Consensus Statement on the Immunohistochemical Detection of Ocular Lymphatic Vessels

Schroedl, Falk; Kaser-Eichberger, Alexandra; Schlereth, Simona L.; Bock, Felix; Regenfuß, Birgit; Reitsamer, Herbert A.; Lutty, Gerard A.; Maruyama, Kouichi; Chen, Lu; Lütjen–Drecoll, Elke; Dana, Reza; Kerjaschki, Dontscho; Alitalo, Kari; Stefano, Maria Egle De; Junghans, Barbara M; Heindl, Ludwig M.; Cursiefen, Claus

doi:10.1167/iovs.14-15638

Cited by 72 publications

(47 citation statements)

References 28 publications

(36 reference statements)

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“…68 An obstacle in detecting lymphatic vessel through immunohistochemistry is the absence of a single exclusive lymphatic marker; thus, current guidelines recommend the use of at least two lymphatic-specific markers for identifying lymphatic vessels in the eye. 70 Cursiefen et al used both podoplanin and LYVE-1 to confirm that lymphangiogenesis occurs in the cornea. 15 Currently, podoplanin is used to identify many different types of tumors: lymphangiomas, 69; 71 Karposi’s sarcomas, 69; 71; 72 angiosarcomas, 69; 71; 73 and squamous cell carcinomas.…”

Section: Lymphatic Markersmentioning

confidence: 99%

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Understanding lymphangiogenesis in knockout models, the cornea, and ocular diseases for the development of therapeutic interventions

Yang

Walia

Huang

et al. 2016

Survey of Ophthalmology

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A major focus of cancer research for several decades has been understanding the ability of tumors to induce new blood vessel formation, a process known as angiogenesis. Unfortunately, only limited success has been achieved in the clinical application of angiogenesis inhibitors. We now know that lymphangiogenesis, the growth of lymphatic vessels, likely also plays a major role in tumor progression. Thus, therapeutic strategies targeting lymphangiogenesis or both lymphangiogenesis and angiogenesis may represent promising approaches for treating cancer and other diseases. Importantly, research progress toward understanding lymphangiogenesis is significantly behind that related to angiogenesis. A PubMed search of ‘angiogenesis’ returns nearly 80,000 articles, whereas a search of ‘lymphangiogenesis’ returns approximately 2,635 articles. This stark contrast can be explained by the lack of molecular markers for identifying the invisible lymphatic vasculature that persisted until less than two decades ago combined with the intensity of research interest in angiogenesis during the past half-century. Still, significant strides have been made in developing strategies to modulate lymphangiogenesis, largely using ocular disease models. Here, we review the current knowledge of lymphangiogenesis in the context of knockout models, ocular diseases, the biology of activators and inhibitors, and the potential for therapeutic interventions targeting this process.

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Section: Lymphatic Markersmentioning

confidence: 99%

“…228 New guidelines for the identification of lymphatic vessels in the eye, including using at least two different immunohistochemical stains, aim to clarify the identification of lymphatic vessels. 70 …”

Section: Diseases Associated With Corneal Lymphangiogenesismentioning

confidence: 99%

Understanding lymphangiogenesis in knockout models, the cornea, and ocular diseases for the development of therapeutic interventions

Yang

Walia

Huang

et al. 2016

Survey of Ophthalmology

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“…2), which revealed dilated lymphatic vessels lined by flattened endothelium within the submucosa which stained positive for podoplanin (D240), a marker specific for lymphatic endothelium. 4,5 Blood tests were unremarkable, and magnetic resonance imaging of the orbits, head, and neck was normal.…”

Section: Casementioning

confidence: 99%

Successful Treatment of Conjunctival Lymphangiectasia With Subconjunctival Injection of Bevacizumab

