Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment

Gut

Volumn 64, Issue 12, 2015, Pages 1921-1935

  Sainz, Bruno ^a,b   Alcala, Sonia ^a,b   Garcia, Elena ^a,c   Sanchez Ripoll, Yolanda ^a   Azevedo, Maria M ^a   Cioffi, Michele ^a   Tatari, Marianthi ^a   Miranda Lorenzo, Irene ^a   Hidalgo, Manuel ^a   Gomez Lopez, Gonzalo ^a   Cañamero, Marta ^a   Erkan, Mert ^d,e   Kleeff, Jörg ^d   García Silva, Susana ^a   Sancho, Patricia ^a   Hermann, Patrick C ^a,f   Heeschen, Christopher ^a,g  

^a Centro Nacional de Investigaciones Oncológicas   (Spain)

^b UNIVERSIDAD AUTÓNOMA DE MADRID   (Spain)

^c HOSPITAL UNIVERSITARIO FUNDACIÓN ALCORCÓN   (Spain)

^d TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^e KOÇ UNIVERSITY   (Turkey)

^f UNIVERSITY OF ULM   (Germany)

^g QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVIN A; CATHELICIDIN ANTIMICROBIAL PEPTIDE LL 37; FORMYL PEPTIDE RECEPTOR 2; PURINERGIC P2X7 RECEPTOR; TRANSFORMING GROWTH FACTOR BETA1; TUMOR PROTEIN; UNCLASSIFIED DRUG; ACTIVIN; ANTIMICROBIAL CATIONIC PEPTIDE; CAP18 LIPOPOLYSACCHARIDE-BINDING PROTEIN; FORMYL PEPTIDE RECEPTOR 2, MOUSE; FORMYLPEPTIDE RECEPTOR; PURINERGIC P2X RECEPTOR ANTAGONIST;

ADVANCED CANCER; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CANCER STEM CELL; CARCINOGENESIS; CELL COMPARTMENTALIZATION; CELL INVASION; CELL RENEWAL; CONTROLLED STUDY; DISEASE ACTIVITY; DISEASE ASSOCIATION; GENE EXPRESSION; HUMAN; HUMAN CELL; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; MACROPHAGE; MICROARRAY ANALYSIS; MOLECULAR DYNAMICS; MOLECULAR PATHOLOGY; MOUSE; NONHUMAN; PANCREAS ADENOCARCINOMA; PRIORITY JOURNAL; PROTEIN EXPRESSION; TUMOR MICROENVIRONMENT; ANIMAL; ANTAGONISTS AND INHIBITORS; CELL SELF-RENEWAL; DRUG EFFECTS; GENETICS; METABOLISM; NUDE MOUSE; PANCREAS CARCINOMA; PANCREAS TUMOR; PATHOLOGY; PROTEIN MICROARRAY; SECRETION (PROCESS); SIGNAL TRANSDUCTION; TISSUE MICROARRAY; TUMOR INVASION;

ACTIVINS; ANIMALS; ANTIMICROBIAL CATIONIC PEPTIDES; CARCINOGENESIS; CARCINOMA, PANCREATIC DUCTAL; CELL SELF RENEWAL; GENE EXPRESSION; HUMANS; MACROPHAGES; MICE; MICE, NUDE; NEOPLASM INVASIVENESS; NEOPLASTIC STEM CELLS; PANCREATIC NEOPLASMS; PROTEIN ARRAY ANALYSIS; PURINERGIC P2X RECEPTOR ANTAGONISTS; RECEPTORS, FORMYL PEPTIDE; RECEPTORS, PURINERGIC P2X7; SIGNAL TRANSDUCTION; TISSUE ARRAY ANALYSIS; TRANSFORMING GROWTH FACTOR BETA1; TUMOR MICROENVIRONMENT;

EID: 84954363411     PISSN: 00175749     EISSN: 14683288     Source Type: Journal    
DOI: 10.1136/gutjnl-2014-308935     Document Type: Article

References (56)

