Tumor-Associated Macrophages Express Lymphatic Endothelial Growth Factors and Are Related to Peritumoral Lymphangiogenesis

Schoppmann, Sebastian F.; Birner, Peter; Stöckl, Johannes; Kalt, Romana; Ullrich, Robert C.; Caucig, Carola; Kriehuber, Ernst; Nagy, Katalin; Alitalo, Kari; Kerjaschki, Dontscho

doi:10.1016/s0002-9440(10)64255-1

Cited by 714 publications

(636 citation statements)

References 33 publications

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“…Intriguingly the presence of large number of lymphatics in tumour areas which were densely infiltrated by inflammatory cells was noted. This finding is supported by studies investigating the role of macrophages and inflammatory cells in inducing lymphangiogenesis in tumours and other tissues [46,47], and could be due to macrophages being a source of angio-and lymphangiogenic growth factors [48].…”

Section: Discussionsupporting

confidence: 52%

Lymphatic and angiogenic characteristics in breast cancer: morphometric analysis and prognostic implications

Mohammed

Ellis

Elsheikh

et al. 2008

Breast Cancer Res Treat

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Controversy exists regarding the topography of lymph vessels in breast cancer, their usefulness as prognostic factors, relationship with angiogenesis and whether active lymphangiogenesis occurs within the tumour. A series of 177 well-characterized breast cancers, with long term follow up, were stained with D2-40, CD31 and CD34. Distribution of lymphatics and lymph vessel density (LVD) were assessed in three areas, intratumoural, peripheral and peritumoural and correlated with clinicopathological criteria and patient prognosis. Microvessel density (MVD) was assessed and correlated with LVD. Double immunohistochemical staining with D2-40 and MIB-1 was carried out to assess the proliferative status of lymphatics and of the tumour emboli within. Peritumoural lymphatics were detected in all tumours whereas peripheral and intratumoural lymphatics were detected in 86 and 41% of specimens, respectively. Tumours with higher total LVD were significantly associated with the presence of lymph node (LN) metastasis and shorter overall survival (OS). In multivariate analysis, tumour grade, LN status and the presence of lymphovascular invasion, but not LVD, were independent poor prognostic factors. No association was found between LVD and MVD. Proliferating lymphatics were detected in 29% of specimens and were significantly associated with dense inflammatory infiltrate. In conclusion, lymphatics are located primarily in the peritumoural and peripheral areas in breast cancer and seem to play an important role in disease progression by being routes for tumour dissemination. The lack of correlation between lymphangiogenic and angiogenic characteristics suggests two distinct processes and the presence of active lymphangiogenesis, albeit in a small portion of specimens, may have important therapeutic implications.Keywords Angiogenesis Á Breast cancer Á D2-40 Á Lymphangiogenesis and prognosis Introduction and aims

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Section: Discussionsupporting

confidence: 52%

Lymphatic and angiogenic characteristics in breast cancer: morphometric analysis and prognostic implications

Mohammed

Ellis

Elsheikh

et al. 2008

Breast Cancer Res Treat

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“…32 Many tumors induce various productions of cytokines, including IL-6, IL-8, IL-10 and tumor necrosis factor, to promote their own growth and limit immune responses. 33,34 Modulation and interactions of these cytokine productions may be pivotal for the control of inflammation and tumor progression. Besides, recent studies using gene expression assays have been used to predict the survival of patients with lung and colorectal carcinoma 35,36 and have proven to be more precise in the classification of the disease stage than the current systems.…”

Section: Discussionmentioning

confidence: 99%

IL-10 polymorphisms and prostate cancer risk: a meta-analysis

Shao

et al. 2011

Prostate Cancer Prostatic Dis

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Evidence is accumulating that chronic inflammation may have an important role in prostate cancer (PCa). Three common polymorphisms in the promoter of interleukin-10 (IL-10) gene, À1082 A4G, À819 C4T and À592 C4A, have been implicated to alter the risk of PCa, but the results of relative studies are inconclusive or controversial. To derive a more precise estimation of the relationship, we performed an updated meta-analysis on the basis of 10 studies. A comprehensive search was conducted to examine all the eligible studies of IL-10 polymorphism and PCa risk. We used odds ratios (ORs) to assess the strength of the association, and 95% confidence intervals (CIs) give a sense of the precision of the estimate. Overall, there were no significant associations between increased risk of PCa and IL-10 À1082 A4G, À819 C4T and À592 C4A polymorphisms. However, meta-analysis suggested that IL-10 À819 C4T and À592 C4A polymorphisms might be modestly associated with PCa aggressiveness (T versus C, OR ¼ 1.162, 95% CI: 1.035-1.305, P ¼ 0.011; A versus C, OR ¼ 1.131, 95% CI: 1.012-1.264, P ¼ 0.030; respectively). IL-10 À819 C4T and À592 C4A polymorphisms might impact PCa progression. Variant alleles at both À819 and À592 were modestly associated with advanced stages of PCa. Additional well-designed studies are warranted to validate these findings.

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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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Tumor-Associated Macrophages Express Lymphatic Endothelial Growth Factors and Are Related to Peritumoral Lymphangiogenesis

Cited by 714 publications

References 33 publications

Lymphatic and angiogenic characteristics in breast cancer: morphometric analysis and prognostic implications

Lymphatic and angiogenic characteristics in breast cancer: morphometric analysis and prognostic implications

IL-10 polymorphisms and prostate cancer risk: a meta-analysis

Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes

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