ets‐1 (low ETS‐1 histoscores and ets‐1 mRNA levels) was 70%. There was a significant difference between the 24‐month survival rates of the 30 patients with high ets‐1 and the 30 with low ets‐1. This indicates that ETS‐1 might act as an angiogenic mediator in, and be a prognostic factor for, ovarian 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.

Steroid receptors and metastatic potential in endometrial cancers.

The relative overexpression of oestrogen receptor (ER)-alpha exon 5 splicing variant (ER-alpha E5SV), ER-beta and progesterone receptor (PR) from B (PR-B) without transcriptional repression by PR from A (PR-A) might be related to the metastatic potential and partially cause deviation from sex steroidal dependency in endometrial cancers.

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)