Merkel cell carcinoma induces lymphatic microvessel formation

Werchau, Siegfried; Toberer, Ferdinand; Enk, Alexander H.; Dammann, Reinhard; Helmbold, Peter

doi:10.1016/j.jaad.2011.09.002

Cited by 39 publications

(33 citation statements)

References 27 publications

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“…Recently, the critical role of VEGF-C producing TAM in lymphangiogenesis and tumor dissemination was found in mantle cell lymphoma (Song et al, 2013). The description of VEGF-C expressing TAM and their prolymphangiogenic influence can also be found in a variety of other studies (Jeon et al, 2008; Moussai et al, 2011; Ding et al, 2012; Werchau et al, 2012; Wu et al, 2012). …”

Section: Factors Produced By Tam That Regulate Lymphangiogenesismentioning

confidence: 77%

“…Similar results were obtained by Werchau et al in a study of Merkel cell carcinoma. Here, VEGF-C secreting CD68 + and/or CD163 + macrophages were also found to increase LYVE-1 + or D2-40 + LVD (Werchau et al, 2012). Unfortunately, both of these studies failed to provide a prognostic significance for these correlations.…”

Section: The Role Of Tam Density In Tumor Tissue and Its Association mentioning

confidence: 89%

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Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis

et al. 2014

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Tumor angiogenesis is an essential process for supplying rapidly growing malignant tissues with essential nutrients and oxygen. An angiogenic switch allows tumor cells to survive and grow, and provides them access to vasculature resulting in metastatic disease. Monocyte-derived macrophages recruited and reprogrammed by tumor cells serve as a major source of angiogenic factors boosting the angiogenic switch. Tumor endothelium releases angiopoietin-2 and further facilitates recruitment of TIE2 receptor expressing monocytes (TEM) into tumor sites. Tumor-associated macrophages (TAM) sense hypoxia in avascular areas of tumors, and react by production of angiogenic factors such as VEGFA. VEGFA stimulates chemotaxis of endothelial cells (EC) and macrophages. In some tumors, TAM appeared to be a major source of MMP9. Elevated expression of MMP9 by TAM mediates extracellular matrix (ECM) degradation and the release of bioactive VEGFA. Other angiogenic factors released by TAM include basic fibroblast growth factor (bFGF), thymidine phosphorylase (TP), urokinase-type plasminogen activator (uPA), and adrenomedullin (ADM). The same factors used by macrophages for the induction of angiogenesis [like vascular endothelial growth factor A (VEGF-A) and MMP9] support lymphangiogenesis. TAM can express LYVE-1, one of the established markers of lymphatic endothelium. TAM support tumor lymphangiogenesis not only by secretion of pro-lymphangiogenic factors but also by trans-differentiation into lymphatic EC. New pro-angiogenic factor YKL-40 belongs to a family of mammalian chitinase-like proteins (CLP) that act as cytokines or growth factors. Human CLP family comprises YKL-40, YKL-39, and SI-CLP. Production of all three CLP in macrophages is antagonistically regulated by cytokines. It was recently established that YKL-40 induces angiogenesis in vitro and in animal tumor models. YKL-40-neutralizing monoclonal antibody blocks tumor angiogenesis and progression. The role of YKL-39 and SI-CLP in tumor angiogenesis and lymphangiogenesis remains to be investigated.

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Section: Factors Produced By Tam That Regulate Lymphangiogenesismentioning

confidence: 77%

Section: The Role Of Tam Density In Tumor Tissue and Its Association mentioning

confidence: 89%

Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis

et al. 2014

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“…In addition to melanoma however, recent studies have reported increased lymphangiogenesis in dermis adjacent to tumor nests in squamous cell carcinoma that also exhibit enhanced levels of VEGF-C produced by CD163 + CD68 + macrophages (91). Similarly, an increase in the absolute numbers of lymphatic capillaries was observed in Merkel cell carcinoma, likely driven again by CD68 + CD163 + tumor-associated macrophages (110), and increased levels of VEGFR3 + cells (both tumor and stroma) and lymphatic (podoplanin + ) vessels correlated with disease progression in one study of Sézary syndrome, an aggressive subtype of cutaneous T-cell lymphoma (111). …”

Section: Lymphatic Vessels Inflammation and Metastasismentioning

confidence: 89%

Lymphatic Vessels, Inflammation, and Immunity in Skin Cancer

et al. 2016

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Skin is a highly ordered immune organ that coordinates rapid responses to external insult while maintaining self-tolerance. In healthy tissue, lymphatic vessels drain fluid and coordinate local immune responses; however, environmental factors induce lymphatic vessel dysfunction, leading to lymph stasis and perturbed regional immunity. These same environmental factors drive the formation of local malignancies, which are also influenced by local inflammation. Herein, we discuss clinical and experimental evidence supporting the tenet that lymphatic vessels participate in regulation of cutaneous inflammation and immunity, are important contributors to malignancy and potential biomarkers and targets for immunotherapy.

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“…Shields and colleagues introduced a prognostic index that clearly discriminated metastatic from non‐metastatic malignant melanoma and showed that the lymphatic density in the dermis surrounding malignant melanoma is an effective predictor of metastasis . Werchau provided the first detailed evidence of intratumoral and peritumoral lymphangiogenesis in MCC . His study focused on lymphovascular anatomy and lymphangiogenesis in MCC, whereas the current study focused on correlating the amount of intra‐ and peritumoral lymphatic vessels with the clinical outcome.…”

Section: Discussionmentioning

confidence: 98%