Role of Delta-like-4/Notch in the Formation and Wiring of the Lymphatic Network in Zebrafish

Geudens, Ilse; Herpers, Robert; Hermans, Karlien; Segura, Inmaculada; Almodóvar, Carmen Ruiz de; Bussmann, Jeroen; Smet, Frederik De; Vandevelde, Wouter; Hogan, Benjamin M.; Siekmann, Arndt F.; Claes, Filip; Moore, John C.; Pistocchi, Anna; Loges, Sonja; Mazzone, Massimiliano; Mariggi, Giovanni; Bruyère, Françoise; Cotelli, Franco; Kerjaschki, Dontscho; Noël, Agnès; Foidart, Jean-Michel; Gerhardt, Holger; Ny, Annelii; Langenberg, Tobias; Lawson, Nathan D.; Duckers, Hendricus J.; Schulte‐Merker, Stefan; Carmeliet, Peter; Dewerchin, Mieke

doi:10.1161/atvbaha.110.203034

Cited by 118 publications

(149 citation statements)

References 28 publications

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“…However, in some cases the eRHA persists without regression, representing an aRHA. The lymphatics travel primarily with blood vessels (6,7). Even if the artery completely regresses, the accompanying lymphatic vessels, lymph nodes and nerves presumably remain (4).…”

Section: Discussionmentioning

confidence: 99%

“…In the pN1 group, lymph node metastases characteristically arise in the pericholedochal area or the posterosuperior pancreaticoduodenal region, rather than around the hepatic artery (2,3). However, no feeding arteries are present around the pericholedochal lymph nodes and posterosuperior pancreaticoduodenal lymph nodes (PPLNs), although lymph nodes and lymphatic vessels generally exist along a feeding artery (4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

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Lymph node spread of gallbladder cancer from the perspective of embryologically-based anatomy and significance of the lymphatic basin along the embryonic right hepatic artery

Nakagawara

Tajima

Miyashita

et al. 2014

Molecular and Clinical Oncology

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Abstract. Lymph node metastasis from gallbladder cancer is often found in the pericholedochal area; however, these regional lymph nodes are not typically accompanied by arteries. We hypothesized that the artery accompanying pericholedochal lymph nodes was either the regressed embryonic right hepatic artery (eRHA) or an aberrant right hepatic artery (aRHA) remaining without regression. This study aimed to determine the artery supplying pericholedochal lymph nodes. We obtained serial tissue sections of resected specimens from 10 patients who underwent pancreaticoduodenectomy with combined resection of the superior mesenteric artery and vein and investigated the association between the distribution of enlarged lymph nodes and the course of blood vessels in each section. In 2 cases with aRHA, enlarged lymph nodes were distributed in the posterosuperior area, pancreaticoduodenal region and retroportal area along this artery. By contrast, no blood vessels accompanied enlarged lymph nodes in 8 patients exhibiting a normal hepatic artery branching pattern, although these nodes exhibited a distribution pattern similar to that of patients with the aRHA. Thus, the artery supplying pericholedochal lymph nodes appears to be either the regressed eRHA or an aRHA persisting without regression. IntroductionThe prognosis of gallbladder cancer (GBC) with lymph node metastases is poor. The 5-year survival rate following surgical resection has been reported to be 65% for patients with no lymph node metastases and <30% for those with regional lymph node metastases (pN1) (1). In the pN1 group, lymph node metastases characteristically arise in the pericholedochal area or the posterosuperior pancreaticoduodenal region, rather than around the hepatic artery (2,3). However, no feeding arteries are present around the pericholedochal lymph nodes and posterosuperior pancreaticoduodenal lymph nodes (PPLNs), although lymph nodes and lymphatic vessels generally exist along a feeding artery (4-7).We previously performed pancreaticoduodenectomy (PD) for pancreatic cancer in patients with an aberrant right hepatic artery (aRHA). In such cases, PPLNs were distributed along the aRHA. This artery is considered to represent an embryonic right hepatic artery (eRHA) that has not regressed. We hypothesized that the artery responsible for PPLNs would be the eRHA. If this hypothesis is accurate, lymphadenectomy for GBC should be performed based on the course of the eRHA (8). The aim of this study was to determine the artery supplying the PPLNs. Materials and methodsPatients. Between 1997 and 2005, a total of 58 patients underwent PD for invasive pancreatic ductal cancer in the Department of Gastroenterologic Surgery at Kanazawa University. Among these cases, radical PD with major vessel resection [superior mesenteric artery (SMA) and superior mesenteric vein (SMV) resection] was performed in 18 patients for complete clearance of the soft tissues around these arteries (9). This study was approved by the Ethics Committee at our institution and was conducted ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lymph node spread of gallbladder cancer from the perspective of embryologically-based anatomy and significance of the lymphatic basin along the embryonic right hepatic artery

