Ovarian cancer (OCa) peritoneal metastasis is the leading cause of cancer–related deaths in women with limited therapeutic options available for treating it and poor prognosis, as the underlying mechanism is not fully understood. The clinicopathological correlation of G9a expression was assessed in tumor specimens of ovarian cancer patients. Knockdown or overexpression of G9a in ovarian cancer cell lines was analysed with regard to its effect on adhesion, migration, invasion and anoikis-resistance. In vivo biological functions of G9a were tested by i.p. xenograft ovarian cancer models. Microarray and quantitative RT-PCR were used to analyze G9a-regulated downstream target genes. We found that the expression of histone methyltransferase G9a was highly correlated with late stage, high grade, and serous-type OCa. Higher G9a expression predicted a shorter survival in ovarian cancer patients. Furthermore, G9a expression was higher in metastatic lesions compared with their corresponding ovarian primary tumors. Knockdown of G9a expression suppressed prometastatic cellular activities including adhesion, migration, invasion and anoikis-resistance of ovarian cancer cell lines, while G9a over-expression promoted these cellular properties. G9a depletion significantly attenuated the development of ascites and tumor nodules in a peritoneal dissemination model. Importantly, microarray and quantitative RT-PCR analysis revealed that G9a regulates a cohort of tumor suppressor genes including CDH1, DUSP5, SPRY4, and PPP1R15A in ovarian cancer. Expression of these genes was also inversely correlated with G9a expression in OCa specimens. We propose that G9a contributes to multiple steps of ovarian cancer metastasis and represents a novel target to combat this deadly disease.
Ovarian clear cell carcinoma (OCCC) is the most common endometriosis-associated ovarian cancer. Ovarian endometriosis may present with atypical or malignant sonographic features and interfere with clinical judgment about whether definitive surgical intervention is required.To compare the characteristics of endometrioma with atypical features and OCCC.This study enrolled patients with pathologic diagnoses of either endometrioma or OCCC. For patients with endometrioma, only those with atypical features, defined as the presence of at least one of the following sonographic characteristics: cyst diameter of 10 ± 1 cm, multi-cystic lesions, any solid component or papillary structure, and blood flow of any degree, were included.Sixty-three patients had endometriomas with atypical features, while 57 patients had OCCC. Patients with endometriomas were younger (39.33 ± 7.04 years vs. 53.11 ± 9.28 years, P < 0.01), had smaller cysts (7.81 ± 2.81 cm vs. 12.68 ± 4.60 cm, P < 0.01), and had smaller solid components (0.93 ± 1.74 cm vs. 4.82 ± 3.53 cm, P < 0.01). In contrast, OCCCs were associated with loss of ground-glass echogenicity (6.3% vs 68.4%, P < 0.01). In multivariate analysis, advanced age (> 47.5 years), large cysts (> 11.55 cm), large solid components (size > 1.37 cm), and loss of ground-glass echogenicity were independent factors suggestive of malignancy.Advanced age, larger cyst sizes, larger solid component sizes, and loss of ground-glass echogenicity are major factors differentiating endometriomas from malignancies. For women in menopausal transition who have finished childbearing who present with endometrioma with atypical features, removal of the adnexa intact could be considered.
Supplementary Methods, Figure Legends 1-12, Tables 1-5 from H3K9 Histone Methyltransferase G9a Promotes Lung Cancer Invasion and Metastasis by Silencing the Cell Adhesion Molecule Ep-CAM
Classic signaling by the proinflammatory cytokine interleukin 6 (IL-6) involves its binding to target cells that express the membrane-bound IL-6 receptor α. However, an alternate signaling pathway exists in which soluble IL-6 receptor (sIL-6Rα) can bind IL-6 and activate target cells that lack mIL-6Rα, such as endothelial cells. This alternate pathway, also termed trans-signaling, serves as the major IL-6 signaling pathway in various pathologic proinflammatory conditions including cancer. Here we report that sIL-6Rα is elevated in malignant ascites from ovarian cancer patients, where it is associated with poor prognosis. IL-6 trans-signaling on endothelial cells prevented chemotherapy-induced apoptosis, induced endothelial hyperpermeability, and increased transendothelial migration of ovarian cancer cells. Selective blockade of the MAPK pathway with ERK inhibitor PD98059 reduced IL-6/sIL-6Rα-mediated endothelial hyperpermeability. ERK activation by the IL-6/sIL-6Rα complex increased endothelial integrity via Src kinase activation and Y685 phosphorylation of VE-cadherin. Selective targeting of IL-6 trans-signaling in vivo reduced ascites formation and enhanced the taxane sensitivity of intraperitoneal human ovarian tumor xenografts in mice. Collectively, our results show that increased levels of sIL-6Rα found in ovarian cancer ascites drive IL-6 trans-signaling on endothelial cells, thereby contributing to cancer progression. Selective blockade of IL-6 trans-signaling may offer a promising therapeutic strategy to improve the management of patients with advanced ovarian cancer.
