Clinical significance of vascular endothelial growth factor-C (VEGF-C) in breast cancer

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Breast Cancer Research and Treatment (Impact Factor: 3.94). 04/2001; 66(2):159-64. DOI: 10.1023/A:1010692132669
Source: PubMed


Vascular endothelial growth factor-C (VEGF-C) is a specific ligand which induces lymphangiogenesis. We examined the expression of VEGF-C protein to determine its role in the progression of breast cancer. Immunohistochemical analysis revealed that VEGF-C was overexpressed in 39 of 98 breast cancer specimens (39.8%) but not in adjacent normal mammary glands. The expression of VEGF-C showed a significant correlation with lymphatic vessel invasion (p = 0.0004). It is noteworthy that the 5-year disease free survival rate of the VEGF-C positive group was significantly poorer than that of negative group (p = 0.0356). We suggest that as expression of VEGF-C is not implicated in lymphatic spread, it may prove to be a promising marker to predict the recurrence of breast cancer.

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    • "It is demonstrated that VEGF-C induces lymphangiogenesis by VEGFR-3 signaling [14]. Studies showed that VEGF-C expression is associated with lymphatic invasion, LMVD, lymph node metastasis, and prognosis in some human tumors, such as breast cancer, gastric cancer and NSCLC [15-18]. "
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    ABSTRACT: Metastatic spread of tumor through lymphatic vasculature is an important adverse prognostic factor in a variety of human cancer and tumor lymphangiogenesis requires the interplay of several growth factors. Platelet-derived growth factor (PDGF)-BB and vascular endothelial growth factor (VEGF)-C are two important molecules involving in tumor metastasis and lymphangiogenesis. Therefore, the aim of this study was to investigate the coexpression of PDGF-BB and VEGF-C in primary human non-small cell lung cancer (NSCLC) and its association with lymphangiogenesis. Using immunohistochemical staining, PDGF-BB and VEGF-C expression were detected in 109 primary NSCLC tissues, while the lymphatic micro-vessel density (LMVD) was counted. Of 109 cases, PDGF-BB and VEGF-C overexpression was 66.97% (73/109) and 65.14% (71/109), respectively. 52 (47.7%) had overexpression of both PDGF-BB and VEGF-C (P + V+), 21 (19.3%) overexpression of PDGF-BB but low expression of VEGF-C (P + V-), 19(17.4%) overexpression of VEGF-C but low expression of PDGF-BB (P-V+) and 17(15.6%) low expression of both PDGF-BB and VEGF-C (P-V-). PDGF-BB expression was positively related to that of VEGF-C (r = 0.451, p = 0.034). LMVD in cases with P + V + was much higher than those with P-V- (p = 0.004). In addition, the patients with P + V + were younger and also had larger tumor size, more likely lymph node metastasis and worse histological differentiation than those with P-V-. Moreover, the overall survival (OS) of patients with P + V + was shorter than those with P-V- (p = 0.015). Coexpression of both PDGF-BB and VEGF-C was associated with lymphangiogenesis and poor prognosis in NSCLC, and might play a critical role in NSCLC progression. Virtual Slides The virtual slide(s) for this article can be found here:
    Full-text · Article · Jun 2014 · Diagnostic Pathology
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    • "VEGF-C is overexpressed in breast cancer specimens as compared to adjacent normal mammary glands, which shows a significant correlation with lymphatic vessel invasion and survival rate [107–109]. Furthermore, nitric oxide (NO) may react with superoxide to generate the highly toxic peroxynitrite, which can react with proteins that form nitrotyrosine. High nitrotyrosine levels can also contribute to the induction of VEGF-C expression and lymph node metastasis, further leading to decreased freedom of disease and overall survival in patients with breast cancer [110]. "
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    ABSTRACT: Vascular endothelial growth factor C (VEGF-C) has been identified as a multifaceted factor participating in the regulation of tumor angiogenesis and lymphangiogenesis. VEGF-C is not only expressed in endothelial cells, but also in tumor cells. VEGF-C signaling is important for progression of various cancer types through both VEGF receptor-2 (VEGFR-2) and VEGF receptor-3 (VEGFR-3). Likewise, both receptors are expressed mainly on endothelial cells, but also expressed in tumor cells. The dimeric VEGF-C undergoes a series of proteolytic cleavage steps that increase the protein binding affinity to VEGFR-3; however, only complete processing, removing both the N- and C-terminal propeptides, yields mature VEGF-C that can bind to VEGFR-2. The processed VEGF-C can bind and activate VEGFR-3 homodimers and VEGFR-2/VEGFR-3 heterodimers to elicit biological responses. High levels of VEGF-C expression and VEGF-C/VEGFRs signaling correlate significantly with poorer prognosis in a variety of malignancies. Therefore, the development of new drugs that selectively target the VEGF-C/VEGFRs axis seems to be an effective means to potentiate anti-tumor therapies in the future.
    Full-text · Article · Dec 2012 · International Journal of Molecular Sciences
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    • "Correlation studies in human cancers, including breast, head and neck, and melanoma, link the expression of VEGF-C and/or VEGF-D to peritumoral lymphangiogenesis , intralymphatic tumor cell clusters, and lymph node metastasis (Kinoshita et al. 2001; Stacker et al. 2002; Dadras et al. 2005; Siriwardena et al. 2008). Other correlative studies imply inflammatory cells and processes involved in regulation of VEGF-C expression in lymphangiogenesis and lymph node metastasis . "
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    ABSTRACT: The lymphatic vascular system and the hematopoietic system are intimately connected in ontogeny and in physiology. During embryonic development, mammalian species derive a first lymphatic vascular plexus from the previously formed anterior cardinal vein, whereas birds and amphibians have a lymphatic vascular system of dual origin, composed of lymphatic endothelial cells (LECs) of venous origin combined with LECs derived from mesenchymal lymphangioblasts. The contribution of hematopoietic cells as building blocks of nascent lymphatic structures in mammals is still under debate. In contrast, the importance of myeloid cells to direct lymphatic vessel growth and function postnatally has been experimentally shown. For example, myeloid cells communicate with LECs via paracrine factors or cell-cell contacts, and they also can acquire lymphatic endothelial morphology and marker gene expression, a process reminiscent of developmental vasculogenesis. Here, we present an overview of the current understanding of how lymphatic vessels and the hematopoietic system, in particular myeloid cells, interact during embryonic development, in normal organ physiology, and in disease.
    Preview · Article · Jun 2012 · Cold Spring Harbor Perspectives in Medicine
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