Vascular Endothelial Growth Factor-A Promotes Peritumoral Lymphangiogenesis and Lymphatic Metastasis

Björndahl, Meit A.; Cao, Renhai; Burton, Jeremy B.; Bråkenhielm, Ebba; Religa, Piotr; Galter, Dagmar; Wu, Lily; Cao, Yihai

doi:10.1158/0008-5472.can-04-2345

Cited by 172 publications

(137 citation statements)

References 32 publications

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“…The first type of new blood vessel to form in response to Ad-VEGF-A 164 has a characteristic morphology and has been given the name 'mother vessel' (MV) (Pettersson et al, 2000). However, similar MV-like blood vessels are also induced by polymers containing VEGF-A 164 or basic fibroblast growth factor (Cao et al, 1998) and by tumours expressing VEGF-A or basic fibroblast growth factor and plateletderived growth factor-BB (Paku and Paweletz, 1991;Bjorndahl et al, 2005;Nagy et al, 2007;Nissen et al, 2007). The other types of angiogenic vessels evolve from MVs and thus may be properly regarded as 'daughter' vessels ( Figure 1) (Pettersson et al, 2000;Dvorak, 2003;Nagy et al, 2007).…”

Section: How Do Tumour Blood Vessels Form?mentioning

confidence: 99%

Why are tumour blood vessels abnormal and why is it important to know?

et al. 2009

Br J Cancer

493

425

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Tumour blood vessels differ from their normal counterparts for reasons that have received little attention. We report here that they are of at least six distinct types, we describe how each forms, and, looking forward, encourage the targeting of tumour vessel subsets that have lost their vascular endothelial growth factor-A (VEGF-A) dependency and so are likely unresponsive to anti-VEGF-A therapies.

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Section: How Do Tumour Blood Vessels Form?mentioning

confidence: 99%

Why are tumour blood vessels abnormal and why is it important to know?

et al. 2009

Br J Cancer

493

425

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“…Stimulates proliferation and migration of cultured LECs Bjorndahl et al (2005a) IGFR-1 and -2 are present in lymphatic endothelium Induces growth of new LYVE-1 expressing lymphatic vessels in murine cornea metastasis via intra-and peritumourous lymphatic vessels Bjorndahl et al, 2005b). It appears that VEGF-A indirectly induces lymphangiogenesis by recruiting VEGFR-1 expressing inflammatory cells including monocytes/ macrophages and neutrophils that produce VEGF-C/-D because VEGFR-3 antagonists are able to block VEGF-A-induced lymphangiogenesis (Cursiefen et al, 2004).…”

Section: Igf-2mentioning

confidence: 99%

“…Thus, exposure of these growth factors to blood vessels and lymphatic vessels leads to simultaneous stimulation of angiogenesis and lymphangiogenesis (Cao, 2005b). However, under certain circumstances, both FGF-2 and VEGF-A have been reported to specifically induce only lymphangiogenesis and not angiogenesis (Chang et al, 2004;Bjorndahl et al, 2005b). The molecular mechanism underlying the differential effects of the same factor is currently unknown.…”

Section: Igf-2mentioning

confidence: 99%

First international consensus on the methodology of lymphangiogenesis quantification in solid human tumours

