Uterine Endometrial Cancer Research Articles

Expression of Interferon-Gamma-Inducible Protein 10 Related to Angiogenesis in Uterine Endometrial Cancers

Objective: Angiogenesis is essential for the development, growth and advancement of solid tumors. Interferon-γ-inducible protein 10 (IP-10) regulates lymphocyte chemotaxis, mediates vascular pericyte proliferation and acts as an angiostatic agent, thus inhibiting tumor growth. This prompted us to study the clinical implications of IP-10 expression related to angiogenesis in uterine endometrial cancers. Method: Sixty patients underwent curative resection for uterine endometrial cancers. In the tissue of these cancers, the levels of IP-10, vascular endothelial growth factor, interleukin-8 and basic fibroblast growth factor (bFGF) were determined by enzyme immunoassay, and the localization of IP-10 and counts of microvessels were determined by immunohistochemistry. Result: IP-10 is diffusely localized in the cancer cells, but not in the stromal cells. There was a significant, reverse correlation between microvessel counts and IP-10 levels in uterine endometrial cancers. The IP-10 levels significantly decreased with more advanced disease and significantly reverse-correlated with bFGF levels in uterine endometrial cancers. Conclusions: IP-10 might affect the suppression of angiogenesis associated with bFGF in advanced cancer. Furthermore, IP-10 activation might be effective in the suppression of regrowth or recurrence after intensive treatment for advanced endometrial cancers.

Body diffusion-weighted MR imaging of uterine endometrial cancer: Is it helpful in the detection of cancer in nonenhanced MR imaging?

Objective In this study, the authors discussed the feasibility and value of diffusion-weighted (DW) MR imaging in the detection of uterine endometrial cancer in addition to conventional nonenhanced MR images. Methods and materials DW images of endometrial cancer in 23 patients were examined by using a 1.5-T MR scanner. This study investigated whether or not DW images offer additional incremental value to conventional nonenhanced MR imaging in comparison with histopathological results. Moreover, the apparent diffusion coefficient (ADC) values were measured in the regions of interest within the endometrial cancer and compared with those of normal endometrium and myometrium in 31 volunteers, leiomyoma in 14 patients and adenomyosis in 10 patients. The Wilcoxon rank sum test was used, with a p < 0.05 considered statistically significant. Results In 19 of 23 patients, endometrial cancers were detected only on T2-weighted images. In the remaining 4 patients, of whom two had coexisting leiomyoma, no cancer was detected on T2-weighted images. This corresponds to an 83% detection sensitivity for the carcinomas. When DW images and fused DW images/T2-weighted images were used in addition to the T2-weighted images, cancers were identified in 3 of the remaining 4 patients in addition to the 19 patients (overall detection sensitivity of 96%). The mean ADC value of endometrial cancer ( n = 22) was (0.97 ± 0.19) × 10 −3 mm 2/s, which was significantly lower than those of the normal endometrium, myometrium, leiomyoma and adenomyosis ( p < 0.05). Conclusion DW imaging can be helpful in the detection of uterine endometrial cancer in nonenhanced MR imaging.

Hepatocyte growth factor induces anoikis resistance by up-regulation of cyclooxygenase-2 expression in uterine endometrial cancer cells

