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.

  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Dec 2014 · British Journal of Cancer
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose Ovarian cancer, like most solid tumors, is in dire need of effective therapies. The significance of this trial lies in its promise to spearhead the development of combination immunotherapy and to introduce novel approaches to therapeutic immunomodulation, which could enable otherwise ineffective vaccines to achieve clinical efficacy. Rationale Tumor-infiltrating T cells have been associated with improved outcome in ovarian cancer, suggesting that activation of antitumor immunity will improve survival. However, molecularly defined vaccines have been generally disappointing. Cancer vaccines elicit a modest frequency of low-to-moderate avidity tumor-specific T-cells, but powerful tumor barriers dampen the engraftment, expansion and function of these effector T-cells in the tumor, thus preventing them from reaching their full therapeutic potential. Our work has identified two important barriers in the tumor microenvironment: the blood-tumor barrier, which prevents homing of effector T cells, and T regulatory cells, which inactivate effector T cells. We hypothesize that cancer vaccine therapy will benefit from combinations that attenuate these two barrier mechanisms. Design We propose a three-cohort sequential study to investigate a combinatorial approach of a new dendritic cell (DC) vaccine pulsed with autologous whole tumor oxidized lysate, in combination with antiangiogenesis therapy (bevacizumab) and metronomic cyclophosphamide, which impacts Treg cells. Innovation This study uses a novel autologous tumor vaccine developed with 4-day DCs pulsed with oxidized lysate to elicit antitumor response. Furthermore, the combination of bevacizumab with a whole tumor antigen vaccine has not been tested in the clinic. Finally the combination of bevacizumab and metronomic cyclophosphamide in immunotherapy is novel.
    Full-text · Article · Jun 2013 · Journal of Translational Medicine
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumor-associated neoangiogenesis and suppression of antitumor immunity are hallmarks of tumor development and progression. Death receptor 6 (DR6) has been reported to be associated with suppression of antitumor immunity and tumor progression in several malignancies. However, expression of DR6 by malignant ovarian epithelial tumors at an early stage is unknown. The goals of this study were to determine whether DR6 is expressed by malignant ovarian epithelial tumors at an early stage and to examine whether DR6 expression is associated with ovarian cancer (OVCA) progression in a laying hen model of spontaneous OVCA. Expression of DR6 was examined in normal and malignant ovaries, normal ovarian surface epithelial (OSE) cells, or malignant epithelial cells and in serum of 3-year-old hens. The population of microvessels expressing DR6 was significantly higher in hens with early-stage OVCA than hens with normal ovaries (P < .01) and increased further in late-stage OVCA. The results of this study showed that, in addition to microvessels, tumor cells in the ovary also express DR6 with a significantly higher intensity than normal OSE cells. Similar patterns of DR6 expression were also observed by immunoblot analysis and gene expression studies. Furthermore, DR6 was also detected in the serum of hens. In conclusion, DR6 expression is associated with OVCA development and progression in laying hens. This study may be helpful to examine the feasibility of DR6 as a useful surrogate marker of OVCA, a target for antitumor immunotherapy and molecular imaging and thus provide a foundation for clinical studies.
    Full-text · Article · Aug 2012 · Translational oncology
Show more