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Role of L1 cell adhesion molecule (L1CAM) in the metastatic cascade: promotion of dissemination, colonization, and metastatic growth

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Abstract

Expression of the L1 cell adhesion molecule (L1CAM) is frequently increased in cancer patients compared to healthy individuals and also linked with bad prognosis of solid tumours. Previously, we could show that full-length L1CAM promotes metastasis formation via up-regulation of gelatinolytic activity in fibrosarcoma. In this study, we aimed to extend this finding to haematogenous malignancies and carcinomas, and to specifically elucidate the impact of L1CAM on major steps of the metastatic cascade. In a well-established T-cell lymphoma spontaneous metastasis model, silencing of L1CAM significantly improved survival of the mice, while intradermal tumour growth remained unaltered. This correlated with significantly decreased spontaneous metastasis formation. L1CAM suppression abrogated the metastatic potential of T-cell lymphoma as well as carcinoma cells as demonstrated by reduced migration and invasion in vitro and reduced formation of experimental metastasis in vivo. At the molecular level, silencing of L1CAM led to reduced expression of gelatinases MMP-2 and -9 in vitro and decreased gelatinolytic activity in primary tumours and metastases in vivo. In accordance, knock down of L1CAM had similar suppressive effects on migration, invasion and in vivo-gelatinolytic activity as treatment with the specific gelatinase inhibitor SB-3CT. This newly discovered impact of L1CAM on distinct steps of the metastatic cascade and MMP activity highlights the potential of possible L1CAM-directed therapies to inhibit metastatic spread.

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Abbreviations

CAM:

Cell adhesion molecule

DAPI:

4′,6-Diamidino-2-phenylindole

DMSO:

Dimethyl sulfoxide

IgSF:

Immunoglobulin superfamily

i.d.:

Intradermal

i.v.:

Intravenous

L1CAM:

L1 cell adhesion molecule

MMP-2:

Matrix metalloproteinase-2

MMP-9:

Matrix metalloproteinase-9

PCNA:

Proliferating cell nuclear antigen

PE:

Phycoerythrin

shRNA:

Short hairpin RNA

X-Gal:

5-Bromo-4-chloro-indolyl-β-d-galactopyranoside

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Acknowledgments

The authors thank Stephanie Hauser, Laura Bickel and Mareike Lehnhoff (all three from Institute for Experimental Oncology and Therapy Research, Klinikum rechts der Isar, Technische Universität München, Germany) for their expert technical support. This work was supported by the Deutsche Forschungsgemeinschaft (Grants KR2047/1-1 and 1-2) to Achim Krüger.

Author information

Authors and Affiliations

  1. Institute for Experimental Oncology and Therapy Research, Klinikum rechts der Isar, Technische Universität München, 81675, Munich, Germany

    Dirk Weinspach, Bastian Seubert, Susanne Schaten, Katja Honert & Achim Krüger

  2. Institute for Experimental Medicine, UKSH, Campus Kiel, 24105, Kiel, Germany

    Susanne Sebens

  3. Translational Immunology Unit (D015), German Cancer Research Center, 69120, Heidelberg, Germany

    Peter Altevogt

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  1. Dirk Weinspach
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  2. Bastian Seubert
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  7. Achim Krüger
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Corresponding author

Correspondence to Achim Krüger.

Additional information

Dirk Weinspach and Bastian Seubert have contributed equally to this work.

Electronic supplementary material

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10585_2013_9613_MOESM1_ESM.ppt

Supplementary Fig. 1 Tumour cell-derived L1CAM expression is an important regulator of the metastatic potential in vitro. L-CI.5s cells were transduced with retroviruses containing a shRNA sequence directed against murine L1CAM (shL1-3) or with a non-targeting shRNA sequence (shscr, scrambled shRNA). a TaqMan® analysis revealed significantly reduced L1CAM expression in L-CI.5s cells. Mean expression of L1CAM mRNA ± SEM (columns ± bars) in L-CI.5s cells. L1CAM mRNA expression levels were normalised to 18S rRNA levels and the mean of the reference group (shscr) was set as 100 % (n = 3; shL1-3 versus shscr: **p = 0.007, as determined by unpaired t-test). b Western blot analysis of immunoprecipitated L1CAM revealed that L1CAM protein levels were significantly reduced in L-CI.5s cells. c Flow cytometric analysis revealed that L1CAM expression was significantly reduced in L-CI.5s cells. d For analysis of cell viability/proliferation, 2 × 103 cells/well were seeded in 96 well plates, and the number of living cells was quantified 0, 24, 48, 72 and 96 h after seeding using the AlamarBlue® proliferation assay (n = 6). e Mean number of migrated cells per image section ± SEM (columns ± bars) for the different L-CI.5s cells as analysed by trans-well migration assay. The mean of the reference group (shscr) was set as 100 % (n = 6; shL1-3 vs. shscr: ***p ≤ 0.001, as determined by unpaired t-test). f Mean number of invaded cells per image section ± SEM (columns ± bars) for the different L-CI.5s cells as analysed by Matrigel invasion assay. The mean of the reference group (shscr) was set as 100 % (n = 6; shL1-3 vs. shscr: **p = 0.005, unpaired t-test). g Mean MMP-2 mRNA expression ± SEM (columns ± bars) in the different L-CI.5s cells as determined by TaqMan analysis. MMP-2 levels were normalised to 18S rRNA levels and the mean of the reference group (shscr) was set as 100 % (n = 3; shL1-3 vs. shscr: *p = 0.028, as determined by unpaired t-test). h Mean MMP-9 mRNA expression ± SEM (columns ± bars) in the different L-CI.5s cells as determined by TaqMan analysis. MMP-9 levels were normalised to 18S rRNA levels and the mean of the reference group (shscr) was set as 100 %. (n = 3; shL1-3 vs. shscr: *p = 0.015, as determined by unpaired t-test). i Mean number of migrated cells per image section ± SEM (columns ± bars) for the different L-CI.5s cells as determined by trans-well migration assay. Cells were either incubated with 20 µM gelatinase inhibitor SB-3CT or DMSO as a control. The mean of the reference group (shscr, DMSO) was set as 100 % (n = 6 each; all group comparison: **p ≤ 0.001; shscr, SB-3CT vs. shscr, DMSO: *p < 0.05; shL1-3, DMSO vs. shscr, DMSO: p > 0.05; shL1-3, SB-3CT vs. shscr, DMSO: *p < 0.05; shL1-3, SB-3CT vs. shL1-3, DMSO: p > 0.05, as determined by Kruskal–Wallis One Way ANOVA on Ranks). j Mean number of invaded cells per image section ± SEM (columns ± bars) for the different L-CI.5s cells as determined by Matrigel invasion assay. Cells were either incubated with 20 μM gelatinase inhibitor SB-3CT or DMSO as a control. The mean of the reference group (shscr, DMSO) was set as 100 % (n = 6 each; all group comparison: *p ≤ 0.001, as determined by One Way ANOVA; single group comparison: shscr, SB-3CT vs. shscr, DMSO: ***p < 0.001; shL1-3, DMSO vs. shscr, DMSO: ***p < 0.001; shL1-3, SB-3CT vs. shscr, DMSO: ***p < 0.001; shL1-3, SB-3CT vs. shL1-2, DMSO: p = 0.090; as determined by One Way ANOVA and subsequent post hoc comparison by Holm–Sidak method). Supplementary material 1 (PPT 646 kb)

