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Enhanced L1CAM expression on pancreatic tumor endothelium mediates selective tumor cell transmigration

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Abstract

L1 cell adhesion molecule (L1CAM) is a transmembrane cell adhesion molecule initially defined as a promigratory molecule in the developing nervous system that appears to be also expressed in some endothelial cells. However, little is known about the functional role of L1CAM on endothelial cells. We observed that L1CAM expression was selectively enhanced on endothelium associated with pancreatic adenocarcinoma in situ and on cultured pancreatic tumor-derived endothelial cells in vitro. L1CAM expression of endothelial cells could be augmented by incubation with immunomodulatory cytokines such as tumor necrosis factor alpha, interferon gamma, or transforming growth factor beta 1. Antibodies to L1CAM and the respective ligand neuropilin-1 blocked tube formation and stromal cell-derived factor 1β induced transmigration of tumor endothelial cells in vitro. L1CAM expression on tumor-derived-endothelial cells enhanced Panc1 carcinoma cell adhesion to endothelial cell monolayers and transendothelial migration. Our data demonstrate a functional role of L1CAM expression on tumor endothelium that could favor metastasis and angiogenesis during tumor progression.

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Abbreviations

CFSE:

Carboxyfluoresceine diacete succinimidyl-ester

EC:

endothelial cells

HUVEC:

human umbilical vein endothelial cells

HPMEC:

human pulmonary microvascular endothelial cells

L1CAM:

L1 cell adhesion molecule

NRP-1:

neuropilin-1

Tu PAMEC:

tumor-derived pancreatic microvascular endothelial cells

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Acknowledgments

We thank Natalie Erbe and Maike Witt for excellent technical assistance. This work was supported by grants from Deutsche Krebshilfe to P.A. (Schwerpunktprogramm: Invasion and Migration) and the EU-FP6 framework program OVCAD project nr. PE-14034 to P.A.

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Authors and Affiliations

  1. Tumor Immunology Programme, D015, German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Yasmin Issa, Daniel Nummer, Tobias Seibel, Philipp Beckhove & Peter Altevogt

  2. Clinic for Internal Medicine, Laboratory of Molecular Gastroenterology and Hepatology, University of Kiel, UKSH-Campus, Kiel, Germany

    Susanne Sebens Müerköster

  3. Department of Visceral Surgery, University Hospital of Heidelberg, Heidelberg, Germany

    Moritz Koch, Friedrich-Hubertus Schmitz-Winnenthal, Luis Galindo & Juergen Weitz

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  1. Yasmin Issa
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Correspondence to Peter Altevogt.

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Supplemental Figure 1

Regulation of NRP-1 expression of cultured EC by proinflammatory cytokines. Flow cytometric analysis of NRP-1 expression on cultured non-malignant ECs (Con HUVEC, left, Con HPMEC, middle) and Tu PAMEC (right) untreated (dark gray histograms) or stimulated for 24 h with immunomodulatory cytokines TNF-α (400 U/ml, dotted line), IFN-γ (1,000 U/ml, dashed line), and TGF-β1 (10 ng/ml, dashed-dotted line). Light gray histograms represent negative control staining with respective secondary antibodies (GIF 12.4 KB).

High-resolution image file (TIF 650 KB)

Supplemental Figure 2

Analysis of conditions for achieving confluent endothelial monolayers. Hematoxylin and eosin staining of cultured non-malignant ECs (Con HUVEC) on gelatin-coated membranes. Different conditions (1 × 105/24 h, left panel and 2 × 105/48h, right panel) were tested to obtain a confluent EC monolayer. Original magnification ×400 (GIF 38.4 KB).

High-resolution image file (TIF 2.82 MB)

Supplemental Figure 3

L1CAM expression of Panc1 tumor cells. Flow cytometry analysis of L1CAM expression on cultured Panc1 cells (black line). Light gray histograms represent negative control staining with respective secondary antibody (GIF 4.83 KB).

High-resolution image file (TIF 220 KB)

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Issa, Y., Nummer, D., Seibel, T. et al. Enhanced L1CAM expression on pancreatic tumor endothelium mediates selective tumor cell transmigration. J Mol Med 87, 99–112 (2009). https://doi.org/10.1007/s00109-008-0410-7

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