Skip to main content

Advertisement

SpringerLink
Log in

Nuclear factor kappaB-activated monocytes contribute to pancreatic cancer progression through the production of Shh

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Recently, it was reported that Hh signaling is activated in tumor stromal cells but not in tumor cells themselves and that stromal cells may play a role in the proliferation of cancer cells. This suggests the possibility that stromal cells have an important role in the proliferation of tumor cells that may be mediated through Hh signaling. In this report, we present for the first time that inflammation-stimulated monocytes produce Shh through activation of the NF-κB signaling pathway, and that the Shh produced promotes the proliferation of pancreatic cancer cells in a paracrine manner through Hh signaling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

PBMCs:

Peripheral blood mononuclear cells

Shh:

Sonic hedgehog

PDAC:

Pancreatic ductal adenocarcinomas

References

  1. Auwerx J (1991) The human leukemia cell line, THP-1: a multifaceted model for the study of monocyte–macrophage differentiation. Experientia 47(1):22–31

    Article  CAS  PubMed  Google Scholar 

  2. Bansal P, Sonnenberg A (1995) Pancreatitis is a risk factor for pancreatic cancer. Gastroenterology 109:247–251

    Article  CAS  PubMed  Google Scholar 

  3. Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, Parker AR, Shimada Y, Eshleman JR, Watkins DN, Beachy PA (2003) Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425:846–851

    Article  CAS  PubMed  Google Scholar 

  4. Boyle P, Maisonneuve P, Bueno de Mesquita B, Ghadirian P, Howe GR, Zatonski W, Baghurst P, Moerman CJ, Simard A, Miller AB, Przewoniak K, McMichael AJ, Hsieh CC, Walker AM (1996) Cigarette smoking and pancreas cancer: a case–control study of the search programme of the IARC. Int J Cancer 67:63–71

    Article  CAS  PubMed  Google Scholar 

  5. Bumcrot DA, Takada R, McMahon AP (1995) Proteolytic processing yields two secreted forms of sonic hedgehog. Mol Cell Biol 15:2294–2303

    CAS  PubMed  Google Scholar 

  6. Cassol E, Alfano M, Biswas P, Poli G (2006) Monocyte-derived macrophages and myeloid cell lines as targets of HIV-1 replication and persistence. J Leukoc Biol 80:1018–1030

    Article  CAS  PubMed  Google Scholar 

  7. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal Biochem 162:156–159

    Article  CAS  PubMed  Google Scholar 

  8. Crouse NR, Ajit D, Udan ML, Nichols MR (2009) Oligomeric amyloid-beta(1–42) induces THP-1 human monocyte adhesion and maturation. Brain Res 1254:109–119

    Article  CAS  PubMed  Google Scholar 

  9. de Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6:24–37

    Article  PubMed  Google Scholar 

  10. Dunaeva M, Michelson P, Kogerman P, Toftgard R (2003) Characterization of the physical interaction of Gli proteins with SUFU proteins. J Biol Chem 278:5116–5122

    Article  CAS  PubMed  Google Scholar 

  11. Fan L, Pepicelli CV, Dibble CC, Catbagan W, Zarycki JL, Laciak R, Gipp J, Shaw A, Lamm ML, Munoz A, Lipinski R, Thrasher JB, Bushman W (2004) Hedgehog signaling promotes prostate xenograft tumor growth. Endocrinology 145:3961–3970

    Article  CAS  PubMed  Google Scholar 

  12. Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M, Karikari C, Alvarez H, Iacobuzio-Donahue C, Jimeno A, Gabrielson KL, Matsui W, Maitra A (2007) Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 67:2187–2196

    Article  CAS  PubMed  Google Scholar 

  13. Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15:3059–3087

    Article  CAS  PubMed  Google Scholar 

  14. Izzi V, Chiurchiù V, D’Aquilio F, Palumbo C, Tresoldi I, Modesti A, Baldini MP (2009) Differential effects of malignant mesothelioma cells on THP-1 monocytes and macrophages. Int J Oncol 34:543–550

