Redefining the origin and evolution of ovarian cancer: a hormonal connection

Cárdenas, Carlos; Alvero, Ayesha B.; Yun, Bo Hyon; Mor, Gil

doi:10.1530/erc-16-0209

Cited by 29 publications

(17 citation statements)

References 92 publications

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“…5–7 Furthermore, 60–70% of patients with ovarian cancer who respond to standard primary treatment relapse or die within 5 years after initial diagnosis. 8,47 This terrible situation has stimulated the development of new strategies to improve therapeutic efficacy.…”

Section: Discussionmentioning

confidence: 99%

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Jumonji domain-containing 6 (JMJD6) identified as a potential therapeutic target in ovarian cancer

Zheng

Tie

Fang

et al. 2019

Sig Transduct Target Ther

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Jumonji domain-containing 6 (JMJD6) is a candidate gene associated with tumorigenesis, and JMJD6 overexpression predicts poor differentiation and unfavorable survival in some cancers. However, there are no studies reporting the expression of JMJD6 in ovarian cancer, and no JMJD6 inhibitors have been developed and applied to targeted cancer therapy research. In the present study, we found that the high expression of JMJD6 in ovarian cancer was correlated with poor prognosis in ovarian cancer. A potential inhibitor (SKLB325) was designed based on the crystal structure of the jmjC domain of JMJD6. This molecule significantly suppressed proliferation and induced apoptosis in a dose-dependent manner in SKOV3 cell lines as detected by CCK-8 cell proliferation assays and flow cytometry. A Matrigel endothelial tube formation assay showed that SKLB325 inhibited capillary tube organization and migration in HUVECs in vitro. We also observed that JMJD6 colocalized with p53 protein in the nucleus, with mRNA and protein expression of p53 as well as its downstream effectors significantly increasing both in vitro and in intraperitoneal tumor tissues treated with SKLB325. In addition, SKLB325 significantly reduced the intraperitoneal tumor weight and markedly prolonged the survival of tumor-bearing mice. Taken together, our findings suggest that JMJD6 may be a marker of poor prognosis in ovarian cancer and that SKLB325 may be a potential candidate drug for the treatment of ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

“…5–7 In addition, more than 70% of ovarian cancer patients are at advanced stages when initially diagnosed, and the 5-year survival rate is less than 30%. 8 This terrible situation reflects a lack of novel, effective and feasible therapeutic approaches to treat ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

Jumonji domain-containing 6 (JMJD6) identified as a potential therapeutic target in ovarian cancer

Zheng

Tie

Fang

et al. 2019

Sig Transduct Target Ther

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“…Understanding the factors that recruit HGSC cells to the ovary could be critical to blocking metastasis. While the ovary is thought to attract malignant cells through production of inflammatory cytokines and hormonal signaling, little is known about intrinsic factors on the tumor cells that are involved in spread to the ovary [18]. A better understanding of the factors that regulate ovarian homing of HGSC cells could lead to the identification of therapeutic targets for preventing ovarian metastasis.…”

Section: Introductionmentioning

confidence: 99%

CD105 Is Expressed in Ovarian Cancer Precursor Lesions and Is Required for Metastasis to the Ovary

Bai

Zhu

Coffman

et al. 2019

Cancers

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Most high-grade serous ovarian cancers (HGSCs) initiate from the fallopian tube epithelium and then metastasize to the ovary and throughout the abdomen. Genomic analyses suggest that most HGSCs seed the ovary prior to abdominal dissemination. Similarly, animal models support a critical role for the ovary in driving abdominal dissemination. Thus, HGSC cell recruitment to the ovary appears to be a critical component of HGSC cell metastasis. We sought to identify factors driving HGSC recruitment to the ovary. We identified CD105 (endoglin, or ENG, a TGF-β receptor family member) as a mediator of HGSC cell ovarian recruitment. We found that CD105 was expressed on both serous tubal intraepithelial carcinoma (STIC) cells (STICs-HGSC precursors in the fallopian tube epithelium) and HGSC cells. Using data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), we showed that high CD105 expression by HGSC cells correlated with a metastatic signature. Furthermore, intravenous injection of CD105(+) HGSC tumor cells, but not CD105(−), resulted in ovarian-specific metastasis and abdominal dissemination of disease. CD105 knockdown or blockade with a clinically relevant CD105-neutralizing mAb (TRC105), inhibited HGSC metastasis, reduced ascites, and impeded growth of abdominal tumor nodules, thereby improving overall survival in animal models of ovarian cancer. CD105 knockdown was associated with a reduction in TGF-β signaling. Together, our data support CD105 as a critical mediator of ovarian cancer spread to the ovary and implicate it as a potential therapeutic target.

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“…Recently, Cardenas et al proposed that the origin and evolution of OC follow a four-step process that includes migration, seeding, induction, and expansion [ 5 ]. If the potential driving factors perturb the interaction between tumor cells, normal stromal cells, and the immune system, this process may be triggered [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Constructing an ovarian cancer metastasis index by dissecting medical records

et al. 2017

Oncotarget

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Globally, ovarian cancer (OC) is the leading cause of gynecological cancer-associated deaths. Metastasis, especially multi-organ metastasis, determines the speed of disease progression. A multicenter retrospective study was performed to identify the factors that drive metastasis, from medical records of 534 patients with OC. The average number of target organs per patient was 3.66, indicating multi-organ metastasis. The most common sites of metastasis were large intestine and greater omentum, which were prone to co-metastasis. Results indicated that ascites and laterality, rather than age and menopausal status, were the potential drivers for multi-organ metastasis. Cancer antigen (CA) 125 (CA-125) and nine other blood indicators were found to show a significant, but weak correlation with multi-organ metastasis. A neural network cascade-multiple linear regression hybrid model was built to create an ovarian cancer metastasis index (OCMI) by integration of six multi-organ metastasis drivers including CA-125, blood platelet count, lymphocytes percentage, prealbumin, ascites, and laterality. In an independent set of 267 OC medical records, OCMI showed a moderate correlation with multi-organ metastasis (Spearman ρ = 0.67), the value being 0.72 in premenopausal patients, and good performance in identifying multi-organ metastasis (area under the receiver operating characteristic curve = 0.832), implying a potential prognostic marker for OC.

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Redefining the origin and evolution of ovarian cancer: a hormonal connection

Cited by 29 publications

References 92 publications

Jumonji domain-containing 6 (JMJD6) identified as a potential therapeutic target in ovarian cancer

Jumonji domain-containing 6 (JMJD6) identified as a potential therapeutic target in ovarian cancer

CD105 Is Expressed in Ovarian Cancer Precursor Lesions and Is Required for Metastasis to the Ovary

Constructing an ovarian cancer metastasis index by dissecting medical records

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