Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

Deficiency of the macrophage growth factor CSF-1 disrupts pancreatic neuroendocrine tumor development

Abstract

Tumor-associated macrophages have recently emerged as a key regulatory cell type during cancer progression, and have been found to promote tumor malignancy in the majority of studies performed to date. We show in this study that CD68+ macrophages positively correlate with tumor grade and liver metastasis in human pancreatic neuroendocrine tumors (PNETs). To investigate the potential mechanisms whereby macrophages can promote PNET progression, we crossed the RIP1-Tag2 (RT2) mouse model of pancreatic islet cancer to colony-stimulating factor-1 (CSF-1)-deficient Csf1op/op mice, which have reduced numbers of tissue macrophages. Csf1op/op RT2 mice had a substantial reduction in cumulative tumor burden, which interestingly resulted from a significant decrease in angiogenic switching and tumor number, rather than an evident effect on tumor growth. In the tumors that did develop in CSF-1-deficient animals, however, there were no significant differences in tumor cell proliferation, apoptosis, angiogenesis or invasion. CSF-1 deficiency decreased macrophage infiltration by approximately 50% during all stages of RT2 tumor progression. Interestingly, several cytokines were upregulated in CSF-1-deficient RT2 tumors, and neutrophil infiltration was increased. These results show that macrophages are important for promoting PNET development and suggest that additional factors contribute to the recruitment and survival of myeloid cells in RT2 tumors in the absence of CSF-1.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Abboud SL, Woodruff K, Liu C, Shen V, Ghosh-Choudhury N . (2002). Rescue of the osteopetrotic defect in op/op mice by osteoblast-specific targeting of soluble colony-stimulating factor-1. Endocrinology 143: 1942–1949.

    Article  CAS  PubMed  Google Scholar 

  • Banaei-Bouchareb L, Gouon-Evans V, Samara-Boustani D, Castellotti MC, Czernichow P, Pollard JW et al. (2004). Insulin cell mass is altered in Csf1op/Csf1op macrophage-deficient mice. J Leukoc Biol 76: 359–367.

    Article  CAS  PubMed  Google Scholar 

  • Bingle L, Brown NJ, Lewis CE . (2002). The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196: 254–265.

    Article  CAS  PubMed  Google Scholar 

  • Chitu V, Stanley ER . (2006). Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol 18: 39–48.

    Article  CAS  PubMed  Google Scholar 

  • Chiu CW, Nozawa H, Hanahan D . (2010). Survival benefit with proapoptotic molecular and pathologic responses from dual targeting of mammalian target of rapamycin and epidermal growth factor receptor in a preclinical model of pancreatic neuroendocrine carcinogenesis. J Clin Oncol 28: 4425–4433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Christofori G, Naik P, Hanahan D . (1995). Vascular endothelial growth factor and its receptors, flt-1 and flk-1, are expressed in normal pancreatic islets and throughout islet cell tumorigenesis. Mol Endocrinol 9: 1760–1770.

    CAS  PubMed  Google Scholar 

  • Gocheva V, Chen X, Peters C, Reinheckel T, Joyce JA . (2010a). Deletion of cathepsin H perturbs angiogenic switching, vascularization and growth of tumors in a mouse model of pancreatic islet cell cancer. Biol Chem 391: 937–945.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gocheva V, Wang H-W, Gadea BB, Shree T, Hunter KE, Garfall AL et al. (2010b). IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev 24: 241–255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greenbaum D, Baruch A, Hayrapetian L, Darula Z, Burlingame A, Medzihradszky KF et al. (2002). Chemical approaches for functionally probing the proteome. Mol Cell Proteomics 1: 60–68.

    Article  CAS  PubMed  Google Scholar 

  • Halfdanarson TR, Rubin J, Farnell MB, Grant CS, Petersen GM . (2008). Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors. Endocr Relat Cancer 15: 409–427.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hamilton JA . (2008). Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 8: 533–544.

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D . (1985). Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315: 115–122.

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.

    Article  CAS  PubMed  Google Scholar 

  • Hu W, Feng Z, Modica I, Klimstra DS, Song L, Allen PJ et al. (2010). Gene amplifications in well-differentiated pancreatic neuroendocrine tumors inactivate the p53 pathway. Genes Cancer 1: 360–368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Joyce JA, Pollard JW . (2009). Microenvironmental regulation of metastasis. Nat Rev Cancer 9: 239–252.

    Article  CAS  PubMed  Google Scholar 

  • Köhler C . (2007). Allograft inflammatory factor-1/ionized calcium-binding adapter molecule 1 is specifically expressed by most subpopulations of macrophages and spermatids in testis. Cell Tissue Res 330: 291–302.

    Article  PubMed  Google Scholar 

  • Lewis CE, Pollard JW . (2006). Distinct role of macrophages in different tumor microenvironments. Cancer Res 66: 605–612.

    Article  CAS  PubMed  Google Scholar 

  • Lin EY, Li J-f, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA et al. (2006). Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66: 11238–11246.

    Article  CAS  PubMed  Google Scholar 

  • Lin EY, Li J-f, Bricard G, Wang W, Deng Y, Sellers R et al. (2007). Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages. Mol Oncol 1: 288–302.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lin EY, Nguyen AV, Russell RG, Pollard JW . (2001). Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193: 727–740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin H, Lee E, Hestir K, Leo C, Huang M, Bosch E et al. (2008). Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 320: 807–811.

