The mechanisms that cause tumors such as melanomas to metastasize into peripheral lymphatic capillaries are poorly defined. Non-mutually-exclusive mechanisms are lymphatic endothelial cell (LEC) chemotaxis and proliferation in response to tumor cells (chemotaxis-lymphangiogenesis hypothesis) or LECs may secrete chemotactic agents that attract cancer cells (chemotactic metastasis hypothesis). Using migration assays, we found evidence supporting both hypotheses. Conditioned medium (CM) from metastatic malignant melanoma (MMM) cell lines attracted LEC migration, consistent with the lymphangiogenesis hypothesis. Conversely, CM from mixed endothelial cells or LECs, but not blood endothelial cells, attracted MMM cells but not non-metastatic melanoma cells, consistent with the chemotactic metastasis hypothesis. MMM cell lines expressed CCR7 receptors for the lymphatic chemokine CCL21 and CCL21 neutralizing antibodies prevented MMM chemotaxis in vitro. To test for chemotactic metastasis in vivo tumor cells were xenotransplanted into nude mice B1 cm from an injected LEC depot. Two different MMM grew directionally towards the LECs, whereas non-metastatic melanomas did not. These observations support the hypothesis that MMM cells grow towards regions of high LEC density owing to chemotactic LEC secretions, including CCL21. This chemotactic metastasis may contribute to the close association between metastasizing tumor cells and peritumor lymphatic density and promote lymphatic invasion.
Malignant melanoma (MM), the most common cause of skin cancer deaths, metastasises to regional lymph nodes. In animal models of other cancers, lymphatic growth is associated with metastasis. To assess if lymphatic density (LD) was increased in human MM, and its association with metastasis, we measured LD inside and around archival MM samples (MM, n ¼ 21), and compared them with normal dermis (n ¼ 11), basal cell carcinoma (BCC, n ¼ 6) and Merkel cell carcinoma (MCC), a skin tumour thought to metastasise through a vascular route (MCC, n ¼ 6). Lymphatic capillary density (mm À2 ), as determined by immunohistochemical staining with the lymphatic specific marker LYVE-1, was significantly increased around MM (10.072.5 mm À2 ) compared with normal dermis (2.470.9 mm À2 ), BCC (3.070.9 mm À2 ) and MCC (2.471.4 mm À2 ) (Po0.0001). There was a small decrease in LD inside MM (1.170.7 mm À2 ) compared with normal dermis, but a highly significant decrease in BCC (0.1470.13) and MCC (0.1272.4) (Po0.01 Kruskal -Wallis). Astonishingly, LD discriminated between melanomas that subsequently metastasised (12.871.6 mm À2 ) and those that did not (5.471.1 mm À2 , Po0.01, Mann -Whitney). Lymphatic invasion by tumour cells was seen mainly in MM that metastasised (70% compared with 12% not metastasising, Po0.05 Fisher's Exact test). The results show that LD was increased around MMs, and that LD and tumour cell invasion of lymphatics may help to predict metastasis. To this end, a prognostic index was calculated using LD, lymphatic invasion and thickness that clearly discriminated metastatic from nonmetastatic tumours.
Phone : 0208 725 0957Fax : 0208 725 3444 Conflict of interestAll authors declare no conflict of interest. AcknowledgementsWe would like to acknowledge the members of the Lymphoedema Research Consortium, UK. We extend our thanks to the patients and their families and the British Heart Foundation for funding the work of KG (FS/11/40/28739) and PO (PG/10/58/28477). CGE-00117-2013Connell et al 2 AbstractHistorically, primary lymphoedema was classified into just three categories depending on the age of onset of swelling; congenital, praecox and tarda. Developments in clinical phenotyping and identification of the genetic cause of some of these conditions have demonstrated that primary lymphoedema is highly heterogenous. In 2010 we introduced a new classification and diagnostic pathway as a clinical and research tool. This algorithm has been used to delineate specific primary lymphoedema phenotypes, facilitating the discovery of new causative genes. This paper reviews the latest molecular findings and provides an updated version of the classification and diagnostic pathway based on this new knowledge. Keywords
This is the first retrospective study of YNS to document clear remission of nail changes. The lack of a positive FH in the majority of patients in our study, the late onset of the disease and recovery of nail changes in our patients suggest that YNS may not be primarily a genetic disease as it is currently classified.
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