Nakagawara

Tajima

Miyashita

et al. 2014

Molecular and Clinical Oncology

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“…Consistent with these in vitro findings, podoplanin and Notch1 are found to be conversely regulated in lymphatic vessels in vivo: LECs with low Notch1 expression tend to express more podoplanin protein, and vice versa. Interestingly, however, knockdown of Notch or its ligand Dll4 in zebrafish embryos impairs lymphangiogenesis, in particular, the initial budding of lymphatically differentiating venous endothelial cells, and lymphatic vessel navigation (Geudens et al 2010), suggesting that despite its repressive role of lymphatic phenotypes, Notch signal is still required for the optimal lymphatic development. Together, these studies proposed a new concept that the expression of the three cell fate controllers is regulated by an exquisite feedback mechanism working in LECs and that LEC fate may be viewed as a phenotypic consequence of Prox1-directed "lymphatic equilibrium" among the cell fate regulators.…”

Section: Plasticity Of Lymphatic Endothelial Cell Fate-lymphatic Equimentioning

confidence: 99%

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

Choi

Lee²,

Hong

2012

Cold Spring Harbor Perspectives in Medicine

118

107

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The blood and lymphatic systems are the two major circulatory systems in our body. Although the blood system has been studied extensively, the lymphatic system has received much less scientific and medical attention because of its elusive morphology and mysterious pathophysiology. However, a series of landmark discoveries made in the past decade has begun to change the previous misconception of the lymphatic system to be secondary to the more essential blood vascular system. In this article, we review the current understanding of the development and pathology of the lymphatic system. We hope to convince readers that the lymphatic system is no less essential than the blood circulatory system for human health and well-being.

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“…In addition to cell autonomous effects, Notch signaling is also critical for migration of lymphatic vessels. In zebrafish, attenuation of Dll4, Notch1, or Notch6 compromise the extension of lymphatic vessels alongside the arterial ISVs, suggesting that Notch signaling may mediate the interaction between arterial and lymphatic vessels to guide migrating lymphatic vessels (Geudens= et al, 2010).…”

Section: Molecular Mechanisms Modulating Development Of the Lymphaticmentioning

confidence: 99%

A Tale of Two Models: Mouse and Zebrafish as Complementary Models for Lymphatic Studies

Kim¹,

Jin²

2014

Molecules and Cells

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Lymphatic vessels provide essential roles in maintaining fluid homeostasis and lipid absorption. Dysfunctions of the lymphatic vessels lead to debilitating pathological conditions, collectively known as lymphedema. In addition, lymphatic vessels are a critical moderator for the onset and progression of diverse human diseases including metastatic cancer and obesity. Despite their clinical importance, there is no currently effective pharmacological therapy to regulate functions of lymphatic vessels. Recent efforts to manipulate the Vascular Endothelial Growth Factor-C (VEGFC) pathway, which is arguably the most important signaling pathway regulating lymphatic endothelial cells, to alleviate lymphedema yielded largely mixed results, necessitating identification of new targetable signaling pathways for therapeutic intervention for lymphedema. Zebrafish, a relatively new model system to investigate lymphatic biology, appears to be an ideal model to identify novel therapeutic targets for lymphatic biology. In this review, we will provide an overview of our current understanding of the lymphatic vessels in vertebrates, and discuss zebrafish as a promising in vivo model to study lymphatic vessels.

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Role of Delta-like-4/Notch in the Formation and Wiring of the Lymphatic Network in Zebrafish

Cited by 118 publications

References 28 publications

Lymph node spread of gallbladder cancer from the perspective of embryologically-based anatomy and significance of the lymphatic basin along the embryonic right hepatic artery

Lymph node spread of gallbladder cancer from the perspective of embryologically-based anatomy and significance of the lymphatic basin along the embryonic right hepatic artery

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

A Tale of Two Models: Mouse and Zebrafish as Complementary Models for Lymphatic Studies

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