Cyclooxygenase-2 (COX-2) has been implicated in the promotion of carcinogenesis. Although the role of COX-2 in endometrial cancer remains unclear, recent experiments suggest that COX-2 antagonizes cell apoptosis, increases the invasiveness of malignant cells, and promotes angiogenesis. Hepatocyte growth factor (HGF) is a mesenchymal-derived cytokine and the interaction between HGF and its tyrosine kinase receptor, c-Met proto-oncogene, is associated with tumor progression and metastasis. To investigate the molecular mechanism of HGF-induced anoikis resistance, we analyzed the signal transduction and COX-2 expression in endometrial cancer cells. Here, we show i) the expression of COX-2 protein significantly increased in a dose-dependent manner after HGF stimulation in endometrial cancer cell lines (HEC-IB and RL95-2), reaching 200-270% stimulation at the highest doses of HGF tested (40 ng/ml); ii) flow cytometry and TUNEL analyses revealed that HGF significantly inhibited anoikis of RL95-2 cells; iii) phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), but not mitogen-activated protein kinase/ERK kinase (MEK) inhibitor (PD98059), specifically blocked HGF-mediated anoikis resistance in RL95-2 cells; and iv) COX-2 inhibitor, Meloxicam, abrogated HGF-mediated anoikis resistance. Our data suggest that HGF induces anoikis resistance in endometrial cancer cells possibly through PI3K/Akt pathway-dependent up-regulation of COX-2 expression.

5036 POSTER Tumor advancement in uterine endometrial cancers patients

5036 POSTER Tumor advancement in uterine endometrial cancers patients

Diffusion‐weighted MR imaging of uterine endometrial cancer

To determine the feasibility of diffusion-weighted (DW) MRI of uterine endometrial cancer and to investigate whether the apparent diffusion coefficient (ADC) values of endometrial cancer differ from those of normal endometrium and whether they differ according to the histologic grade of the tumor. Study population included 18 consecutive females with surgically proven endometrial cancer and 12 females with pathologically confirmed normal endometrium in cervical cancer patients. Visual evaluation and ADC measurement were performed in endometrial cancer and normal endometrium. All endometrial cancer and the normal endometrium appeared hyperintense on DW images. The mean ADC value (10(-3) mm(2)/second) of endometrial cancer was 0.88 +/- 0.16, which was significantly lower (P < 0.01) than that of normal endometrium (1.53 +/- 0.10). The mean ADC value for each histologic grade was 0.93 +/- 0.16 (G1), 0.92 +/- 0.13 (G2), and 0.73 +/- 0.09 (G3). The present study showed that DW imaging is feasible in demonstrating uterine endometrial cancer and ADC measurement has a potential ability to differentiate between normal and cancerous tissue of the endometrium. The ADC values of endometrial cancers of higher grade show tendency to decrease compared to those of lower grade, although estimation of histologic grade based on ADC values seems difficult because of considerable overlap.

Stromal reaction of adenomyosis protects from uterine endometrial cancer invasion to myometrium

16064 Background: It is unclear that stromal reaction plays role in endometrial cancer (Em Ca) invasion to uterine muscle with adenomyosis. Methods: One hundred and five patients with Em Ca (stage 0=38, 1a=18, 1b=26, 1c=10, 2b=3, 3a=4, 3c=5, 4a=1) received operative therapy with hysterectomy. Evaluation of stromal reaction using immunohistochemical method with alpha-smooth muscle actin and h-caldesmon antibody. In case of alpha-smooth muscle actin had immunoreactivity and h-caldesmon had not immunoreactivity, there was stromal reaction with myofibroblast. Evaluation of cell proliferation, using immunohistochemical method with epidermal growth factor receptor (EGFR) by global score with six degrees and MIB-1 by labeling Index (LI). Results: All cases had stromal reaction with myofibloblast in myometrial invasion area in forty nine cases with myometrial invasion equal or more than stage 1b. Em Ca invaded near to and in adenomyosis lesion in eleven cases. In stroma of adenomyosis without cancer invasion, EGFR was positive in one case (9%) and global score was two (average 0.18). In contrast, EGFR was positive in eight cases (73%) with Em Ca invasion to adenomyosis stroma and global score was from two to three (average 1.6). LI of MIB-1 was from 0 to 0.2 (average 0.05) in adenomyosis stroma without Em Ca invasion and 0.2 to 0.75 (average 0.41) with Em Ca invasion. Conclusions: When Em Ca invades to adenomyosis, myofibloblast cell proliferation in stromal reaction increases more than in adenomyosis without Em Ca invasion. Stromal reaction of adenomyosis plays role in protecting from Em Ca invasion to uterine muscle and it may contribute to being good prognosis compared with Em Ca without adenomyosis. No significant financial relationships to disclose.

