Chemokine-mediated migration of melanoma cells towards lymphatics – a mechanism contributing to metastasis

Shields, JD; Emmett, Maxine S.; Dunn, D B A; Joory, K. D.; Sage, Leslie M.; Rigby, H.S.; Mortimer, P. S.; Orlando, Antonio; Levick, J. R.; Bates, David O.

doi:10.1038/sj.onc.1210114

Cited by 154 publications

(151 citation statements)

References 28 publications

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“…Recent studies have identified lymphatic density of the primary tumour upon excision as a potential predictor of metastasis (Dadras et al, 2003;Shields et al, 2004). This increased lymphatic density may be brought about by growth of new lymphatics towards tumours expressing VEGF-C or VEGF-D (Skobe et al, 2001), by stochastic variation of melanomas or metastatic chemotaxis towards lymphatic endothelial cells (Shields et al, 2007). The identification of increased lymphatic density has been combined with thickness and lymphatic invasion to generate a prognostic index (Shields' index) that predicts the likelihood of metastasis, at least in a relatively small number of patients .…”

Section: Discussionmentioning

confidence: 99%

Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma

et al. 2007

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Malignant melanoma is the most lethal of the skin cancers and the UK incidence is rising faster than that of any other cancer. Angiogenesis -the growth of new vessels from preexisting vasculature -is an absolute requirement for tumour survival and progression beyond a few hundred microns in diameter. We previously described a class of anti-angiogenic isoforms of VEGF, VEGF xxx b, that inhibit tumour growth in animal models, and are downregulated in some cancers, but have not been investigated in melanoma. To determine whether VEGF xxx b expression was altered in melanoma, PCR and immunohistochemistry of archived human tumour samples were used. In normal epidermis and in a proportion of melanoma samples, VEGF xxx b staining was seen. Some melanomas had much weaker staining. Subsequent examination revealed that expression was significantly reduced in primary melanoma samples (both horizontal and vertical growth phases) from patients who subsequently developed tumour metastasis compared with those who did not (analysis of variance (ANOVA) Po0.001 metastatic vs nonmetastatic), irrespective of tumour thickness, while the surrounding epidermis showed no difference in expression. Staining for total VEGF expression showed staining in metastatic and nonmetastatic melanomas, and normal epidermis. An absence of VEGF xxx b expression appears to predict metastatic spread in patients with primary melanoma. These results suggest that there is a switch in splicing as part of the metastatic process, from anti-angiogenic to pro-angiogenic VEGF isoforms. This may form part of a wider metastatic splicing phenotype.

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Section: Discussionmentioning

confidence: 99%

Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma

et al. 2007

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“…It has been proposed that the increase in lymphatic surface area increases the chances of intravasation and subsequent dissemination of neoplastic cells [19]. A recent study by Shields et al described both lymphatic endothelial cell (LEC) chemotaxis and proliferation in response to metasatic melanoma cells and secretion by endothelial cells of chemotactic agents that attract melanoma cells, suggesting that bidirectional interactions between these partners may promote lymphatic invasion [20]. Consistent with this hypothesis, the present study unequivocally showed that lymphatic invasion is common in primary VGP melanomas.…”

Section: Discussionmentioning

confidence: 99%

Lymphatic invasion revealed by multispectral imaging is common in primary melanomas and associates with prognosis

Gimotty

Guerry

et al. 2008

Human Pathology

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Lymphatic invasion by tumor cells has been noted infrequently in primary melanomas. Our primary hypotheses were that using immunohistochemical markers of lymphatic vessels and of tumor cells would improve detection of lymphatic invasion and that lymphatic invasion would correlate with regional nodal metastatic disease. This study included 106 patients who were diagnosed between 1972 and 1991 and who had ≥ 10 years of follow up. We performed dual immunohistochemical stains for podoplanin (for lymphatic vessels) and S-100 (for melanoma cells). Lymphatic invasion was identified by light microscopy and confirmed by multispectral imaging analysis. Lymphatic invasion was detected by morphology alone in 5 cases (4.7%) in contrast to immunohistochemical staining augmented by multispectral imaging analysis where 35 cases (33%) were identified (p <0.0001). Lymphatic invasion was significantly associated with time to regional nodal metastatic disease, as well as first metastasis and melanoma-specific death. "Local metastasis", defined by immunohistochemistry-detected lymphatic invasion, satellites or neural invasion, identified 64% of those who had regional nodal metastatic disease within 5 years of diagnosis. Lymphatic invasion is an under-observed phenomenon in primary melanomas that can be better detected by immunohistochemical staining. The presence of lymphatic invasion may be a clinically useful predictor of regionally metastatic disease.