    CAS  PubMed  Google Scholar 

  15. Karin M, Greten FR (2005) NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5:749–759

    Article  CAS  PubMed  Google Scholar 

  16. Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441:431–436

    Article  CAS  PubMed  Google Scholar 

  17. Kasperczyk H, Baumann B, Debatin KM, Fulda S (2009) Characterization of sonic hedgehog as a novel NF-kappaB target gene that promotes NF-kappaB-mediated apoptosis resistance and tumor growth in vivo. FASEB J 23:21–33

    Article  CAS  PubMed  Google Scholar 

  18. Kuga H, Morisaki T, Nakamura K, Onishi H, Noshiro H, Uchiyama A, Tanaka M, Katano M (2003) Interferon-gamma suppresses transforming growth factor-beta-induced invasion of gastric carcinoma cells through cross-talk of Smad pathway in a three-dimensional culture model. Oncogene 22:7838–7847

    Article  CAS  PubMed  Google Scholar 

  19. Kusano KF, Pola R, Murayama T, Curry C, Kawamoto A, Iwakura A, Shintani S, Ii M, Asai J, Tkebuchava T, Thorne T, Takenaka H, Aikawa R, Goukassian D, von Samson P, Hamada H, Yoon YS, Silver M, Eaton E, Ma H, Heyd L, Kearney M, Munger W, Porter JA, Kishore R, Losordo DW (2005) Sonic hedgehog myocardial gene therapy: tissue repair through transient reconstitution of embryonic signaling. Nat Med 11:1197–1204

    Article  CAS  PubMed  Google Scholar 

  20. Li Q, Withoff S, Verma IM (2005) Inflammation-associated cancer: NF-kappaB is the lynchpin. Trends Immunol 26:318–325

    Article  PubMed  Google Scholar 

  21. Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR, Dimagno EP, Andren-Sandberg A, Domellof L (1993) Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 328:1433–1437

    Article  CAS  PubMed  Google Scholar 

  22. Luo JL, Maeda S, Hsu LC, Yagita H, Karin M (2004) Inhibition of NF-kappaB in cancer cells converts inflammation-induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell 6:297–305

    Article  CAS  PubMed  Google Scholar 

  23. Morton JP, Mongeau ME, Klimstra DS, Morris JP, Lee YC, Kawaguchi Y, Wright CV, Hebrok M, Lewis BC (2007) Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci USA 104:5103–5108

    Article  CAS  PubMed  Google Scholar 

  24. Nagai S, Nakamura M, Yanai K, Wada J, Akiyoshi T, Nakashima H, Ohuchida K, Sato N, Tanaka M, Katano M (2008) Gli1 contributes to the invasiveness of pancreatic cancer through matrix metalloproteinase-9 activation. Cancer Sci 99:1377–1384

    Article  CAS  PubMed  Google Scholar 

  25. Nakashima H, Nakamura M, Yamaguchi H, Yamanaka N, Akiyoshi T, Koga K, Yamaguchi K, Tsuneyoshi M, Tanaka M, Katano M (2006) Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer. Cancer Res 66:7041–7049

    Article  CAS  PubMed  Google Scholar 

  26. Otsuki M (2003) Chronic pancreatitis in Japan: epidemiology, prognosis, diagnostic criteria, and future problems. J Gastroenterol 38:315–326

    Article  PubMed  Google Scholar 

  27. Pasca di Magliano M, Sekine S, Ermilov A, Ferris J, Dlugosz AA, Hebrok M (2006) Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev 20:3161–3173

    Article  CAS  PubMed  Google Scholar 

  28. Preiss S, Namgaladze D, Brüne B (2007) Critical role for classical PKC in activating Akt by phospholipase A2-modified LDL in monocytic cells. Cardiovasc Res 73:833–840