1. Paulson AS, Tran Cao HS, Tempero MA, et al. Therapeutic advances in pancreatic cancer. Gastroenterology 2013;144:1316-26.
2. Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007;1:313-23.
3. Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007;67:1030-7.
4. Rasheed ZA, Yang J, Wang Q, et al. Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J Natl Cancer Inst 2010;102:340-51.
5. Miranda-Lorenzo I, Dorado J, Lonardo E, et al. Intracellular autofluorescence: a biomarker for epithelial cancer stem cells. Nat Methods 2014;11:1161-9.
6. Lonardo E, Hermann PC, Mueller MT, et al. Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. Cell Stem Cell 2011;9:433-46.
7. Mueller MT, Hermann PC, Witthauer J, et al. Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer. Gastroenterology 2009;137:1102-13.
8. Chu GC, Kimmelman AC, Hezel AF, et al. Stromal biology of pancreatic cancer. J Cell Biochem 2007;101:887-907.
9. Bachem MG, Schunemann M, Ramadani M, et al. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 2005;128:907-21.
10. Lonardo E, Frias-Aldeguer J, Hermann PC, et al. Pancreatic stellate cells form a niche for cancer stem cells and promote their self-renewal and invasiveness. Cell Cycle 2012;11:1282-90.
11. Farrow B, Sugiyama Y, Chen A, et al. Inflammatory mechanisms contributing to pancreatic cancer development. Ann Surg 2004;239:763-9; discussion 9-71.
12. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 2010;11:889-96.
13. Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 2010;22:231-7.
14. Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002;23:549-55.
15. Kurahara H, Shinchi H, Mataki Y, et al. Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res 2011;167:e211-9.
16. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004;4:71-8.
17. Sica A, Schioppa T, Mantovani A, et al. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 2006;42:717-27.
18. Coffelt SB, Waterman RS, Florez L, et al. Ovarian cancers overexpress the antimicrobial protein hCAP-18 and its derivative LL-37 increases ovarian cancer cell proliferation and invasion. Int J Cancer 2008;122:1030-9.
19. Agerberth B, Gunne H, Odeberg J, et al. FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis. Proc Natl Acad Sci U S A 1995;92:195-9.
20. Larrick JW, Hirata M, Balint RF, et al. Human CAP18: a novel antimicrobial lipopolysaccharide-binding protein. Infect Immun 1995;63:1291-7.
21. De Y, Chen Q, Schmidt AP, et al. LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med 2000;192:1069-74.
22. Nagaoka I, Tamura H, Hirata M. An antimicrobial cathelicidin peptide, human CAP18/LL-37, suppresses neutrophil apoptosis via the activation of formyl-peptide receptor-like 1 and P2X7. J Immunol 2006;176:3044-52.
23. Coffelt SB, Tomchuck SL, Zwezdaryk KJ, et al. Leucine leucine-37 uses formyl peptide receptor-like 1 to activate signal transduction pathways, stimulate oncogenic gene expression, and enhance the invasiveness of ovarian cancer cells. Mol Cancer Res 2009;7:907-15.
24. Sierra-Filardi E, Puig-Kroger A, Blanco FJ, et al. Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers. Blood 2011;117:5092-101.
25. Chao MP, Alizadeh AA, Tang C, et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 2010;142:699-713.
26. Verreck FA, de Boer T, Langenberg DM, et al. Phenotypic and functional profiling of human proinflammatory type-1 and anti-inflammatory type-2 macrophages in response to microbial antigens and IFN-gamma- and CD40L-mediated costimulation. J Leukoc Biol 2006;79:285-93.
27. Hingorani SR, Wang L, Multani AS, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005;7:469-83.
28. Nizet V, Ohtake T, Lauth X, et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 2001;414:454-7.
29. Heilborn JD, Nilsson MF, Jimenez CI, et al. Antimicrobial protein hCAP18/LL-37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells. Int J Cancer 2005;114:713-9.
30. Weber G, Chamorro CI, Granath F, et al. Human antimicrobial protein hCAP18/LL-37 promotes a metastatic phenotype in breast cancer. Breast Cancer Res 2009;11:R6.
