Human antimicrobial protein hCAP18/LL-37 promotes a metastatic phenotype in breast cancer

Weber, Günther; Chamorro, Clara Ibel; Granath, Fredrik; Liljegren, Annelie; Zreika, Sami; Saidak, Zuzana; Sandstedt, Bengt; Rotstein, Samuel; Mentaverri, Romuald; Sánchez, Fabio; Pivarcsi, Andor; Ståhle, Mona

doi:10.1186/bcr2221

Cited by 83 publications

(86 citation statements)

References 38 publications

(60 reference statements)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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%

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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

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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 ...

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“…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.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

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“…Overexpression of hCAP-18 in breast cancer cell line MJ1105 reportedly promotes the development of metastases in mice with severe combined immunodeficiency (SCID). The findings also revealed enhanced activation of MAPK signaling in hCAP-18 transgenic tumors [56]. It has been shown that LL-37 induces migration of breast cancer cell lines (MCF7, MDA-MB-435s and MDA-MB-231) by activating the transient receptor potential cation (TRPV2) and recruiting it to pseudopodia through activation of the PI3K/Akt pathway [54].…”

Section: Breast Cancermentioning

confidence: 85%

“…ErbB2 upregulation by LL-37 activates Heregulin (an ErbB3/ErbB4 ligand)-mediated MAPK signaling pathway in breast cancer cells, resulting not only in enhanced cell migration but also anchorage-independent growth (Fig. 3A) [56]. Overexpression of hCAP-18 in breast cancer cell line MJ1105 reportedly promotes the development of metastases in mice with severe combined immunodeficiency (SCID).…”

Section: Breast Cancermentioning

confidence: 99%

Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer

Chen

Zou

et al. 2018

Cell Physiol Biochem

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LL-37, the C-terminal peptide of human cathelicidin antimicrobial peptide (CAMP, hCAP18), reportedly increases resistance to microbial invasion and exerts important physiological functions in chemotaxis, promotion of wound closure, and angiogenesis. Accumulating evidence indicates that LL-37 also plays a significant role in human cancer. LL-37 induces tumorigenic effects in cancers of the ovary, lung, breast, prostate, pancreas, as well as in malignant melanoma and skin squamous cell carcinoma. In contrast, LL-37 displays an anti-cancer effect in colon cancer, gastric cancer, hematologic malignancy and oral squamous cell carcinoma. Mechanistically, LL-37-induced activation of membrane receptors and subsequent signaling pathways lead to alteration of cellular functions. Different membrane receptors on various cancer cells appear to be responsible for the tissue-specific effects of LL-37. Meanwhile, the findings that vitamin D-dependent induction of cathelicidin in human macrophages activates the anti-cancer activity of tumor-associated macrophages (TAMs) and enhances antibody-dependent cellular cytotoxicity (ADCC) support critical roles of vitamin D-dependent induction of cathelicidin in cancer progression. This review describes novel advances involving the roles and mechanisms of human cathelicidin LL-37 in cancer.

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Unique features of human cathelicidin LL‐37

et al. 2015

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Cathelicidins are antimicrobial peptides produced by humans and animals in response to various pathogenic microbes. This review intends to provide a brief overview of the expression, structure, properties and function of human cathelicidin LL-37 which may be a therapeutic agent against a variety of bacterial and viral diseases, cancers, and hard-to-heal wounds. Cathelicidins act as a primary defense against bacteria and other pathogens in the case of inflammation. They are able to kill bacteria and fungi, inhibit and destroy bacterial biofilms, and possess antiviral and antiparasitics properties. They can also play a role in angiogenesis, wound healing, and the regulation of apoptosis. The host defense peptide LL-37 has emerged as a novel modulator of tumor growth and metastasis in carcinogenesis of various types of cancers. LL-37 is an antimicrobial peptide able of inducing various effects. It acts as an anti- and pro- inflammatory factor. Cathelicidins are able to directly and selectively destroy membranes of various microbes and cancer cells, but they do not attack normal cells. The role of cathelicidins in cancer is double-sided. They play an important role in killing cancer cells and may provide a new possibility for the development of cancer therapeutics. However, they also can participate in carcinogenesis. Due to its activity spectrum LL-37 could be applied in pharmacotherapy. Cathelicidin peptides could serve as a template for the development of modern anti-microbial and anti-viral drugs. LL-37 is an excellent candidate to develop into therapeutics for infected wounds.

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Human antimicrobial protein hCAP18/LL-37 promotes a metastatic phenotype in breast cancer

Cited by 83 publications

References 38 publications

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

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

Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer

Unique features of human cathelicidin LL‐37

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Human antimicrobial protein hCAP18/LL-37 promotes a metastatic phenotype in breast cancer

Cited by 83 publications

References 38 publications

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

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

Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer

Unique features of human cathelicidin LL‐37

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Product

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

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