Analysis of biomarker expression in severe endometriosis and determination of possibilities for targeted intraoperative imaging

Berg, Liseth L. van den; Crane, Lucia M. A.; Oosten, Marleen van; Dam, Gooitzen M. van; Simons, Arnold; Hofker, H. Sijbrand; Bart, Joost

doi:10.1016/j.ijgo.2012.10.025

Cited by 19 publications

(11 citation statements)

References 25 publications

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“…The HIF isoforms expression are increased in OMA, in agreement with a previous study reporting an upregulation of HIF-1a expression in the endometriosis-like lesions in a mouse model of endometriosis, only during the early stages of transplantation and invasion. 29 The lack of HIF-1/2a expression in DIE is in agreement with a previous study, where the authors reported no HIF-1a expression in severe endometriosis, 11 suggesting that HIF and its hypoxic-related responses may not have an active role in the DIE but only in OMA.…”

Section: Discussionsupporting

confidence: 90%

“…4 –6 Hypoxia inducible factor 1α (HIF-1α) and HIF-2α are known to be stabilized at different oxygen levels and to have different temporal responses 7 and are expressed in human and rat endometrium. 8,9 Expression of HIF-1α mRNA was observed in eutopic endometrium of women with endometriosis 10 but not in endometriotic tissue, 11 while no data about HIF-2α expression in endometriotic lesions are referred.…”

Section: Introductionmentioning

confidence: 99%

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Different Expression of Hypoxic and Angiogenic Factors in Human Endometriotic Lesions

et al. 2016

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Endometriosis is associated with local angiogenic and hypoxic mechanisms. Indeed, peritoneal fluid of women with endometriosis generates a specific microenvironment to support the growth and development of ectopic endometrial tissues. The association between proangiogenic markers and hypoxic processes in different endometriosis phenotypes was investigated in the present study, analyzing the expression of several genes, related to hypoxic signaling pathway and involved in angiogenic processes, in nonpregnant women with different forms of endometriosis. Samples of ovarian endometrioma (OMA; n = 16) or deep infiltrating endometriosis (DIE; n = 11) were collected, and in addition, control endometrium was collected from healthy women by hysteroscopy. The gene expression of the hypoxia-inducible factors (HIF) 1/2α, protease-activated receptors (PARs) ¼, and vascular endothelial growth factor (VEGF) A was evaluated by quantitative reverse-transcription polymerase chain reaction. Ovarian endometrioma expresses high levels of HIF-1/2α, PAR-1/4, and VEGF-A, while DIE did not show significantly different gene expression compared to endometrium from unaffected women. A positive correlation between the expression of HIF-1/2α and VEGF-A mRNA was observed in OMA. The overall data point out that the heterogeneity of the disease reflects differences in expression levels of genes associated with hypoxia and angiogenesis, suggesting that such conditions may have an active role in the development of the disease.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Different Expression of Hypoxic and Angiogenic Factors in Human Endometriotic Lesions

et al. 2016

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“…Previous studies report on constitutive FRα expression on normal uterine epithelium, but high expression on various EC tumor tissues [ 12 , 26 ]. An additional finding observed after histopathological analysis of uterine tissues was strong FRα expression in adenomyosis cells, which has been previously described in 17/18 endometriosis samples [ 27 ]. Since the aim of surgery in severe endometriosis patients is to resect all visible lesions, it is plausible that OTL-38 may enhance intraoperative detection in those patients, enabling better patient outcome.…”