Serum albumin‐associated peptides of patients with uterine endometrial cancer

The incidence of endometrial cancer is predicted to increase in developed countries. Because of the relatively high incidence of complications and low diagnostic sensitivity associated with endometrial tissue sampling, there is an urgent need for the development of a safe and non-invasive diagnostic method. The proteomic spectrum of albumin-associated peptides was obtained from a total of 125 serum samples (92 from endometrial cancer patients and 33 from controls) by matrix-assisted laser desorption/ionization hybrid quadrupole time-of-flight mass spectrometry, and the candidate markers were selected by the Mann-Whitney U-test and receiver operator characteristics analysis. We selected three mass peaks at 4769, 6254 and 11 792 m/z from a total of 507 peaks as distinguishing cancer patients from controls (P < 0.00001 and area under curve of over 0.8). When the cut-off points were defined as the averages of the values in the controls + 2 SD, the combination of the three peptides detected endometrial cancer with a sensitivity of 65.2% (60/92). Even stage I early endometrial cancers were detected with a sensitivity of 60.3% (38/63). Unfortunately, the three peptides were also detected in 44.6% (33/74) of myoma uteri patients, indicating that they are not specific to endometrial cancer. Although a large-scale study is necessary to confirm the clinical significance of the peptide biomarkers identified in this study, direct profiling of serum-albumin-bound peptides by high-resolution mass spectrometry was proven to have potential as a means of identifying biomarkers for a variety of diseases.

Plausible Linkage of Hypoxia-Inducible Factor (HIF) in Uterine Endometrial Cancers

Objective: Angiogenesis is essential for the development, growth and advancement of solid tumors. Angiogenesis is induced by hypoxia with the angiogenic transcription factor hypoxia-inducible factor (HIF). This prompted us to study the clinical implications of HIF relative to angiogenesis in uterine endometrial cancers. Methods: Sixty patients underwent curative resection for uterine endometrial cancers. In the tissue of 60 uterine endometrial cancers, HIF-1α, HIF-2α and HIF-1β mRNA levels, and the ratio of angiopoietin (Ang)-2 to Ang-1 (Ang-2/Ang-1) mRNA levels were determined by RT real-time PCR; histochemical scores and localization of HIF-1α were determined by immunohistochemistry. Levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), thymidine phosphorylase (TP) and interleukin-8 (IL-8) were determined by enzyme immunoassay. Results: In stage I uterine endometrial cancers, HIF-1α histochemical scores and mRNA levels significantly increased with myometrial invasion of uterine endometrial cancers. HIF-1α histochemical scores and mRNA levels correlated with the levels of Ang-2/Ang-1 and IL-8. Conclusion: The angiogenic mediator HIF-1α, linked to Angs and IL-8, might work on angiogenesis with myometrial invasion of cancer cells in uterine endometrial cancers.

Mucinous Cystadenocarcinoma of the Pancreas Developing During Hormone Replacement Therapy

Hormone replacement therapy (HRT) containing estrogens is generally used to relieve climacteric symptoms and to prevent osteoporosis and coronary heart disease [1], however, there has been increasing evidence of the HRT as the risk of hormone-dependent neoplasms including breast cancer [2], uterine endometrial cancer [3], ovarian cancer [4], and even lung cancer [5]. Noteworthy is mucinous cyst neoplasms (MCNs) of the pancreas, characterized by mucin-producing columnar epithelium supported by "ovarian-like" mesenchymal stroma, occur mostly in females expressing estrogen receptors [6, 7]. Although several reports regarding the closed relationship between MCNs and pregnancy [8, 9] might imply potential sex hormone-dependency of the MCNs [10], no correlation has been reported. This is the first case report of malignant MCN developing during continuous HRT after hysterectomy.

