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      Serum vascular endothelial growth factor (VEGF) levels correlate with number and location of micrometastases in a murine model of uveal melanoma

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          Abstract

          Background

          A preliminary animal study was performed to determine if hepatic micrometastases from uveal melanoma secrete vascular endothelial growth factor (VEGF) that is measurable in serum.

          Methods

          We analysed the serum of a C57Bl/6 mouse model of uveal melanoma (n=10) at days 4, 7, 14 and 21 post-inoculation for VEGF levels. We compared the serum VEGF levels with the number and location of hepatic micrometastases and their respective expression of VEGF mRNA.

          Results

          Serum VEGF levels rose after inoculation of C57Bl/6 mice eyes with B16LS9 cutaneous melanoma cells. Beginning on day 14 there was a statistically significant (p<0.05) increase in VEGF levels, rising to an average peak level of 37.985 pg/ml at day 21. Peak serum VEGF levels correlated with the total number of hepatic micrometastases (R=0.444) and there was moderate correlation of peak VEGF serum levels with micrometastases in more hypoxic locations (R=0.572). VEGF mRNA expression by micrometastases was highest in the most hypoxic regions of the hepatic lobule.

          Conclusions

          Hepatic micrometastastic melanoma arising in a mouse model of ocular melanoma secretes VEGF. The number and location of the micrometastases correlate with serum VEGF levels.

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          Most cited references21

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          Incidence of uveal melanoma in the United States: 1973-1997.

          Arun Singh, Allan K. Topham (2003)
          To determine the incidence of primary uveal melanoma in the United States over a 25-year period from 1973 to 1997. Systematic review of existing databases. Two thousand four hundred ninety-three patients with primary uveal melanoma (International Classification of Oncology [ICDO-2] codes C69.3 [choroid melanoma] and C69.4 [ciliary body and iris]) derived from the Surveillance, Epidemiology, and End Results (SEER) program database in the United States from 1973 to 1997. The significance of trend in age-adjusted incidence rate was determined using chi-square test, and 95% confidence intervals were calculated. The age-adjusted incidence rate. There was a total of 2493 cases of uveal melanoma, representing 2.9% of all recorded cases of melanoma. Almost all cases (99.4%) were reported by the hospitals, and histopathologic confirmation was available in 81.3% of cases. The mean age-adjusted incidence of uveal melanoma in the United States was 4.3 per million (4.1-4.5; 95% confidence interval [CI]). Most cases (97.8%) occurred in the white population. There was significant variation of incidence between genders (males, 4.9 [4.6-5.2] 95% CI interval; females, 3.7 [3.5-3.9] 95% CI interval). There was no significant variation of incidence by the geographic location of the registry and over the entire period of observation (chi-square test). The mean age-adjusted incidence of uveal melanoma (4.3 per million) in the United States is similar to that reported from European countries. The age-adjusted incidence rate of uveal melanoma has remained stable for the past 25 years.
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            Uveal melanoma: epidemiologic aspects.

            Marie-Louise Bergman, Stefan Seregard, U. Singh (2005)
            Melanomas of the ocular and adnexal structures comprise approximately 5% of all melanomas. The majority (85%) of ocular melanomas are uveal in origin; primary conjunctival and orbital melanomas are rare. The diagnosis of uveal melanoma is made by clinical examination including indirect ophthalmoscopy and by ancillary studies such as fluorescein angiography and ultrasonography. Metastases to the liver develop within 15 years after the initial diagnosis and treatment in approximately 50% of patients with posterior uveal melanoma; however, clinically evident metastatic disease at the time of initial presentation is uncommon, indicating that there is early subclinical metastasis in most cases.
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              Vascular endothelial growth factor a in eyes with uveal melanoma.

              Kitty Jager, Reinier Schlingemann, Irene C Notting … (2006)
              To determine the presence of vascular endothelial growth factor A (VEGF-A) in the aqueous humor of eyes with uveal melanoma and to identify its source. The VEGF-A concentrations were determined in aqueous humor samples obtained after enucleation from 74 eyes with untreated uveal melanoma and from 8 eyes with treated uveal melanoma. Patient survival and clinical and histopathological tumor variables were compared. In situ hybridization, Western blot analysis, and enzyme-linked immunosorbent assay were used to determine expression of VEGF-A in tumor tissue and in overlying retina. Aqueous VEGF-A concentrations ranged from 18 to 826 pg/mL in 74 untreated eyes, while concentrations in 30 control eyes were significantly lower (median, 50.1 pg/mL) (P<.001). Concentrations in 8 treated eyes were much higher (median, 364 pg/mL). In situ hybridization on tissue sections and Western blot analysis and enzyme-linked immunosorbent assay on tissue extracts revealed VEGF-A in uveal melanoma tissue and in retinal tissue. Uveal melanoma is associated with increased concentrations of VEGF-A in aqueous humor. Aqueous VEGF-A concentration correlates with largest basal tumor diameter and with the tumor height. In eyes with uveal melanoma, tumor and retinal tissues are sources of VEGF-A.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Br J Ophthalmol
                Journal ID (publisher-id): bjo
                Journal ID (hwp): bjophthalmol
                Title: The British Journal of Ophthalmology
                Publisher: BMJ Group (BMA House, Tavistock Square, London, WC1H 9JR )
                ISSN (Print): 0007-1161
                ISSN (Electronic): 1468-2079
                Publication date (Electronic): 6 September 2010
                Publication date (Print): January 2011
                Publication date PMC-release: 6 September 2010
                Volume: 95
                Issue: 1
                Pages: 112-117
                Affiliations
                [1 ]Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA
                [2 ]Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA
                Author notes
                Correspondence to Dr Hans E Grossniklaus, L.F. Montgomery Ophthalmic Pathology Laboratory, BT 428 Emory Eye Center, 1365 Clifton Road, Atlanta, GA 30322, USA; ophtheg@ 123456emory.edu

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                Article
                Publisher ID: bjophthalmol182402
                DOI: 10.1136/bjo.2010.182402
                PMC ID: 3000446
                PubMed ID: 20819828
                SO-VID: 0f593fa9-a3dc-4e25-816a-381bb6cef7d7
                Copyright © © 2011, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

                History
                Date accepted : 13 June 2010
                Categories
                Subject: Laboratory Science
                Subject: 1506
                Series title: Original article

                ScienceOpen disciplines: Ophthalmology & Optometry
                Keywords: neoplasia,pathology
                Data availability:
                ScienceOpen disciplines: Ophthalmology & Optometry
                Keywords: neoplasia, pathology

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