Tan

Mann

Coroneo³

2016

Cornea

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“…Nonspecific binding was blocked by incubation in PBS containing 5% calf serum (1 hour, room temperature) and the following primary antibodies were used: S100B/S100 (monoclonal rabbit anti-mouse; Biozol, Munich, Germany), tyrosinase related protein 2 (TRP2) (polyclonal goat anti-mouse antibody; Santa Cruz Biotechnology, Heidelberg, Germany), Ki67 (rabbit anti-mouse; DCS innovative diagnostic systeme, Hamburg, Germany), CD31-FITC (BD Pharmingen, Heidelberg, Germany), and lymphatic vessel endothelium hyaluronan receptor 1 (LYVE1) (AngioBioCo, Del Mar, CA, USA). 21 The primary antibodies were added in a dilution of 1:100 in PBS (containing 2% fetal calf serum) (overnight incubation, 48C). The next day, samples were washed three times for 5 minutes with PBS with continuous shaking.…”

Section: Histology and Immunostainingmentioning

confidence: 99%

A Novel Model of Metastatic Conjunctival Melanoma in Immune-Competent Mice

Schlereth

Iden

Mescher

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Conjunctival melanoma (CM) is an ocular surface tumor that can lead to fatal metastases. Patients developing, tumor-associated lymphangiogenesis have a significantly increased risk of metastatic disease, because tumor spread primarily occurs via lymphatic vessels to the draining lymph node. Here, we describe a novel immune-competent mouse model of CM that displays tumor-associated lymphangiogenesis with development of metastatic tumors.METHODS. C57BL/6N mice received C57BL/6N-derived dermal melanoma cells (hepatocyte growth factor [HGF] cyclin dependent kinase-4 [Cdk4]þ) or B16F10 via subconjunctival injection. A clinical score quantified primary tumor growth and metastases were identified by macroscopic examination of the draining lymph nodes, lung, and spleen. Confirmation of tumors and metastases was achieved by immunohistochemical staining for markers of pigmented cells (tyrosinase related protein-2 [TRP2]) and S-100, and of cell proliferation (Ki67). The intra-and peritumoral CD31þ blood and lymphatic vessel endothelium hyaluronan receptor-1 (LYVE-1)þ lymphatic vessels were quantified immunohistochemically.RESULTS. All mice rapidly developed aggressive TRP2þ, S100þ, and Ki67þ CM. Metastatic tumors were found in the lymph node (9%) and lung (6%) of HGF-Cdk4 R24C -treated mice and in the spleen (8%) and lung (17%) of B16F10-treated mice. The amount of peri-and intratumoral blood vessels was significantly increased compared with lymphatic vessels.CONCLUSIONS. This CM model in immune-competent animals offers new possibilities to study the pathobiology of tumor growth, invasion, and mechanisms of metastatic tumor spread, and provides a robust model to explore new immune-based and antilymphangiogenic treatment modalities of this malignancy.Keywords: conjunctival melanoma, mouse model, (lymph)-angiogenesis, ocular melanoma, B16F10, hepatocyte growth factor, metastasis C onjunctival melanoma (CM) is the second most common malignancy of the ocular surface. The current treatment of primary CM is complete surgical removal of the tumor combined with adjuvant therapy in terms of radio-, cryo-, topical chemo-, and/or immunotherapy. However, even though surgical specimens indicate intact tumor-negative margins and apparent tumor removal, CM patients still display an unusually high rate of local recurrence (36%-62% of patients [1][2][3][4][5][6] ). Tumor recurrence coincides with a high risk for the development of metastases, which occurs in 12% to 25% of patients. [1][2][3] Metastatic tumors in CM patients are typically first detected in the lymph nodes draining the tumor-containing eye, indicating the primary route of tumor cell dissemination occurs via the lymphatic vessels. In support of this, we previously demonstrated that lymphangiogenesis is associated with the transition of premalignant precursors into CM.7 Moreover, the extent of lymphatic vessels within CM coincided with an increased risk of local recurrence, lymphatic spread of tumor cells, and development of metastatic disease. [8][9][10] Melanomas ar...

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Consensus Statement on the Immunohistochemical Detection of Ocular Lymphatic Vessels

Cited by 72 publications

References 28 publications

Understanding lymphangiogenesis in knockout models, the cornea, and ocular diseases for the development of therapeutic interventions

Understanding lymphangiogenesis in knockout models, the cornea, and ocular diseases for the development of therapeutic interventions

Successful Treatment of Conjunctival Lymphangiectasia With Subconjunctival Injection of Bevacizumab

A Novel Model of Metastatic Conjunctival Melanoma in Immune-Competent Mice

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