    Article  CAS  PubMed  Google Scholar 

  • Lopez T, Hanahan D . (2002). Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 1: 339–353.

    Article  CAS  PubMed  Google Scholar 

  • Macdonald KPA, Palmer JS, Cronau S, Seppanen E, Olver S, Raffelt NC et al. (2010). An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation. Blood 116: 3955–3963.

    Article  CAS  PubMed  Google Scholar 

  • Mantovani A, Savino B, Locati M, Zammataro L, Allavena P, Bonecchi R . (2010). The chemokine system in cancer biology and therapy. Cytokine Growth Factor Rev 21: 27–39.

    Article  CAS  PubMed  Google Scholar 

  • Nozawa H, Chiu C, Hanahan D . (2006). Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci USA 103: 12493–12498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oguma K, Oshima H, Aoki M, Uchio R, Naka K, Nakamura S et al. (2008). Activated macrophages promote Wnt signalling through tumour necrosis factor-α in gastric tumourtumor cells. EMBO J 27: 1671–1681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pahler JC, Tazzyman S, Erez N, Chen Y-Y, Murdoch C, Nozawa H et al. (2008). Plasticity in tumor-promoting inflammation: impairment of macrophage recruitment evokes a compensatory neutrophil response. Neoplasia 10: 329–340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pietras K, Hanahan D . (2005). A multitargeted, metronomic, and maximum-tolerated dose ″chemo-switch″ regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 23: 939–952.

    Article  CAS  PubMed  Google Scholar 

  • Qian B-Z, Pollard JW . (2010). Macrophage diversity enhances tumor progression and metastasis. Cell 141: 39–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Raymond E, Dahan L, Raoul J-L, Bang Y-J, Borbath I, Lombard-Bohas C et al. (2011). Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364: 501–513.

    Article  CAS  PubMed  Google Scholar 

  • Reidy DL, Tang LH, Saltz LB . (2009). Treatment of advanced disease in patients with well-differentiated neuroendocrine tumors. Nat Clin Pract Oncol 6: 143–152.

    Article  CAS  PubMed  Google Scholar 

  • Robinson BD, Sica GL, Liu Y-F, Rohan TE, Gertler FB, Condeelis JS et al. (2009). Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clin Cancer Res 15: 2433–2441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ryder M, Ghossein RA, Ricarte-Filho JCM, Knauf JA, Fagin JA . (2008). Increased density of tumor-associated macrophages is associated with decreased survival in advanced thyroid cancer. Endocr Relat Cancer 15: 1069–1074.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song S, Ewald AJ, Stallcup W, Werb Z, Bergers G . (2005). PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol 7: 870–879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T et al. (2010). Tumor-associated macrophages and survival in classic Hodgkin′s lymphoma. N Engl J Med 362: 875–885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steiner GE, Ecker RC, Kramer G, Stockenhuber F, Marberger MJ . (2000). Automated data acquisition by confocal laser scanning microscopy and image analysis of triple stained immunofluorescent leukocytes in tissue. J Immunol Methods 237: 39–50.

    Article  CAS  PubMed  Google Scholar 

  • Tuveson D, Hanahan D . (2011). Translational medicine: cancer lessons from mice to humans. Nature 471: 316–317.

    Article  CAS  PubMed  Google Scholar 

  • Wei S, Nandi S, Chitu V, Yeung Y-G, Yu W, Huang M et al. (2010). Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells. J Leukoc Biol 88: 495–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wiktor-Jedrzejczak W, Bartocci A, Ferrante AW, Ahmed-Ansari A, Sell KW, Pollard JW et al. (1990). Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci USA 87: 4828–4832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E et al. (2011). Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364: 514–523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H et al. (1990). The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345: 442–444.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Xiaoping Chen and Kenishana Simpson for excellent technical assistance; Dr Jeffrey Pollard, Albert Einstein College of Medicine for the Csf1op pyrosequencing protocol; Drs Jan Hendrikx and Jennifer Wilshire, MSKCC Flow Cytometry Core Facility for assistance with flow cytometric sorting; Drs Agnes Viale, Juan Li, Magali Cavatore, Liliana Villafania, MSKCC Genomics Core Facility for assistance with RT–PCR and pyrosequencing; Drs Guangli Li and Ouathek Ouerfelli, MSKCC Organic Synthesis Core Facility for synthesis of the Cy3B-Cathepsin-ABP; and Elyn Reidel, MSKCC Epidemiology and Biostatistics Department, for statistical analysis of tumor size distribution. This research was supported by the following: National Cancer Institute TMEN Grant (NIH U54-CA126518), NCI R01 (CA125162), and the Geoffrey Beene Foundation (JAJ); NIH T32 Training Fellowship (SMP); American Cancer Society Postdoctoral Fellowship (BBG); Frank L. Horsfall Fellowship (HWW, VG); and Geoffrey Beene Fellowship (VG).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J A Joyce.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pyonteck, S., Gadea, B., Wang, HW. et al. Deficiency of the macrophage growth factor CSF-1 disrupts pancreatic neuroendocrine tumor development. Oncogene 31, 1459–1467 (2012). https://doi.org/10.1038/onc.2011.337

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.337

Keywords

This article is cited by

Search

Quick links