Antilymphangiogenic therapy to promote transplant survival and to reduce cancer metastasis: What can we learn from the eye?

Hos, Deniz; Schlereth, Simona L.; Bock, Felix; Heindl, Ludwig M.; Cursiefen, Claus

doi:10.1016/j.semcdb.2014.11.003

Cited by 60 publications

(55 citation statements)

References 138 publications

(256 reference statements)

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“…27 However, to date there are no immune-competent mouse models to study the biology of CM and to test new therapeutic approaches. 28,29 In this study, we aimed to develop a new model for CM in immune-competent mice. In patients, CM growth is initiated within the epithelium and invasion across the basement membrane is a major indicator of malignancy.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…227 Recently, Hos et al described the role of tumor-associated lymphangiogenesis in ocular malignancies and its potential role in future therapeutic development. 20 …”

Section: Diseases Associated With Corneal Lymphangiogenesismentioning

confidence: 99%

“…16; 17; 18 Elucidation of the mechanisms by which lymphangiogenesis occurs in the cornea can lead to the development of therapeutics targeted at reducing corneal neovascularization and may be extrapolated to the prevention of tumor cell metastasis in cancer patients. 19; 20; 21 …”

Section: Introductionmentioning

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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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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“…Alternatively, mitomycin C or interferon alfa-2b can be considered for topical administration [43,44,45]. Additionally, anti-VEGF (vascular endothelial growth factor) targeted therapies such as bevacizumab eye drops have recently been proposed as a novel possibility to prevent metastasis [46]. …”

Section: Introductionmentioning

confidence: 99%

Systemic BRAF/MEK Inhibitors as a Potential Treatment Option in Metastatic Conjunctival Melanoma

Mor

Heindl

2016

Ocul Oncol Pathol

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Aim: In this review, we outline similarities between conjunctival and skin melanoma as well as the effectiveness of combined BRAF/MEK inhibition in melanoma, and discuss the applicability of these agents in conjunctival melanoma. Methods: The study provides a PubMed literature review. Results: Conjunctival melanoma and skin melanoma are genetically and phenotypically related. Both tumors typically harbor BRAF mutations in more than 50% of cases. New targeted therapies in metastatic skin melanoma include selective inhibition of BRAF and MEK. Combined BRAF/MEK inhibition has revolutionized the treatment of metastatic skin melanoma, significantly improving patients' prognoses. While these new substances have been investigated extensively in the treatment of skin melanoma, comparable studies in conjunctival melanoma do not exist owing to the rarity of the malignancy. Conclusions: The application of combined BRAF/MEK inhibition in metastatic or unresectable conjunctival melanoma shows great potential for improving patients' prognoses. Future studies are needed to investigate the assumed benefit.

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Antilymphangiogenic therapy to promote transplant survival and to reduce cancer metastasis: What can we learn from the eye?

Cited by 60 publications

References 138 publications

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

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

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

Systemic BRAF/MEK Inhibitors as a Potential Treatment Option in Metastatic Conjunctival Melanoma

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