10585_2013_9613_MOESM2_ESM.ppt

Supplementary Fig. 2 a Respective close-up picture showing X-Gal staining of a liver from a mouse that has not been inoculated with tumour cells. b X-Gal staining was performed on cryo-sections of primary tumours (upper panel) and livers bearing metastases (lower panel) originating from the L-CI.5s spontaneous metastasis assay (bars: 100 μm). Supplementary material 2 (PPT 10466 kb)

10585_2013_9613_MOESM3_ESM.ppt

Supplementary Fig. 3 L1CAM positively regulates the metastatic potential of ovarian carcinoma cells. SKOV3ip-lacZ cells were transduced with retroviruses containing a shRNA sequence directed against human L1CAM (shL1-3) or with a non-targeting shRNA sequence (shscr, scrambled shRNA). a TaqMan® analysis revealed significantly reduced L1CAM expression in L-CI.5s cells. Mean expression of L1CAM mRNA ± SEM (columns ± bars) in SKOV3ip-lacZ cells. L1CAM mRNA expression levels were normalised to 18S rRNA levels and the mean of the reference group (shscr) was set as 100 % (n = 3; shL1-3 vs. shscr: ***p ≤ 0.001, as determined by unpaired t-test). b Western blot analysis revealed that L1CAM protein levels were significantly reduced in SKOV3ip-lacZ cells. c Flow cytometric analysis revealed that L1CAM expression was significantly reduced in SKOV3ip-lacZ cells. d Mean number of migrated cells per image section ± SEM (columns ± bars) for the different SKOV3ip-lacZ cells as analysed by trans-well migration assay. Cells were either incubated with 20 µM gelatinase inhibitor SB-3CT or DMSO as a control. The mean of the reference group (shscr, DMSO) was set as 100 % (n = 6 each; all group comparison: ***p ≤ 0.001, as determined by One Way ANOVA; single group comparison: shscr, SB-3CT vs. shscr, DMSO: ***p < 0.001; shL1-3, DMSO vs. shscr, DMSO: ***p ≤ 0.001; shL1-3, SB-3CT vs. shscr, DMSO: ***p < 0.001; shL1-3, SB-3CT vs. shL1-3, DMSO: *p = 0.048, as determined by One Way ANOVA and subsequent post hoc comparison by Holm-Sidak method). e Mean number of invaded cells per image section ± SEM (columns ± bars) for the different SKOV3ip-lacZ cells as determined by Matrigel invasion assay. Cells were either incubated with 20 μM gelatinase inhibitor SB-3CT or DMSO as a control. The mean of the reference group (shscr, DMSO) was set as 100 % (n = 6 each; all group comparison: ***p ≤ 0.001, as determined by Kruskal–Wallis One Way ANOVA; single group comparison: shscr, SB-3CT vs. shscr, DMSO: *p > 0.05; shL1-3, DMSO vs. shscr, DMSO: *p < 0.05; shL1-3, SB-3CT vs. shscr, DMSO: *p < 0.05; shL1-3, SB-3CT vs. shL1-3, DMSO: not testable, as determined by Kruskal–Wallis One Way ANOVA on Ranks and subsequent post hoc comparison by Dunn’s method). f For analysis of cell viability/proliferation, 2 × 103 cells/well were seeded in 96 well plates, and the number of living cells was quantified 0 h, 24 h, 48 h, 72 h and 96 h after seeding using the AlamarBlue® proliferation assay (n = 6). Supplementary material 3 (PPT 802 kb)

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Weinspach, D., Seubert, B., Schaten, S. et al. Role of L1 cell adhesion molecule (L1CAM) in the metastatic cascade: promotion of dissemination, colonization, and metastatic growth. Clin Exp Metastasis 31, 87–100 (2014). https://doi.org/10.1007/s10585-013-9613-6

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