Concurrent Induction of Lymphangiogenesis, Angiogenesis, and Macrophage Recruitment by Vascular Endothelial Growth Factor-C in Melanoma

Skobe, Mihaela; Hamberg, Leena M.; Hawighorst, T.; Schirner, Michael; Wolf, Gerald; Alitalo, Kari; Detmar, Michael

doi:10.1016/s0002-9440(10)61765-8

Cited by 350 publications

(349 citation statements)

References 55 publications

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“…A correlation between VEGF-C mRNA levels and melanoma metastasis to lymph nodes was previously reported. 23,24 However, the importance of tumor cell-derived VEGF-C vs VEGF-C produced by tumor-associated macrophages 25,26 has remained unclear. Our study shows that tumor cells themselves make a significant contribution to VEGF-C production and, therefore, to tumor lymphangiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes

et al. 2005

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Cutaneous melanoma is a common melanocytic neoplasm that can quickly metastasize to regional lymph nodes. Currently, prognosis is determined by measuring tumor thickness but more reliable markers for metastatic spread are urgently needed. We investigated whether the extent of tumor lymphangiogenesis can predict melanoma metastasis to sentinel lymph nodes. We quantified the extent of tumor lymphangiogenesis, as well as other factors, in excised primary tumors and in sentinel lymph node biopsy samples from 45 patients with primary cutaneous melanoma. The results were correlated with histological and clinical outcome. Primary melanomas from patients whose tumors had metastasized to the sentinel lymph nodes contained prominent 'hot spots' of increased lymphatic vessel density, compared to nonmetastatic tumors. Multivariate risk analysis revealed that the lymphatic vascular area of primary melanomas, an index of tumor lymphangiogenesis, was the most sensitive prognostic marker for sentinel lymph node metastasis, and was even able to more accurately predict which tumors were metastatic to sentinel lymph nodes than the currently used method of measuring tumor thickness. Highly lymphangiogenic melanomas maintained their lymphangiogenic activity after metastasis to the sentinel lymph node. The extent of tumor lymphangiogenesis is a highly sensitive (83%) and specific (89%) prognostic marker of lymph node metastasis. Assessment of lymphangiogenesis in primary melanomas may be a more effective approach than the currently used technique of measuring tumor thickness in selecting patients with early metastatic disease for aggressive therapy. Keywords: LYVE-1; lymphangiogenesis; angiogenesis; sentinel lymph node; VEGF-C and VEGF-D In 2003, it was estimated that 7700 patients in the US would die from cutaneous melanoma, 1 a melanocytic tumor with increasing worldwide incidence and mortality rates. 2 Melanoma is among the most common types of cancer in young adults, and death from melanoma occurs at a younger age than for any other common malignancy, 3 representing a substantial public health problem. The prognosis of patients with melanoma depends on the tumor stage at diagnosis, and is currently based on microstaging and clinical/radiologic evaluation for metastases. In addition to a complete surgical excision with wide margins, patients with primary melanomas 41.0 mm thick undergo intraoperative lymphatic mapping and sentinel lymph node (SLN) biopsy to identify the first deposition of microscopic metastatic cells. 4 Among several prognostic parameters, tumor thickness is currently the most sensitive parameter for predicting the metastatic risk of cutaneous melanoma. However, the prognosis for individual melanoma patients is still difficult to determine, since thin melanomas can also develop into lethal metastases. 5 More accurate prognostic indicators for melanoma metastasis are therefore urgently needed.Recently, studies in mouse tumor models have shown that some types of malignant tumors actively induce the formation of lym...

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Section: Discussionmentioning

confidence: 99%

Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes

et al. 2005

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“…Human MM in situ expresses VEGF-C (Salven et al, 1998), but direct evidence for lymphangiogenesis into the melanomas is lacking. Recently, however, overexpression of VEGF-C had been shown to stimulate lymphangiogenesis in xenotransplanted human melanomas (Skobe et al, 2001a), and in the chick chorioallantoic membrane, and this occurs through activation of VEGF receptor 3 (flt-4) in lymphatic endothelial cells (Papoutsi et al, 2000). Vascular endothelial growth factor D, another lymphangiogenic growth factor, has also been shown to be upregulated in melanoma and other tumours ) (Yokoyama et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Lymphatic density and metastatic spread in human malignant melanoma

et al. 2004

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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.

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“…These include monocyte chemotactic protein-1, M-CSF, GM-CSF and VEGF-C (Skobe et al, 2001). Tumour-associated macrophages form a major component of the inflammatory cell infiltrate within and around primary and metastatic melanomas, and TAM numbers have been shown to correlate with melanoma invasion (Torisu et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Malignant melanoma and bone resorption

et al. 2006

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The cellular and humoral mechanisms accounting for osteolysis in skeletal metastases of malignant melanoma are uncertain. Osteoclasts, the specialised multinucleated cells that carry out bone resorption, are derived from monocyte/macrophage precursors. We isolated tumour-associated macrophages (TAMs) from metastatic (lymph node/skin) melanomas and cultured them in the presence and absence of osteoclastogenic cytokines and growth factors. The effect of tumour-derived fibroblasts and melanoma cells on osteoclast formation and resorption was also analysed. Melanoma TAMs (CD14 þ /CD51À) differentiated into osteoclasts (CD14À/CD51 þ ) in the presence of receptor activator for nuclear factor kB ligand (RANKL) and macrophage-colony stimulating factor. Tumour-associated macrophage-osteoclast differentiation also occurred via a RANKL-independent pathway when TAMs were cultured with tumour necrosis factor-a and interleukin (IL)-1a. RT -PCR showed that fibroblasts isolated from metastatic melanomas expressed RANKL messenger RNA and the conditioned medium of cultured melanoma fibroblasts was found to be capable of inducing osteoclast formation in the absence of RANKL; this effect was inhibited by the addition of osteoprotegerin (OPG). We also found that cultured human SK-Mel-29 melanoma cells produce a soluble factor that induces osteoclast differentiation; this effect was not inhibited by OPG. Our findings indicate that TAMs in metastatic melanomas can differentiate into osteoclasts and that melanoma fibroblasts and melanoma tumour cells can induce osteoclast formation by RANKL-dependent and RANKL-independent mechanisms, respectively.

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Concurrent Induction of Lymphangiogenesis, Angiogenesis, and Macrophage Recruitment by Vascular Endothelial Growth Factor-C in Melanoma

Cited by 350 publications

References 55 publications

Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes

Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes

Lymphatic density and metastatic spread in human malignant melanoma

Malignant melanoma and bone resorption

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