Clinical implications of steroid receptor coactivator (SRC)-3 in uterine endometrial cancers

Estrogen is recognized as a significant modifier in the development, growth and invasion of uterine endometrial cancer. Steroid receptor coactivator-3 (SRC-3; AIB1, ACTR, RAC3, TRAM-1, and pCIP) is a member of the p160 family of coactivator for nuclear hormone receptors including estrogen receptor (ER). It is reported that SRC-3 is overexpressed in various cancers. However, SRC-3 expression manner in uterine endometrial cancer is not fully understood. In this study, we showed SRC-3 mRNA expression correlates with clinical stage, depth of myometrial invasion and dedifferentiation. The prognosis of the 25 patients with higher expression of SRC-3 mRNA in uterine endometrial cancers was extremely poor (36%), whereas the 24-month survival rate of the 15 patients with lower expression of SRC-3 mRNA was 96%. These data indicate that SRC-3 might be an important indicator of uterine endometrial cancer advancement and survival.

Overexpression of ephrinB2 and EphB4 in tumor advancement of uterine endometrial cancers

The ligand ephrinB2 and the corresponding receptor EphB4 contribute to tumor growth in various human tumors. This prompted us to study the expression and localization of ephrinB2 and EphB4 in uterine endometrial cancers to analyze the ephrinB2/EphB4 functions against clinical backgrounds. We carried out immunohistochemistry and real-time RT-PCR to determine the histoscores and messenger RNA (mRNA) levels of ephrinB2 and EphB4, respectively, in 68 uterine endometrial cancers and 16 normal endometrium tissue samples. Patient prognoses were analyzed with a 60-month survival rate. The localization of ephrinB2 and EphB4 was dominantly in the cancer cells of uterine endometrial cancer of all cases given. EphrinB2 and EphB4 histoscores were highly correlated with ephrinB2 and EphB4 mRNA levels, respectively (r = 0.864 and r = 0.615, P < 0.01). Both the histoscores and mRNA levels of ephrinB2 and EphB4 significantly increased with clinical stages (I < II < III, P < 0.01), dedifferentiation (G(1) < G(2) < G(3), P < 0.01) and myometrial invasion (A < B < C, P < 0.01 for ephrinB2 and P < 0.05 for EphB4) in uterine endometrial cancers. The 60-month survival rates of the 34 patients with high ephrinB2 and EphB4 expression were poor (59% and 62% respectively), while for the other 34 patients with low ephrinB2 and EphB4 expression, they were significantly higher (85% and 82%, respectively). EphrinB2 and EphB4 were overexpressed during the tumor advancement as dedifferentiation and myometrial invasion. Therefore, ephrinB2/EphB4 might work on tumor advancement and may be recognized as a novel prognostic indicator for uterine endometrial cancers.

Expression of protease activated receptor-2 related to angiogenesis in tumor advancement of uterine endometrial cancers

Protease activated receptor-2 (PAR-2) is the second member of a novel family of G-protein coupled seven-transmembrane domain receptors. PAR-2 has been reported to be expressed in various tumors and play a vital role in the regulation of cancer cell growth. The purpose of this study was to clarify the roles of PAR-2 in the angiogenic pathway in uterine endometrial cancers. PAR-2 expression was analyzed in 61 uterine endometrial cancer and 15 normal endometrium tissue specimens. PAR-2 histoscores and mRNA levels were determined by immunohistochemistry and real-time RT-PCR, respectively. Microvessel counts were determined by immunohistochemistry for CD31 and factor VIII-related antigen. The localization of PAR-2 was dominant in the cancer cells of endometrial cancer tissues of all cases studied. PAR-2 histoscores highly correlated with PAR-2 mRNA levels in the same tissues (r=0.87, p<0.001). PAR-2 histoscores and mRNA levels both significantly increased in uterine endometrial cancers with clinical stages (I<II<III, p<0.001), dedifferentiation (G1<G2<G3, p<0.001) and myometrial invasion (A<B, p<0.001; B<C, p<0.05) in comparison to normal endometria. There were significant correlations between PAR-2 histoscores and mRNA levels with microvessel counts in uterine endometrial cancers. PAR-2 was upregulated during uterine endometrial cancer progression with dedifferentiation and myometrial invasion. Therefore, PAR-2 might work on tumor advancement of uterine endometrial cancers via angiogenic activity.

