High expression of prostate-specific membrane antigen in the tumor-associated neo-vasculature is associated with worse prognosis in squamous cell carcinoma of the oral cavity

Haffner, Michael C.; Laimer, Johannes; Chaux, Alcides; Schäfer, Georg; Obrist, Peter; Brunner, Andrea; Kronberger, Irmgard; Laimer, Klaus; Gürel, Bora; Koller, Johann; Seifarth, Christof; Zelger, Bettina; Klocker, Helmut; Rasse, Michael; Doppler, Wolfgang; Bander, Neil H.

doi:10.1038/modpathol.2012.66

Cited by 68 publications

(64 citation statements)

References 30 publications

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“…Another 2 studies were also excluded due to lack of data integrity (Figure 1). Eventually, 12 clinical cohort studies with a total of 979 oral cancer patients met our inclusion criteria for quantitative data analysis [8, 11, 18, 19, 21–23, 27–31]. There were 5 independent analyses focused on the prognosis of oral cancer, some of which were divided into two groups, including COX2-positive group ( n = 157) and COX2-negative group ( n = 254).…”

Section: Resultsmentioning

confidence: 99%

“…To be specific, the upregulation of COX2, at both mRNA and protein levels, may result in the enhanced synthesis of prostaglandins, increasing proliferative activity of neoplastic cells, and further accelerating angiogenesis and inhibiting immune surveillance; additionally, immunohistochemical overexpression of COX2 may thereby inhibit apoptosis and strength invasiveness [27]. In this regard, high expression levels of COX2-derived prostaglandin can be identified to be active in highly vascularized tumors, and in turn selective suppression of COX2 could lead to a decreased tumor growth because of the transformation in the neovasculature [23]. Therefore, we can postulate that the elevated expression of COX2 may have an important role in predicting the clinical outcome in oral cancer, and these many essential processes in carcinogenesis make COX2 an attractive therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, it may also be useful for the adoption of selective COX2 receptor-blocking agents in prevention of oral cancer by blocking initiation, progression, or metastasis of tumors [20]. In recent decades, several previous studies have confirmed that the elevated COX2 levels may be an indicator of biologically aggressive tumor prognosis based on its important role on tumor cells growth and metastasis [21, 22]; meanwhile other studies have also illustrated inconsistent results [8, 23]. Given the conflicting evidence on this issue, we conducted a meta-analysis of all available cohort studies to explore the associations between the serum level of COX2 and the prognosis in oral cancer patients.…”

Section: Introductionmentioning

confidence: 99%

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Abnormal COX2 Protein Expression May Be Correlated with Poor Prognosis in Oral Cancer: A Meta-Analysis

Wang

Liu

et al. 2014

BioMed Research International

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Background. The prognostic significance of COX2 for survival of patients with oral cancer remains controversial. Thus, the meta-analysis was performed in order to identify COX2 expression impact on prognosis of oral cancer. Method. Relevant literatures were searched using the following electronic databases without any language restrictions: Web of Science, the Cochrane Library Database, PubMed, EMBASE, CINAHL, and CBM. Version 12.0 STATA software (Stata Corporation, College Station, Texas, USA) was used for the current meta-analysis. Odds ratios (ORs) and hazard ratios (HRs) with their corresponding 95% confidence interval (95% CI) were also calculated to clarify the correlation between COX2 expression and prognosis of oral cancer. Results. Final analysis of 979 oral cancer patients from 12 clinical cohort studies was performed. The meta-analysis results show that COX2 expression in cancer tissues was significantly higher than those in normal and benign tissues (all P < 0.05). Combined HR of COX2 suggests that positive COX2 expression has a shorter overall survival (OS) than those of negative COX2 expression (P < 0.05). Conclusion. The meta-analysis study shows that elevated COX2 expression may be associated with the pathogenesis of oral cancer and with a worse prognosis in oral cancer patients.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Abnormal COX2 Protein Expression May Be Correlated with Poor Prognosis in Oral Cancer: A Meta-Analysis

Wang

Liu

et al. 2014

BioMed Research International

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“…This opposite gene modulation may favor the angiopoietin 1 (ANGPT1)-TIE2 interaction and, together with the down-modulation of VEGFR1 (FLT1) and VEGFR2 (KDR), drive a physiological normalization of the vasculature at tumor site [2]. This hypothesis is also supported by the findings that genes encoding for proteins expressed by endothelial precursor cells or by the tumor-associated neo-vasculature such as Folate receptor 1 (FOLH1, known also as PMSA), CXCR7 and ESM1, [3-6] were also down-modulated. Gene profiling also revealed that in cediranib treated ASPS, CCL2 mRNA was associated to the presence of high level of CD163 gene expression.…”

Section: Commentarymentioning

confidence: 99%

Structured myeloid cells and anti-angiogenic therapy in alveolar soft part sarcoma