2041 Despite the success of arsenic trioxide in the treatment of some hematological malignancies, its therapeutic role in solid tumors remains elusive. We now report that arsenic trioxide inhibits hypoxia-induced expression of the chemokine receptor CXCR4, and suppress the ability of tumor cell to metastasize. Here we have demonstrated that the mRNA and protein production of CXCR4 on HeLa cells could be significantly reduced by arsenic trioxide at the clinical achievable levels, under both normoxic and hypoxic conditions. Luciferase reporter gene assay confirms that arsenic trioxide negatively regulates hypoxia-induced CXCR4 expression in various cancer cell lines, including breast, cervical, and ovarian cancer cells. In keeping with the above, reduction of CXCR4 is essentially responsible for the arsenic-mediated inhibition of tumor migration in vitro as well as distant metastasis in vivo. Studies to date have delineated the hypoxia-HIF (hypoxia-inducible factor)-CXCR4 signaling as a pivotal pathway tuning cancer metastasis. To substantiate our finding we investigate whether arsenic trioxide negatively regulates CXCR4 expression owing to its capacity to target HIF for degradation under hypoxic conditions. Our experimental results have demonstrated that arsenic trioxide destabilized HIF-1α protein under hypoxic condition through interrupting histone deacetylase (HDAC) 1 associating with HIF-1α, thus resulting in reduction of CXCR4 expression. Further, arsenic trioxide dephosphorylated HDAC1, a process by activating PP1 phosphatase, is critically responsible for the interruption of HDAC1 binding to HIF-1α. Collectively, these results unveil Hypoxia-HIF-1-CXCR4 pathway as a novel molecular therapeutic target for arsenic trioxide. As starving tumor cells of oxygen is the major microenvironmental factor that triggers metastasis, the data presents herein may provide insight into the rational development of chemotherapeutic combinations involving arsenic trioxide as well as into molecular mechanisms of arsenic-suppressed cancer metastasis.
Abstract Intrinsic intra-tumor heterogeneity (ITH) has been linked to worse patient outcomes. The development of spatial profiling technology has enabled the deciphering of ITH with multiple analysis readouts. Advanced ovarian clear cell carcinoma (OCCC), known to harbor ITH, is chemoresistant, poor prognostic, and possesses distinct molecular and histological characteristics. However, detailed spatial information of the nature of ITH within OCCC remains unclear. Here, we utilized the NanoString Digital spatial profiling (DSP) GeoMx platform to perform multiplex protein expression analysis on tumor samples of primary and colonic metastatic sites from one advanced OCCC patient. The spatial resolution revealed the existence of an epithelial-mesenchymal (EM) gradient within the metastatic tumor but not the primary tumor, and similar EM gradient was not observed within the primary tumor. The EM gradient exhibited a distinct pattern from the periphery to the core of the metastatic tumor. Compared to tumor cells at the primary site, there was an intermediate zone in between the tumor periphery and the tumor core in the colonic metastasis with differential expression patterns of pan-cytokeratin (PanCK), fibronectin (FN), smooth muscle actin (SMA), neural cell adhesion molecule (NCAM), integrin alpha X (ITGAX), and Ki-67. Our study provides the first spatially resolved in situ evidence of intermediate or hybrid EM states within the tumor samples of similar morphology. This not only demonstrates the promising applications of spatial profiling in precision medicine but also provides an unprecedented view of the EM gradient during the progression of cancer such as OCCC.
To evaluate feasibility and oncological outcome of laparoscopic radical hysterectomy (LRH) with lymphadenectomy in patients with cervical cancer, we performed a retrospective study to compare LRH to radical abdominal hysterectomy (RAH). Data of patients with stage Ia1-IIb cervical cancer who underwent LRH or RAH were retrospectively collected. Their operation data, complications, oncological outcome, and survival were compared between the two groups. 178 patients diagnosed with cervical cancer and underwent radical hysterectomy in Dept. O & G, the People's Hospital, Peking University from November 2004 to December 2010 were recruited. 55 underwent LRH successful and 120 underwent RAH. Conversion to open surgery was necessary in 3 cases due to bleeding (2 cases) and severe adhesion of pelvic cavity (1 case). Compared with the patients with RAH, patients in LRH group were experienced less blood loss (336 ml vs 682 ml, P<0.001) and a relative short operation time (239 min vs 249 min, P = 0.079). The number of resected pelvic lymph nodes in LRH group was less than that in RAH group (24.8 vs 32.4, P = 0.002). However, the lymph nodes metastasis were found with no significant different between the two groups (14.5% vs 26.1%, P = 0.118). Postoperative complications occurred in 4 LRH patients (ureterostenosis in 3 cases, bladder dysfunction in 1 cases) and 6 RAH patients (bladder dysfunction in 3 cases, lymphocyst in 2 cases, deep venous thrombosis in 1 cases). The median follow-up was 29.3 months (range, 4-64 months). 10 patients had a recurrence, 2 patients died of disease. No significant different of survival rate was detected between the two groups. LRH with pelvic lymphadenotomy can be considered a safe and effective treatment for patients with cervical cancer. Compared with laparotomy, it's with advantages of minimal blood loss and has similar oncologic outcomes without increase the operative complications.
'/%3e%3cuse xlink:href='%23a' transform='rotate(60)'/%3e%3ccircle r='17' fill='%23000095'/%3e%3ccircle r='15' fill='%23fff'/%3e%3c/svg%3e)
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)