Inhibitory effects of Hochu-ekki-to on endometrial carcinogenesis induced by N-methyl-N-nitrosourea and 17β-estradiol in mice

An evaluation of the effects of a traditional Chinese herbal medicine, Hochu-ekki-to (Bu-zong-yi-qi-tang) on endometrial carcinogenesis was performed in experiments with female mice. In the short-term experiment, dietary exposure of Hochu-ekki-to (0.2% for 2 weeks) decreased the estradiol-17beta (E2)-stimulated expression levels of c-jun (P<0.001), tumor necrosis factor (TNF)-alpha (P<0.005), estrogen receptors (ER)-alpha (P<0.001) and ER-beta (P<0.005), as determined by reverse transcription-polymerase chain reaction and a Southern blot analysis in the uteri of the ovarectomized mice. In the long-term experiment, the mice were given N-methyl-N-nitrosourea (MNU) solution (1 mg/100 g body weight) and normal saline (as controls) into their left and right uterine corpora, respectively, and then were divided into four groups. Group 1 (25 mice) was given a diet with Hochu-ekki-to and 5 ppm E2. Group 2 (25 mice) was given a diet with E2 alone. Group 3 (25 mice) was given a diet with Hochu-ekki-to alone. Group 4 (25 mice) was kept on the basal diet alone and treated as a control. The incidence of uterine endometrial cancer in the group with Hochu-ekki-to treatment was substantially lower than of the control group. The inhibitory effect of Hochu-ekki-to on endometrial carcinogenesis is thus suggested to decrease the expressions of c-jun, TNF-alpha, ER-alpha and -beta.

Combination therapy with pegylated liposomal doxorubicin and carboplatin in malignant gynecologic tumors. A prospective multicenter phase II trial of the AGO-OVAR and the AGO Kommission Uterus (AGO-K-Ut)

5095 Background: To determine the toxicity and efficacy of combination therapy with pegylated liposomal doxorubicin (PLD) and carboplatin in patients with malignant gynecologic tumors. Methods: Patients with recurrent or advanced uterine sarcomas, endometrial, cervical or vaginal cancer or with recurrent platinum-sensitive ovarian cancer were treated with PLD 40mg/m2 and carboplatin AUC 6, q28 over 6 cycles (up to 10 cycles allowed). Primary and secondary endpoints were tolerability and efficacy. Efficacy was measured according to RECIST and/or CA-125 GCIG criteria. Results: 67 pts with recurrent ovarian cancer, 11 pts with uterine sarcomas, 31 pts with endometrial cancer and 31 pts with cervical or vaginal cancer have been recruited (total 140 pts, 87 pts evaluable for response). Grade 3/4 hematologic toxicities occured in 8% for anemia, 14% for thrombocytopenia, 23% for leukopenia, and 25% for neutropenia of whom 2% developed febrile neutropenia. Non-hematologic Grade 3/4 toxicities have been observed in more than 5% of all patients for the following items: asthenia (14%), pain (10%), dyspnea (9%), palmo-plantar-erythema (7%), nausea and vomiting (7%), diarrhea (5%). The median dose intensity was 94% for PLD and 97% for carboplatin. 76% of all non-progressing patients received at least 5 cycles. The overall response rate was 56% in ovarian cancer, 43% in uterine sarcomas, 44% in endometrial cancer, and 14% in cervical and vaginal cancer. Conclusions: PLD/carboplatin was well tolerated, even in pretreated patients. The combination showed remarkable efficacy in patients with uterine sarcomas, endometrial cancer, and ovarian cancer which merits further evaluation. CA 125 response criteria in ovarian cancer are under evaluation and will be presented on ASCO. However, the regimen had limited efficacy in cervical and vaginal cancer. A prospective randomized trial in recurrent ovarian cancer patients comparing carboplatin/PLD with paclitaxel/carboplatin has already been started within the international study group network (AGO-OVAR 2.9; CALYPSO-trial). [Table: see text]