et al. 2006

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The lymphatic system is the primary pathway of metastasis for most human cancers. Recent research efforts in studying lymphangiogenesis have suggested the existence of a relationship between lymphatic vessel density and patient survival. However, current methodology of lymphangiogenesis quantification is still characterised by high intra-and interobserver variability. For the amount of lymphatic vessels in a tumour to be a clinically useful parameter, a reliable quantification technique needs to be developed. With this consensus report, we therefore would like to initiate discussion on the standardisation of the immunohistochemical method for lymphangiogenesis assessment. Metastasis is the leading cause of cancer mortality. Metastatic cancer cells can escape from their site of origin and spread to distant organs through invasion of the vascular system and/or the lymphatic system. Tumour vascularisation is widely accepted as a bona fide indicator of tumour growth, metastases and patient survival. In 1996, Peter Vermeulen et al (1996) published a first international consensus on the methodology and criteria of the evaluation of angiogenesis quantification in solid tumours and 5 years later, a second consensus report, in which new concepts and mechanisms of tumour vascularisation were integrated, appeared (Vermeulen et al, 2002). Both reports were aimed at improving the standardisation of angiogenesis quantification in order to allow intratumourous microvessel density to be applied as a prognostic indicator and, moreover, as a reliable predictor of the risk of malignant transformation of premalignant lesions and of response to cancer treatment. Contrary to angiogenesis, the de novo formation of lymphatic vessels or lymphangiogenesis and its role in promoting the metastatic spread of tumour cells has only recently become a focal point of cancer research with an increasing number of studies showing a relationship between patient survival and lymphatic density in different tumour types. In order to confirm the potential prognostic value of lymphangiogenesis in patients with cancer, a quantification method that is characterised by a low intra-and interobserver variability needs to be developed. In this first consensus report, we would like to provide an overview of current concepts of the lymphatic vasculature and its regulating factors and propose guidelines for the estimation of the ongoing lymphangiogenesis in solid human tumour sections.

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“…Clinic pathological data from research using animal models indicates that tumor-induced lymphangiogenesis driven by vascular endothelial growth factor (VEGF)-C-and/or VEGF-D-induced activation of VEGF receptor (VEGFR)-3 could promote metastasis to regional lymph nodes. [5][6][7][8] Honokiol is a bioactive constituent isolated from the bark of Magnoliae. Previous reports have demonstrated that honokiol induces cell apoptosis in several cell lines, such as leukemia cell lines HL-60, colon cancer cell lines RKO, lung cancer cell lines A549 and CH27.…”

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confidence: 99%

Liposomal honokiol inhibits VEGF‐D‐induced lymphangiogenesis and metastasis in xenograft tumor model

Wen

Chen

et al. 2009

Intl Journal of Cancer

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Lymph nodes metastasis of tumor could be a crucial early step in the metastatic process. Induction of tumor lymphangiogenesis by vascular endothelial growth factor-D may play an important role in promoting tumor metastasis to regional lymph nodes and these processes can be inhibited by inactivation of the VEGFR-3 signaling pathway. Honokiol has been reported to possess potent antiangiogenesis and antitumor properties in several cell lines and xenograft tumor models. However, its role in tumor-associated lymphangiogenesis and lymphatic metastasis remains unclear. Here, we established lymph node metastasis models by injecting overexpressing VEGF-D Lewis lung carcinoma cells into C57BL/6 mice to explore the effect of honokiol on tumor-associated lymphangiogenesis and related lymph node metastasis. The underlying mechanisms were systematically investigated in vitro and in vivo. In in vivo study, liposomal honokiol significantly inhibited the tumor-associated lymphangiogenesis and metastasis in Lewis lung carcinoma model. A remarkable delay of tumor growth and prolonged life span were also observed. In in vitro study, honokiol inhibited VEGF-D-induced survival, proliferation and tube-formation of both human umbilical vein endothelial cells (HUVECs) and lymphatic vascular endothelial cells (HLECs). Western blotting analysis showed that liposomal honokiol-inhibited Akt and MAPK phosphorylation in 2 endothelial cells, and downregulated expressions of VEGFR-2 of human vascular endothelial cells and VEGFR-3 of lymphatic endothelial cells. Thus, we identified for the first time that honokiol provided therapeutic benefit not only by direct effects on tumor cells and antiangiogenesis but also by inhibiting lymphangiogenesis and metastasis via the VEGFR-3 pathway. The present findings may be of importance to investigate the molecular mechanisms underlying the spread of cancer via the lymphatics and explore the therapeutical strategy of honokiol on antilymphangiogenesis and antimetastasis.

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Vascular Endothelial Growth Factor-A Promotes Peritumoral Lymphangiogenesis and Lymphatic Metastasis

Abstract: Metastases are commonly found in the lymphatic system.

Cited by 172 publications

References 32 publications

Why are tumour blood vessels abnormal and why is it important to know?

Why are tumour blood vessels abnormal and why is it important to know?

First international consensus on the methodology of lymphangiogenesis quantification in solid human tumours

Liposomal honokiol inhibits VEGF‐D‐induced lymphangiogenesis and metastasis in xenograft tumor model

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