    Article  CAS  PubMed  Google Scholar 

  29. Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78

    Article  CAS  PubMed  Google Scholar 

  30. Raderer M, Kurtaran A, Yang Q, Meghdadi S, Vorbeck F, Hejna M, Angelberger P, Kornek G, Pidlich J, Scheithauer W, Virgolini I (1998) Iodine-123-vasoactive intestinal peptide receptor scanning in patients with pancreatic cancer. J Nucl Med 39:1570–1575

    CAS  PubMed  Google Scholar 

  31. Sasaki H, Nishizaki Y, Hui C, Nakafuku M, Kondoh H (1999) Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development 126:3915–3924

    CAS  PubMed  Google Scholar 

  32. Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K, Akira S (2003) Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J Immunol 171:4304–4310

    CAS  PubMed  Google Scholar 

  33. Schnoor M, Buers I, Sietmann A, Brodde MF, Hofnagel O, Robenek H, Lorkowski S (2009) Efficient non-viral transfection of THP-1 cells. J Immunol Methods 344:109–115

    Article  CAS  PubMed  Google Scholar 

  34. Schreck R, Schreck R, Meier B, Männel DN, Dröge W, Baeuerle PA (1992) Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J Exp Med 175:1181–1194

    Article  CAS  PubMed  Google Scholar 

  35. Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernandez-del Castillo C, Yajnik V, Antoniu B, McMahon M, Warshaw AL, Hebrok M (2003) Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425:851–856

    Article  CAS  PubMed  Google Scholar 

  36. Tian H, Callahan CA, DuPree KJ, Darbonne WC, Ahn CP, Scales SJ, de Sauvage FJ (2009) Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci USA 106:4254–4259

    Article  CAS  PubMed  Google Scholar 

  37. Yamanaka N, Morisaki T, Nakashima H, Tasaki A, Kubo M, Kuga H, Nakahara C, Nakamura K, Noshiro H, Yao T, Tsuneyoshi M, Tanaka M, Katano M (2004) Interleukin 1beta enhances invasive ability of gastric carcinoma through nuclear factor-kappaB activation. Clin Cancer Res 10:1853–1859

    Article  CAS  PubMed  Google Scholar 

  38. Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, Marshall D, Fu L, Januario T, Kallop D, Nannini-Pepe M, Kotkow K, Marsters JC, Rubin LL, de Sauvage FJ (2008) A paracrine requirement for hedgehog signalling in cancer. Nature 455:406–410

    Article  CAS  PubMed  Google Scholar 

  39. Zhang B, Ma Y, Guo H, Sun B, Niu R, Ying G, Zhang N (2009) Akt2 is required for macrophage chemotaxis. Eur J Immunol 39:894–901

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by General Scientific Research Grants (21390363) from the Ministry of Education, Culture, Sports and Technology of Japan. We thank Dr. K. Takeda for kindly providing us with the NF-κB-dependent luciferase reporter, Dr. Aubie Shaw for kindly providing us with pSHH-GFP plasmids, and Dr. H. Yamamoto from Department of Anatomic Pathology, Kyushu University, for giving us an appropriate technical advice about immunohistochemistry. We also thank Kaori Nomiyama for the skillful technical assistance.

Author information

Authors and Affiliations

  1. Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Akio Yamasaki, Chizu Kameda, Rui Xu, Haruo Tanaka, Takehiko Tasaka, Nobuhito Chikazawa, Hiroyuki Suzuki, Takashi Morisaki, Hideya Onishi & Mitsuo Katano

  2. Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Makoto Kubo & Masao Tanaka

Authors
  1. Akio Yamasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chizu Kameda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rui Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haruo Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takehiko Tasaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nobuhito Chikazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroyuki Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takashi Morisaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Makoto Kubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hideya Onishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Masao Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mitsuo Katano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mitsuo Katano.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamasaki, A., Kameda, C., Xu, R. et al. Nuclear factor kappaB-activated monocytes contribute to pancreatic cancer progression through the production of Shh. Cancer Immunol Immunother 59, 675–686 (2010). https://doi.org/10.1007/s00262-009-0783-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-009-0783-7

Keywords

Search

Navigation