Novel surface targets and serum biomarkers from the ovarian cancer vasculature

Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, PA USA.
Cancer biology & therapy (Impact Factor: 3.07). 08/2011; 12(3):169-80. DOI: 10.4161/cbt.12.3.16260
Source: PubMed


The molecular phenotype of tumor vasculature is different from normal vasculature, offering new opportunities for diagnosis and therapy of cancer, but the identification of tumor-restricted targets remains a challenge. We investigated 13 tumor vascular markers (TVMs) from 50 candidates identified through expression profiling of ovarian cancer vascular cells and selected to be either transmembrane or secreted, and to be either absent or expressed at low levels in normal tissues while overexpressed in tumors, based on analysis of 1,110 normal and tumor tissues from publicly available Affymetrix microarray data. Tumor-specific expression of each TVM was confirmed at the protein level in tumor tissue and/or in serum. Among the 13 TVMs, 11 were expressed on tumor vascular endothelium; the remaining 2 TVMs were expressed by tumor leukocytes. Our results demonstrate that certain transmembrane TVMs such as ADAM12 and CDCP1 are selectively expressed in tumor vasculature and represent promising targets for vascular imaging or anti-vascular therapy of epithelial ovarian cancer, while secreted or shed molecules such as TNFRSF21/DR6 can function as serum biomarkers. We have identified novel tumor-specific vasculature markers which appear promising for cancer serum diagnostics, molecular imaging and/or therapeutic targeting applications and warrant further clinical development.

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Article: Novel surface targets and serum biomarkers from the ovarian cancer vasculature

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    • "These efforts identified several targets including the EDB domain of fibronectin, a series of numbered TEMs, annexin A and recently CLEC14A reviewed in Meyer, 2010. Recent studies have shown that TEMs are often tissue dependent, and that endothelial transcriptomes have been documented for colon (Van Beijnum et al, 2006), breast (Bhati et al, 2008; Jones et al, 2012) and ovarian cancer (Sasaroli et al, 2011). Known TEMs are often weakly expressed in lung tumours (Mura et al, 2012) and this prompted us to investigate TEMs in the lung. "
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    ABSTRACT: Background: Lung cancer remains the leading cause of cancer-related death, largely owing to the lack of effective treatments. A tumour vascular targeting strategy presents an attractive alternative; however, the molecular signature of the vasculature in lung cancer is poorly explored. This work aimed to identify novel tumour vascular targets in lung cancer. Methods: Enzymatic digestion of fresh tissue followed by endothelial capture with Ulex lectin-coated magnetic beads was used to isolate the endothelium from fresh tumour specimens of lung cancer patients. Endothelial isolates from the healthy and tumour lung tissue were subjected to whole human genome expression profiling using microarray technology. Results: Bioinformatics analysis identified tumour endothelial expression of angiogenic factors, matrix metalloproteases and cell-surface transmembrane proteins. Predicted novel tumour vascular targets were verified by RNA-seq, quantitative real-time PCR analysis and immunohistochemistry. Further detailed expression profiling of STEAP1 on 82 lung cancer patients confirmed STEAP1 as a novel target in the tumour vasculature. Functional analysis of STEAP1 using siRNA silencing implicates a role in endothelial cell migration and tube formation. Conclusions: The identification of cell-surface tumour endothelial markers in lung is of interest in therapeutic antibody and vaccine development.
    British Journal of Cancer 12/2014; 112(3). DOI:10.1038/bjc.2014.626 · 4.84 Impact Factor
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    • "It is quite possible that some of these tumor endothelial immunomodulatory mechanisms may not be directly mediated by VEGF. For example, we previoulsy found that many of the specific markers of tumor endothelium in ovarian cancer are induced not by VEGF but rather by a combination of hypoxia and inflammatory mediators [156]. Importantly, low dose cyclophosphamide used in this study to target Treg cells also exerts an antiangiogenic effect through direct cytotoxicity to tumor endothelium, which could synergize with bevacizumab to abate these aspects of the tumor endothelial barrier. "
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    Journal of Translational Medicine 06/2013; 11(1):149. DOI:10.1186/1479-5876-11-149 · 3.93 Impact Factor
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    • "Compared to hens with normal ovaries, the number of DR6-expressing microvessels was significantly higher in hens with early-stage OVCA and increased further in hens with late-stage OVCA. A recent study has reported increased expression of DR6 by ovarian tumors in patients with advanced-stage OVCA [6]. "
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