Castelli

Tazzari

Negri³

et al. 2013

J Transl Med

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Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma and the clinical management of patients with unresectable, metastatic disease is still challenging. ASPS expresses an array of potentially therapeutically targetable, angiogenesis-related molecules and, importantly, it has a distinctive angiogenic phenotype marked by a peculiar tumor-associated vasculature. Several studies, conducted in transgenic mouse models and in a large variety of human tumors of different histotype, clearly proved the substantial contribution of tumor-infiltrating myeloid cells, such as myeloid derived suppressor cells, monocytes and macrophages, in the formation and maintenance of abnormal blood vessels in tumors. By immunohistochemistry we thus explored the presence and the distribution of cells expressing myeloid markers in the inflammatory infiltrate of surgical treated metastatic ASPS. Indeed, we found that myeloid cells expressing CD14 and CD163 markers constitute the prominent cells in the inflammatory infiltrate of ASPS. These macrophage-like cells form a network surrounding the endothelial cells, or, interspersed in the tumor nest, they keep deep contact with tumor cells. In this commentary, we discussed our findings in relation to the recently published paper by Kummar and colleagues reporting the clinical and molecular results of a phase II clinical trial in patients with unresectable, metastatic ASPS treated with the anti-angiogenic drug cediranib, targeting the VEGFR-1,-2,-3 tyrosine kinases.

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“…Immunohistochemical studies reported that PSMA is strongly expressed by normal and neoplastic prostatic epithelium, along with the epithelium of other genitourinary organs (bladder, kidney, fallopian tubes) and intestine 3–5 . Several recent studies found that PSMA could be expressed not only by epithelial cells, but also by vascular endothelium of various malignancies including oral 6 , gastric and colorectal 7 , lung 8 , breast 9 , endometrial and ovarian 10 , renal 11 , urothelial 12 , and glial tumors 13, 14 .…”

Section: Introductionmentioning

confidence: 99%

PSMA expression by microvasculature of thyroid tumors – Potential implications for PSMA theranostics

Bychkov

Vutrapongwatana

Tepmongkol

et al. 2017

Sci Rep

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Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer epithelium, making it a promising target for molecular imaging and therapy. Recently, several studies found unexpected PSMA radiotracer uptake by thyroid tumors, including radioiodine-refractory (RAIR) cancers. PSMA expression was reported in tumor-associated endothelium of various malignancies, however it has not been systematically addressed in thyroid tumors. We found that PSMA was frequently expressed in microvessels of thyroid tumors (120/267), but not in benign thyroid tissue. PSMA expression in neovasculature was highly irregular ranging from 19% in benign tumors to over 50% in thyroid cancer. Such heterogeneity was not directly attributed to endothelial cell proliferation as confirmed by immunostaining with proliferation-associated endothelial marker CD105. PSMA expression was associated with tumor size (p = 0.02) and vascular invasion in follicular carcinoma (p = 0.03), but not with other baseline histological, and clinical parameters. Significant translational implication is that RAIR tumors and high-grade cancers maintain high level of PSMA expression, and can be targeted by PSMA ligand radiopharmaceuticals. Our study predicts several pitfalls potentially associated with PSMA imaging of the thyroid, such as low expression in oncocytic tumors, absence of organ specificity, and PSMA-positivity in dendritic cells of chronic thyroiditis, which is described for the first time.Prostate specific membrane antigen (PSMA) is a type II transmembrane glycoprotein highly restricted to prostate epithelium 1, 2 . It is also known as FOLH1 (folate hydrolase 1) or glutamate carboxypeptidase II. Immunohistochemical studies reported that PSMA is strongly expressed by normal and neoplastic prostatic epithelium, along with the epithelium of other genitourinary organs (bladder, kidney, fallopian tubes) and intestine [3][4][5] . Several recent studies found that PSMA could be expressed not only by epithelial cells, but also by vascular endothelium of various malignancies including oral 6 , gastric and colorectal 7 , lung 8 , breast 9 , endometrial and ovarian 10 , renal 11 , urothelial 12 , and glial tumors 13,14 .PSMA is an integral membrane protein, anchored to the epithelial cells. This makes an important advantage of being a targeting marker over prostate-related secretory antigens released into bloodstream, such as prostate specific antigen, prostatic acid phosphatase and prostate secretory protein 15 . Molecular imaging of PSMA is now being widely adopted in prostate cancer diagnostics [16][17][18] . 68 Ga-PSMA PET/CT is a novel imaging modality based on 68 Ga conjugated with anti-PSMA monoclonal antibody, which is highly accurate in detecting prostate cancer 19 . It also has promising therapeutic potential, being a carrier for radionuclides directed against cancer cells. One of such theranostic example is 177 Lu-labelled tracer PSMA-DKFZ-617, which demonstrated radiological response in preclinical model and clinical studies of prostate canc...

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High expression of prostate-specific membrane antigen in the tumor-associated neo-vasculature is associated with worse prognosis in squamous cell carcinoma of the oral cavity

Cited by 68 publications

References 30 publications

Abnormal COX2 Protein Expression May Be Correlated with Poor Prognosis in Oral Cancer: A Meta-Analysis

Abnormal COX2 Protein Expression May Be Correlated with Poor Prognosis in Oral Cancer: A Meta-Analysis

Structured myeloid cells and anti-angiogenic therapy in alveolar soft part sarcoma

PSMA expression by microvasculature of thyroid tumors – Potential implications for PSMA theranostics

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