Impact of the Prolymphangiogenic Crosstalk in the Tumor Microenvironment on Lymphatic Cancer Metastasis

Schlereth, Simona L.; Refaian, Nasrin; Iden, Sandra; Cursiefen, Claus; Heindl, Ludwig M.

doi:10.1155/2014/639058

Cited by 21 publications

(13 citation statements)

References 186 publications

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“…Interestingly, we detected an association between high depth of tumor invasion and high proportion of lymphatic vessels. This is in line with observations, that crosstalk between invasive tumor and microenvironment might result in lymphangiogenesis [35]. We found that high RDLV did not affect patients' survival in the subgroup with metastatic tongue cancer.…”

Section: Discussionsupporting

confidence: 93%

High relative density of lymphatic vessels predicts poor survival in tongue squamous cell carcinoma

Seppälä

Pohjola

Laranne

et al. 2016

Eur Arch Otorhinolaryngol

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Tongue cancer has a poor prognosis due to its early metastasis via lymphatic vessels. The present study aimed at evaluating lymphatic vessel density, relative density of lymphatic vessel, and diameter of lymphatic vessels and its predictive role in tongue cancer. Paraffin-embedded tongue and lymph node specimens (n = 113) were stained immunohistochemically with a polyclonal antibody von Willebrand factor, recognizing blood and lymphatic endothelium and with a monoclonal antibody podoplanin, recognizing lymphatic endothelium. The relative density of lymphatic vessels was counted by dividing the mean number of lymphatic vessels per microscopic field (podoplanin) by the mean number of all vessels (vWf) per microscopic field. The high relative density of lymphatic vessels (≥80 %) was associated with poor prognosis in tongue cancer. The relative density of lymphatic vessels predicted poor prognosis in the group of primary tumor size T1-T2 and in the group of non-metastatic cancer. The lymphatic vessel density and diameter of lymphatic vessels were not associated with tongue cancer survival. The relative density of lymphatic vessels might have clinically relevant prognostic impact. Further studies with increased number of patients are needed.

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Section: Discussionsupporting

confidence: 93%

High relative density of lymphatic vessels predicts poor survival in tongue squamous cell carcinoma

Seppälä

Pohjola

Laranne

et al. 2016

Eur Arch Otorhinolaryngol

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“…It is an early step for tumor metastasis, which is stimulated by tumor microenvironmental factors, including cellular and non-cellular compartments and tumor cells themselves [23]. While most malignant tumors can migrate into other organs, lymphatic vessels and blood vessels play a key role in supporting metastasis.…”

Section: Discussionmentioning

confidence: 99%

Blockade of FLT4 suppresses metastasis of melanoma cells by impaired lymphatic vessels

Lee

Hong

Shin³

et al. 2016

Biochemical and Biophysical Research Communications

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“…[37][38][39][40] It is well accepted that the tumor microenvironment is essential for progression of tumors, 41,42 therefore our model presented here allows studying the effect of the tumor microenvironment on the host's immune system, neovascularization, and metastasis. 43 The role of different murine immune cells, cytokines, or growth factors can be studied in detail in this model (e.g., cancer-associated fibroblasts or macrophages, chemokine receptors, or the origin of tumoral lymphatic vessels).…”

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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Impact of the Prolymphangiogenic Crosstalk in the Tumor Microenvironment on Lymphatic Cancer Metastasis

Cited by 21 publications

References 186 publications

High relative density of lymphatic vessels predicts poor survival in tongue squamous cell carcinoma

High relative density of lymphatic vessels predicts poor survival in tongue squamous cell carcinoma

Blockade of FLT4 suppresses metastasis of melanoma cells by impaired lymphatic vessels

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

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