Correlation between cytopathologic findings and relative DNA content of cancer cells in uterine endometrial cancer

Correlation between cytopathologic findings and relative DNA content of cancer cells in uterine endometrial cancer

The role of adenomyosis in uterine endometrial cancer (Em Ca) invasion to myometrium

5179 Background: It is unclear what adenomyosis play roles in Em Ca invasion. Methods: Eighty five patients with Em Ca (stage 0=31, 1a=15, 1b=21, 1c=8, 2b=2, 3a=3, 3c=4, 4a=1, Age 22–82 years old, mean 54.1) received operative therapy with hysterectomy between January 2001 and November 2004. Evaluation of stromal reaction using immunohistochemical method with alpha-smooth muscle actin and h-caldesmon antibody. In case of alpha-smooth muscle actin had immunoreactivity and h-caldesmon had not immunoreactivity, there was stromal reaction with myofibroblast. Immunoreactivity scored from zero to four degrees. Results: Forty seven patients had adenomyosis in 85 Em Ca patients. In nine cases, Em Ca invaded near to adenomyosis lesion. In thirty nine cases with myometrial invasion (stage 1b-), all cases had stromal reaction with myofibloblast in myometrial invasion area (scored 1–10 cases, 2–15 cases, 3–10 cases, 4–4 cases). In contrast, nine cases with Em Ca invasion near to adenomyosis, stromal reaction with myofibloblast score were more high (scored 1–0 cases, 1–0 case, 2–3 cases, 3–3 cases, 4–3 cases). Conclusions: When Em Ca invaded around the adenomyosis in myometrium, stromal rection with myofibloblasts appeared stronger than in myometrium without adenomyosis. This may be the adenomyosis reaction of protection from Em Ca invasion. No significant financial relationships to disclose.

Cyclooxygenase inhibitors may be more effective in hormone-dependent endometrial cancers: interaction between cyclooxygenase and aromatase

We read with great interest the article by Toyoki et al. [1]. They found a positive association between vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (cox-2) on angiogenesis at an early stage in the growth of uterine endometrial cancer. They suggested that long-term administration of cox-2 inhibitors might be effective in the suppression of recurrent initiation of uterine endometrial cancers after curative resection. Currently, in vivo and in vitro studies on the uterine effects of aromatase inhibitors are limited.

Expression of cyclooxygenase-2 in uterine endometrial cancer and anti-tumor effects of a selective COX-2 inhibitor