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“…43 LEC chemotaxis and proliferation in response to tumor cells (chemotaxis-lymphangiogenesis hypothesis) may occur or LECs may secrete chemotactic agents that attract cancer cells (chemotactic metastasis hypothesis). 44 Melanoma cells seem to grow more toward regions of high LEC density owing to chemotactic LEC secretions, including the chemokine CCL21. 44 We propose that increased iNOS and the possible consequent increased NO levels being associated to an augmented number of lymphatic vessels, might contribute to lymphangiogenesis in melanoma.…”

Section: Discussionmentioning

confidence: 99%

Inducible nitric oxide synthase expression in melanoma: implications in lymphangiogenesis

et al. 2009

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Cutaneous melanoma preferentially metastasizes via the lymphatic route. However, the mechanisms of lymphatic invasion and metastasis to regional lymph nodes are poorly understood. Nitric oxide is a free radical molecule synthesized from L-arginine by nitric oxide synthases that plays a critical role in various physiological and pathological processes, including tumor growth and angiogenesis. We have tested whether inducible nitric oxide synthase expression correlates with lymphatic vessel density identified with D2-40 antibody and/or blood microvessel density identified with CD105/endoglin in a series of melanocytic nevi (n ¼ 28) and cutaneous melanomas (n ¼ 38), representative of various pT. Inducible nitric oxide synthase expression was significantly lower in melanocytic nevi in comparison with primary and metastatic melanomas (Po0.001). Mean microvessel density was significantly higher in primary and metastatic melanomas in comparison with melanocytic nevi (Po0.001 for intratumoral and P ¼ 0.001 for peritumoral vessels). Vertical growth phase melanomas showed a higher intratumoral microvessel density in comparison with radial growth phase melanomas (P ¼ 0.02). The number of peritumoral lymphatics was significantly lower in nevi as compared with primary and metastatic melanomas (P ¼ 0.01). No correlation between microvessel or lymphatic vessel and clinical outcome was found in melanomas. A significant direct correlation was observed between inducible nitric oxide synthase immunostaining in melanocytic tumor cells and the density of lymphatic vessels (peritumoral: P ¼ 0.001; intratumoral: P ¼ 0.08), and the density of peritumoral blood microvessel (P ¼ 0.02). Our findings support the hypothesis that inducible nitric oxide synthase is implicated not only in blood, but also in lymphatic vascular neoformation in melanoma. Mechanistic studies are needed to address the possibility that inducible nitric oxide synthase controls lymphangiogenesis, dissemination and lymphatic borne metastases. Keywords: iNOS; CD105; D2-40; microvessel density; melanoma; nevi Cutaneous melanoma metastasizes at least initially through the lymphatic route and lymph node metastasis is currently still a major determinant for patients staging and clinical management. The mechanisms of lymphatic invasion and metastasis to regional lymph nodes are mostly unknown and whether human tumors promote de novo lymphangiogenesis is still unclear. Although the pathways that regulate tumorrelated angiogenesis have been partially investigated, poor information is available on the processes that result in lymphangiogenesis in melanoma.Nitric oxide (NO) is a diatomic free radical molecule synthesized from L-arginine by NO synthases (NOS) that plays a critical role in various physiological and pathological processes, including tumor growth. Although the Ca 2 þ -dependent isoforms NOS1 and NOS3 are constitutively expressed by neural and endothelial cells, the Ca 2 þ -independent form (NOS2 or iNOS) can be induced by many cell types upon stimulation by inflamma...

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Chemokine-mediated migration of melanoma cells towards lymphatics – a mechanism contributing to metastasis

Cited by 154 publications

References 28 publications

Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma

Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma

Lymphatic invasion revealed by multispectral imaging is common in primary melanomas and associates with prognosis

Inducible nitric oxide synthase expression in melanoma: implications in lymphangiogenesis

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