31. von Haussen J, Koczulla R, Shaykhiev R, et al. The host defence peptide LL-37/hCAP-18 is a growth factor for lung cancer cells. Lung Cancer 2008;59:12-23.
32. Li D, Beisswenger C, Herr C, et al. Expression of the antimicrobial peptide cathelicidin in myeloid cells is required for lung tumor growth. Oncogene 2014;33:2709-16.
33. Li D, Wang X, Wu JL, et al. Tumor-produced versican V1 enhances hCAP18/LL-37 expression in macrophages through activation of TLR2 and vitamin D3 signaling to promote ovarian cancer progression in vitro. PLoS One 2013;8:e56616.
34. Coffelt SB, Marini FC, Watson K, et al. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells. Proc Natl Acad Sci U S A 2009;106:3806-11.
35. Ren SX, Cheng AS, To KF, et al. Host immune defense peptide LL-37 activates caspase-independent apoptosis and suppresses colon cancer. Cancer Res 2012;72:6512-23.
36. Kreso A, Dick JE. Evolution of the cancer stem cell model. Cell Stem Cell 2014;14:275-91.
37. Hamilton TA, Zhao C, Pavicic PG Jr, et al. Myeloid colony-stimulating factors as regulators of macrophage polarization. Front Immunol 2014;5:554.
38. Heusinkveld M, de Vos van Steenwijk PJ, Goedemans R, et al. M2 macrophages induced by prostaglandin E2 and IL-6 from cervical carcinoma are switched to activated M1 macrophages by CD4+ Th1 cells. J Immunol 2011;187:1157-65.
39. Heusinkveld M, van der Burg SH. Identification and manipulation of tumor associated macrophages in human cancers. J Transl Med 2011;9:216.
40. Flavell RA, Sanjabi S, Wrzesinski SH, et al. The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol 2010;10:554-67.
41. Massague J. TGFbeta in Cancer. Cell 2008;134:215-30.
42. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 2009;27:1806-13.
43. Tomasinsig L, Pizzirani C, Skerlavaj B, et al. The human cathelicidin LL-37 modulates the activities of the P2X7 receptor in a structure-dependent manner. J Biol Chem 2008;283:30471-81.
44. Gordon S. Alternative activation of macrophages. Nat Rev Immunol 2003;3:23-35.
45. Bonde AK, Tischler V, Kumar S, et al. Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors. BMC Cancer 2012;12:35.
46. Sainz B Jr, Martin B, Tatari M, et al. ISG15 is a critical microenvironmental factor for pancreatic cancer stem cells. Cancer Res 2014;74:7309-20.
47. Tsai YC, Pestka S, Wang LH, et al. Interferon-beta signaling contributes to Ras transformation. PLoS One 2011;6:e24291.
48. Heilborn JD, Nilsson MF, Kratz G, et al. The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J Invest Dermatol 2003;120:379-89.
49. Koczulla R, von Degenfeld G, Kupatt C, et al. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest 2003;111:1665-72.
50. Rivas-Santiago B, Hernandez-Pando R, Carranza C, et al. Expression of cathelicidin LL-37 during Mycobacterium tuberculosis infection in human alveolar macrophages, monocytes, neutrophils, and epithelial cells. Infect Immun 2008;76:935-41.
51. Dai X, Sayama K, Tohyama M, et al. PPARgamma mediates innate immunity by regulating the 1alpha,25-dihydroxyvitamin D3 induced hBD-3 and cathelicidin in human keratinocytes. J Dermatol Sci 2010;60:179-86.
52. Park K, Elias PM, Oda Y, et al. Regulation of cathelicidin antimicrobial peptide expression by an endoplasmic reticulum (ER) stress signaling, vitamin D receptor-independent pathway. J Biol Chem 2011;286:34121-30.
53. Grosse-Steffen T, Giese T, Giese N, et al. Epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma and pancreatic tumor cell lines: the role of neutrophils and neutrophil-derived elastase. Clin Dev Immunol 2012;2012:720768.
54. Acharyya S, Oskarsson T, Vanharanta S, et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 2012;150:165-78.
55. Wu W, Kim CH, Liu R, et al. The bone marrow-expressed antimicrobial cationic peptide LL-37 enhances the responsiveness of hematopoietic stem progenitor cells to an SDF-1 gradient and accelerates their engraftment after transplantation. Leukemia 2012;26:736-45.
56. Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J 2005;19:1067-77.