Section: Discussionsupporting

confidence: 62%

Folate receptor-α targeted near-infrared fluorescence imaging in high-risk endometrial cancer patients: a tissue microarray and clinical feasibility study

et al. 2017

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ObjectiveDetection and resection of all malignant lesions is pivotal in staging and cytoreductive surgery (CRS) of endometrial cancer (EC). Intraoperative EC detection could be enhanced using OTL-38, a fluorescent-labelled folate receptor-α (FRα) targeted imaging agent. The objectives of this study were to investigate which subgroups of high-risk EC patients express FRα and assess feasibility of intraoperative EC detection using OTL-38.ResultsFRα expression on TMA was significantly correlated with tumor type (p < 0.01). Eighty-two percent of serous and clear cell carcinomas showed FRα expression. Four patients were enrolled in the clinical study. Using fluorescence imaging all omental (n = 3) and lymph node (LN) metastases (n = 16) could be clearly identified, including one otherwise undetected omental metastasis. However, false-positive fluorescence was identified in 17/50 non-metastatic LNs, caused by OTL-38 targeting of FRβ, expressed by tumor-associated activated macrophages.ConclusionsThis study describes high FRα expression in serous and clear cell EC and demonstrates the first experience of intraoperative FRα-targeted tumor detection in patients with these subtypes of EC. Although all metastases could be clearly identified using OTL-38, the role of tumor-associated macrophages should be further evaluated.MethodsImmunohistochemical (IHC) staining of FRα expression was performed on tissue micro arrays (TMA) of 116 patients with high-risk EC features. Patients with either serous or clear cell EC, planned for staging or CRS, were eligible for inclusion in the clinical study and received an intravenous dose of 0.0125 mg/kg OTL-38, 2-3 hours prior to surgery. Resected lesions, identified by standard-of-care and/or fluorescence imaging, were histopathologically assessed for FRα and tumor status.

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“…Given few examples of its expression at the site of disease, the mechanism by which NrCAM is secreted into the circulation remains unclear. Similar unexpected results were found for EpCAM which has also been shown to be increased in extrauterine tissues, while we saw a corresponding drop in the plasma of our endometriosis patients [20].…”

Section: Discussionsupporting

confidence: 88%

Discovering endometriosis biomarkers with multiplex cytokine arrays

et al. 2019

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Background Chronic pelvic pain is often overlooked during primary examinations because of the numerous causes of such “vague” symptoms. However, this pain can often mask endometriosis, a smoldering disease that is not easily identified as a cause of the problem. As such, endometriosis has been shown to be a potentially long-term and often undiagnosed disease due to its vague symptoms and lack of any non-invasive testing technique. Only after more severe symptoms arise (severe pelvic pain, excessive vaginal bleeding, or infertility) is the disease finally uncovered by the attending physician. Due to the nature and complexity of endometriosis, high throughput approaches for investigating changes in protein levels may be useful for elucidating novel biomarkers of the disease and to provide clues to help understand its development and progression. Methods A large multiplex cytokine array which detects the expression levels of 260 proteins including cytokines, chemokines, growth factors, adhesion molecules, angiogenesis factors and other was used to probe biomarkers in plasma samples from endometriosis patients with the intent of detecting and/or understanding the cause of this disease. The protein levels were then analyzed using K-nearest neighbor and split-point score analysis. Results This technique identified a 14-marker cytokine profile with the area under the curve of 0.874 under a confidence interval of 0.81–0.94. Our training set further validated the panel for significance, specificity, and sensitivity to the disease samples. Conclusions These findings show the utility and reliability of multiplex arrays in deciphering new biomarker panels for disease detection and may offer clues for understanding this mysterious disease. Electronic supplementary material The online version of this article (10.1186/s12014-019-9248-y) contains supplementary material, which is available to authorized users.

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Analysis of biomarker expression in severe endometriosis and determination of possibilities for targeted intraoperative imaging

Abstract: Of the 7 biomarkers assessed in the present study, EpCAM, FR-α, and VEGF-A seem the most promising for targeted intraoperative imaging of endometriosis.

Cited by 19 publications

References 25 publications

Different Expression of Hypoxic and Angiogenic Factors in Human Endometriotic Lesions

Different Expression of Hypoxic and Angiogenic Factors in Human Endometriotic Lesions

Folate receptor-α targeted near-infrared fluorescence imaging in high-risk endometrial cancer patients: a tissue microarray and clinical feasibility study

Discovering endometriosis biomarkers with multiplex cytokine arrays

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