The host defence peptide LL-37/hCAP-18 is a growth factor for lung cancer cells

Haussen, Judith von; Koczulla, Rembert; Shaykhiev, Renat; Herr, Christian; Pinkenburg, Olaf; Reimer, D; Wiewrodt, Rainer; Biesterfeld, Stefan; Aigner, Achim; Czubayko, Frank; Bals, Robert

doi:10.1016/j.lungcan.2007.07.014

Cited by 136 publications

(151 citation statements)

References 42 publications

Supporting

Mentioning

134

Contrasting

Unclassified

Order By: Relevance

“…CRAMP is the mouse orthologue of human LL37, which is an anti-microbial peptide contained in neutrophil granules and is also produced by normal epithelial cells (25) and cancer cells (26). In mice, CRAMP enhances OVA-induced immune responses including the production of Th1 and Th2 cytokines (15).…”

Section: Discussionmentioning

confidence: 99%

The Formylpeptide Receptor 2 (Fpr2) and Its Endogenous Ligand Cathelin-related Antimicrobial Peptide (CRAMP) Promote Dendritic Cell Maturation

Chen

Xiang

Huang

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Chemoattractant receptor Fpr2 interacts with host-derived agonist CRAMP and promotes dentritic cell maturation in immune responses. Results: Deficiency in Fpr2 or CRAMP results in impaired maturation of dendritic cells in vitro and in vivo.Conclusion: Fpr2 and its agonist CRAMP play a nonredundant role in DC maturation. Significance: Fpr2 and its agonist CRAMP are potential targets for disease intervention.

show abstract

Section: Discussionmentioning

confidence: 99%

The Formylpeptide Receptor 2 (Fpr2) and Its Endogenous Ligand Cathelin-related Antimicrobial Peptide (CRAMP) Promote Dendritic Cell Maturation

Chen

Xiang

Huang

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…10,11 Furthermore, LL-37 has been found in breast and ovarian carcinomas, 16,17 and acts as a growth factor for lung cancer cells. 18 Tumor-associated angiogenesis is required to sustain tumor cell function and survival. 1 Hence, LL-37 has been described as an inducer of angiogenesis by a direct action on EC.…”

Section: Discussionmentioning

confidence: 99%

“…[12][13][14] Furthermore, hCAP18/LL-37 is actively involved in tissue repair and wound healing 15 processes that share fundamental features with tumor growth and progression. Histological examination of ovarian, 16 breast, 17 and lung tumors 18 has shown that LL-37 is upregulated in these malignancies. LL-37 further promotes recruitment and engraftment of multipotent mesenchymal stromal cells into tumors.…”

mentioning

confidence: 99%

Cathelicidin LL-37 Induces Angiogenesis via PGE ₂ –EP3 Signaling in Endothelial Cells, In Vivo Inhibition by Aspirin

