VEGF-C expressing tumor-associated macrophages in lymph node positive breast cancer: impact on lymphangiogenesis and survival

Schoppmann, Sebastian F.; Fenzl, A.; Nagy, Katalin; Unger, S.; Bayer, G.; Geleff, Silvana; Gnant, Michael; Horvat, Reinhard; Jakesz, R.; Birner, Peter

doi:10.1016/j.surg.2005.12.008

Cited by 147 publications

(128 citation statements)

References 23 publications

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“…It is also important to identify the functions of the VEGF-C/VEGFR-3 axis in macrophage infiltration/activation and to determine how these tumour-educated macrophages affect tumour progression. This is because infiltrating macrophages have correlated significantly and negatively with cancer patient prognosis and survival Schoppmann et al, 2006). It has been reported that tumour-associated macrophages play a crucial role in angiogenesis and lymphangiogenesis under inflammatory condition (Cursiefen et al, 2004;Maruyama et al, 2005).…”

Section: Gastric Cancermentioning

confidence: 99%

The role of the VEGF-C/VEGFR-3 axis in cancer progression

et al. 2006

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Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) (also called VEGFR-3) is activated by its specific ligand, VEGF-C, which promotes cancer progression. The VEGF-C/VEGFR-3 axis is expressed not only by lymphatic endothelial cells but also by a variety of human tumour cells. Activation of the VEGF-C/VEGFR-3 axis in lymphatic endothelial cells can facilitate metastasis by increasing the formation of lymphatic vessels (lymphangiogenesis) within and around tumours. The VEGF-C/VEGFR-3 axis plays a critical role in leukaemic cell proliferation, survival, and resistance to chemotherapy. Moreover, activation of the VEGF-C/VEGFR-3 axis in several types of solid tumours enhances cancer cell mobility and invasion capabilities, promoting cancer cell metastasis. In this review, we discuss the novel function and molecular mechanism of the VEGF-C/VEGFR-3 axis in cancer progression.

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Section: Gastric Cancermentioning

confidence: 99%

The role of the VEGF-C/VEGFR-3 axis in cancer progression

et al. 2006

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“…TAMs are critical regulators of angiogenesis and lymphangiogenesis; they express VEGFA and VEGFC and induce tip-cell formation and fusion (16,(30)(31)(32)(33). In addition, they are thought to directly contribute to lymphatic vessel formation by transdifferentiating into lymphatic endothelial cells (25,28,33,34).…”

Section: Introductionmentioning

confidence: 99%

SAR131675, a Potent and Selective VEGFR-3–TK Inhibitor with Antilymphangiogenic, Antitumoral, and Antimetastatic Activities

Alam

Blanc

Gueguen-Dorbes

et al. 2012

Molecular Cancer Therapeutics

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SAR131675 is a potent and selective VEGFR-3 inhibitor. It inhibited VEGFR-3 tyrosine kinase activity and VEGFR-3 autophosphorylation in HEK cells with IC 50 values of 20 and 45 nmol/L, respectively. SAR131675 dose dependently inhibited the proliferation of primary human lymphatic cells, induced by the VEGFR-3 ligands VEGFC and VEGFD, with an IC 50 of about 20 nmol/L. SAR131675 was found to be highly selective for VEGFR-3 versus 107 receptors, enzymes, ion channels, and 65 kinases. However, it was moderately active on VEGFR-2 with a VEGFR-3/VEGFR-2 ratio of about 10. SAR131675 had no antiproliferative activity on a panel of 30 tumors and primary cells, further showing its high specificity and indicating that SAR131675 is not a cytotoxic or cytostatic agent. SAR131675 was very well tolerated in mice and showed a potent antitumoral effect in several orthotopic and syngenic models, including mammary 4T1 carcinoma and RIP1.Tag2 tumors. Interestingly, it significantly reduced lymph node invasion and lung metastasis, showing its antilymphangiogenic activity in vivo. Moreover, treatment of mice before resection of 4T1 primary tumors was sufficient to prevent metastasis. Tumor-associated macrophages (TAM) play an important role in tumor growth and metastasis. The expression of VEGFR-3 on TAMs has been recently described. F4/80 immunostaining clearly showed that SAR131675 significantly reduced TAM infiltration and aggregation in 4T1 tumors. Taken together, SAR131675 is the first highly specific VEGFR-3-TK inhibitor described to date, displaying significant antitumoral and antimetastatic activities in vivo through inhibition of lymphangiogenesis and TAM invasion.

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“…Invasion of tumor cells into lymphatic vessels is a critical step in metastasis, and lymph vessel invasion (LVI) is a predictor for axillary lymph node metastasis and a prognostic factor in node-negative cancer [2][3][4][5][6][7][8]. LVI can also be used to determine the appropriate indications for chemotherapy [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies have indicated that lymphangiogenesis occurred in breast cancer, and that specific lymphangiogenic factors, such as vascular endothelial growth factors (VEGF)-C and D, were expressed [2][3][4]. However, other immunohistochemical studies have found no evidence of proliferation in lymphatic vessels [10,11].…”

Section: Introductionmentioning

confidence: 99%