A role for cyclooxygenase-2 (COX-2) in the development and progression of various tumors has been identified. Selective COX-2 inhibitors produce anti-proliferative effects in various cancer cell lines that express COX-2. However, the mechanisms underlying anti-tumor effects are unclear. Furthermore, few studies have studied COX-2 expression in gynecological cancers, especially endometrial cancer. The current study had two goals. We investigated the correlation between COX-2 expression and clinicopathological factors of uterine endometrial cancer. We also investigated effects of treatment with etodolac, a selective COX-2 inhibitor, on the uterine endometrial cancer cell line TMG-L, which expresses COX-2. We conclusively confirmed expression of COX-2 mRNA and protein in endometrial cancer that exceeded levels of COX-2 seen in normal endometrium. However, no significant correlations were observed between COX-2 expression in endometrial cancer tumor samples and clinicopathological factors or disease-free survival rate of patients with endometrial cancer. Study of COX-2 inhibition of TMG-L cells showed that etodolac produced dose-dependent inhibition of cell proliferation through G1 phase cell-cycle arrest. Etodolac-induced cell-cycle arrest might be caused by increases in p53 and P21WAF1 protein expression. Production of basic-fibroblast growth factor (bFGF, a pro-angiogenesis factor) was inhibited by etodolac in a dose-dependent manner. Furthermore, telomerase activity was inhibited and expression of hTERT mRNA was significantly inhibited with etodolac, leading to the conclusion that anti-tumor effects of etodolac on TMG-L cells are due to inhibition of both angiogenesis and telomerase activity. These results strongly suggest that COX-2 inhibitors have potential as therapeutic (and possibly, chemopreventive) agents for endometrial cancers that overexpress COX-2.

Clinical implications of expression of cyclooxygenase-2 related to angiogenesis in uterine endometrial cancers

BackgroundAngiogenesis is essential for development, growth and advancement of solid tumors. Cyclooxygenase (cox)-2 is recognized as an angiogenic factor in various tumors. This prompted us to study the clinical implications of cox-2 expression and angiogenesis in uterine endometrial cancers. Patients and methodsFifty patients underwent curative resection for uterine endometrial cancers. In uterine endometrial cancers, cox-2 levels were determined by enzyme immunoassay, and the localization and counts of microvessels were determined by immunohistochemistry. ResultsThere was a significant correlation between microvessel counts and cox-2 levels in uterine endometrial cancers. Cox-2 localized in the cancer cells, but not in the stromal cells of uterine endometrial cancer tissues. Cox-2 levels decreased with the advancement. Furthermore, cox-2 levels significantly correlated with VEGF levels in uterine endometrial cancers. ConclusionsVEGF associated with cox-2 might work on angiogenesis at an early status in growth. Therefore, long-term administration of cox-2 inhibitors might be effective in the suppression of recurrent initiation of uterine endometrial cancers after curative resection.

HMMC-1

The purpose of this research was to generate a human monoclonal antibody specific to gynecological cancers and to evaluate such an antibody as therapy for gynecological cancers. Transchromosomal KM mice were immunized with the human uterine endometrial cancer cell line SNG-S. Hybridomas were constructed between spleen cells from KM mice and mouse myeloma cells. Reactivity of the antibody was evaluated by immunohistochemistry of pathological specimens of gynecological cancers. Cytotoxicity of HMMC-1 against SNG-S cells was tested by in vitro cytotoxicity assays. The epitope of HMMC-1 was determined by transfection with a panel of glycosyltransferase cDNAs and by inhibition assays with chemically synthesized oligosaccharides. HMMC-1 is a human IgM monoclonal antibody that reacts positively with mullerian duct-related carcinomas with positive rates of 54.6% against uterine endometrial adenocarcinoma, 76.9% against uterine cervical adenocarcinoma, and 75.0% against epithelial ovarian cancer. HMMC-1 does not react with normal endometrium at proliferative or secretory phases, normal uterine cervix, or normal and malignant tissue from other organs, whereas it reacts weakly with the epithelium of the gall bladder and the collecting duct of the kidney. HMMC-1 exhibits antigen-dependent and complement-mediated cytotoxicity. Upon cotransfection with cDNAs encoding two glycosyltransferases required for fucosylated extended core 1 O-glycan, mammalian cells express HMMC-1 antigen. Finally, binding of HMMC-1 to SNG-S cells is inhibited by synthetic Fucalpha1-->2Galbeta1-->4GlcNAcbeta1-->3Galbeta1-->3GalNAcalpha1-octyl. These results indicate that HMMC-1 specifically recognizes a novel O-glycan structure. The unique specificity and cytotoxicity of HMMC-1 strongly suggest a therapeutic potential of this antibody.