Salvado

Gennaro

Lindbom

et al. 2013

ATVB

View full text Add to dashboard Cite

Objective-LL-37, the unique cathelicidin expressed in humans, in addition to acting as an endogenous antibiotic, is an important cell-signaling molecule upregulated in ovarian, breast, and lung tumors. However, the role of LL-37 in tumor microenvironment and its specific actions on the endothelial compartment remain elusive. Prostanoids are key regulators of inflammation, and cyclooxygenases (COXs) display proangiogenic activity in vitro and in vivo, mediated principally through prostaglandin E 2 (PGE 2 ). Here, we provide evidence for a novel proangiogenic role of LL-37, exerted via activation of endothelial cells and subsequent PGE 2 biosynthesis. Approach and Results-LL-37 triggers PGE 2 synthesis in endothelial cells in a dose-dependent manner with maximal induction after 4 hours. Endothelial PGE 2 biosynthesis was dependent on COX-1, rather than COX-2, as judged by pharmacological inhibition and gene silencing. In vitro matrigel assays supported these findings because LL-37-induced cord formation was abolished by COX-1, but not COX-2, small interfering RNA, and the angiogenic phenotype could be rescued by addition of exogenous PGE 2 . We find that LL-37 acts on endothelial cells as a potent calcium agonist, inducing phosphorylation and activation of cytosolic phospholipase A 2 (cPLA 2 ), promoting a cPLA 2 →COX-1→PGE 2 biosynthetic pathway and subsequent signaling via PGE 2 receptor EP3. Moreover, cathelicidin-related antimicrobial peptide, which is the murine ortholog of LL-37, induced prostaglandin-dependent angiogenesis in vivo, which could be blocked by aspirin. Conclusions-Our results identify a novel proangiogenic role of LL-37, suggesting that the axis LL-37/COX-1/PGE 2 followed by EP3 signaling is amenable to therapeutic intervention in pathological angiogenesis, for instance by aspirin. 16 However, the role of LL-37 in tumor microenvironment and its specific actions on the endothelial compartment, an essential player in the angiogenic process, remain elusive.Here, we investigate the angiogenic role of LL-37 in human primary ECs. Our findings indicate that LL-37 elicits angiogenic responses via COX-1-derived PGE 2 , which triggers EP3 signaling. These results provide new insights to the molecular basis of LL-37 proangiogenic properties that could help develop novel antiangiogenic therapies. Results LL-37 Induces PGE 2 Biosynthesis in ECsLL-37 stimulation triggers PGE 2 synthesis by EC in a dosedependent manner with a maximal induction at 60 µg/mL of peptide ( Figure 1A). At this LL-37 concentration, the PGE 2 production reached its plateau after 4 hours of stimulation ( Figure 1B). At 60 µg/mL, we did not detect any cytotoxic effects of LL-37 on human umbilical vein endothelial cells (HUVECs), as assessed by Trypan blue exclusion. On the contrary, this dose induced a moderate, but statistically significant, increase of cell viability after 4 and 8 hours of treatment ( Figure 1C). Biosynthesis of prostacyclin and thromboxane was also modestly increased by LL-37 but only at the highest concentration ...

show abstract

“…Human cationic antimicrobial protein 18 (hCAP-18) is the only known member of the cathelicidin family in humans. The active peptide LL-37 is overexpressed in breast, lung, and ovarian tumors, probably functioning as an autocrine survival factor (91)(92)(93). It may also promote tumor growth through angiogenesis and recruitment of CD45 + cells (69).…”

Section: Cancermentioning

confidence: 99%

Alarmins: awaiting a clinical response

Chan

Roth²,

Oppenheim³

et al. 2012

J. Clin. Invest.

439

331

View full text Add to dashboard Cite

The host defence peptide LL-37/hCAP-18 is a growth factor for lung cancer cells

Cited by 136 publications

References 42 publications

The Formylpeptide Receptor 2 (Fpr2) and Its Endogenous Ligand Cathelin-related Antimicrobial Peptide (CRAMP) Promote Dendritic Cell Maturation

The Formylpeptide Receptor 2 (Fpr2) and Its Endogenous Ligand Cathelin-related Antimicrobial Peptide (CRAMP) Promote Dendritic Cell Maturation

Cathelicidin LL-37 Induces Angiogenesis via PGE ₂ –EP3 Signaling in Endothelial Cells, In Vivo Inhibition by Aspirin

Alarmins: awaiting a clinical response

Contact Info

Product

Resources

About

The host defence peptide LL-37/hCAP-18 is a growth factor for lung cancer cells

Cited by 136 publications

References 42 publications

The Formylpeptide Receptor 2 (Fpr2) and Its Endogenous Ligand Cathelin-related Antimicrobial Peptide (CRAMP) Promote Dendritic Cell Maturation

The Formylpeptide Receptor 2 (Fpr2) and Its Endogenous Ligand Cathelin-related Antimicrobial Peptide (CRAMP) Promote Dendritic Cell Maturation

Cathelicidin LL-37 Induces Angiogenesis via PGE 2 –EP3 Signaling in Endothelial Cells, In Vivo Inhibition by Aspirin

Alarmins: awaiting a clinical response

Contact Info

Product

Resources

About

Cathelicidin LL-37 Induces Angiogenesis via PGE ₂ –EP3 Signaling in Endothelial Cells, In Vivo Inhibition by Aspirin