Granulocyte-colony Stimulating Factor Promotes Lung Metastasis Through Mobilization of Ly6G+Ly6C+ Granulocytes

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Nov 18

PMID 21081700

Citations 360

Authors

Marcin Kowanetz

Xiumin Wu

John Lee

Martha Tan

Thijs Hagenbeek

Xueping Qu

Lanlan Yu

Jed Ross

Nina Korsisaari

Tim Cao

Hani Bou-Reslan

Dara Kallop

Robby Weimer

Mary J C Ludlam

Joshua S Kaminker

Zora Modrusan

Nicholas van Bruggen

Franklin V Peale

Richard Carano

Y Gloria Meng

Napoleone Ferrara

Affiliations

Soon will be listed here.

Abstract

Priming of the organ-specific premetastatic sites is thought to be an important yet incompletely understood step during metastasis. In this study, we show that the metastatic tumors we examined overexpress granulocyte-colony stimulating factor (G-CSF), which expands and mobilizes Ly6G+Ly6C+ granulocytes and facilitates their subsequent homing at distant organs even before the arrival of tumor cells. Moreover, G-CSF-mobilized Ly6G+Ly6C+ cells produce the Bv8 protein, which has been implicated in angiogenesis and mobilization of myeloid cells. Anti-G-CSF or anti-Bv8 antibodies significantly reduced lung metastasis. Transplantation of Bv8 null fetal liver cells into lethally irradiated hosts also reduced metastasis. We identified an unexpected role for Bv8: the ability to stimulate tumor cell migration through activation of one of the Bv8 receptors, prokineticin receptor (PKR)-1. Finally, we show that administration of recombinant G-CSF is sufficient to increase the numbers of Ly6G+Ly6C+ cells in organ-specific metastatic sites and results in enhanced metastatic ability of several tumors.

Citing Articles

The multi-faceted immune modulatory role of S100A4 in cancer and chronic inflammatory disease.

Wong T, Kang R, Yun K Front Immunol. 2025; 16:1525567.

PMID: 40078995 PMC: 11897520. DOI: 10.3389/fimmu.2025.1525567.

Harnessing myeloid cells in cancer.

Park S, Pylaeva E, Bhuria V, Gambardella A, Schiavoni G, Mougiakakos D Mol Cancer. 2025; 24(1):69.

PMID: 40050933 PMC: 11887392. DOI: 10.1186/s12943-025-02249-2.

Impact of Prophylactic Use of PEG-rhG-CSF on First-Line Immunochemotherapy in Advanced NSCLC: A Cohort Study.

Sun L, Tian Y, Zhang S, Huang L, Ma J, Han C JTO Clin Res Rep. 2025; 6(2):100780.

PMID: 39877027 PMC: 11773054. DOI: 10.1016/j.jtocrr.2024.100780.

Triple-negative breast cancer modifies the systemic immune landscape and alters neutrophil functionality.

Bakker N, Garner H, van Dyk E, Champanhet E, Klaver C, Duijst M NPJ Breast Cancer. 2025; 11(1):5.

PMID: 39843922 PMC: 11754814. DOI: 10.1038/s41523-025-00721-2.

Immune Microenvironment in Breast Cancer Metastasis.

Qian B, Ma R Adv Exp Med Biol. 2025; 1464():413-432.

PMID: 39821036 DOI: 10.1007/978-3-031-70875-6_20.

References

Zhong C, Qu X, Tan M, Meng Y, Ferrara N . Characterization and regulation of bv8 in human blood cells. Clin Cancer Res. 2009; 15(8):2675-84. DOI: 10.1158/1078-0432.CCR-08-1954. View

Yang L, Huang J, Ren X, Gorska A, Chytil A, Aakre M . Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell. 2008; 13(1):23-35. PMC: 2245859. DOI: 10.1016/j.ccr.2007.12.004. View

Mabuchi S, Matsumoto Y, Morii E, Morishige K, Kimura T . The first 2 cases of granulocyte colony-stimulating factor producing adenocarcinoma of the uterine cervix. Int J Gynecol Pathol. 2010; 29(5):483-7. DOI: 10.1097/PGP.0b013e3181d29729. View

LeCouter J, Lin R, Tejada M, Frantz G, Peale F, Hillan K . The endocrine-gland-derived VEGF homologue Bv8 promotes angiogenesis in the testis: Localization of Bv8 receptors to endothelial cells. Proc Natl Acad Sci U S A. 2003; 100(5):2685-90. PMC: 151401. DOI: 10.1073/pnas.0337667100. View

Tao K, Fang M, Alroy J, Sahagian G . Imagable 4T1 model for the study of late stage breast cancer. BMC Cancer. 2008; 8:228. PMC: 2529338. DOI: 10.1186/1471-2407-8-228. View

Dawson M, Duda D, Fukumura D, Jain R . VEGFR1-activity-independent metastasis formation. Nature. 2009; 461(7262):E4. PMC: 3065241. DOI: 10.1038/nature08254. View

Nguyen D, Bos P, Massague J . Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 2009; 9(4):274-84. DOI: 10.1038/nrc2622. View

Young M, Lathers D . Myeloid progenitor cells mediate immune suppression in patients with head and neck cancers. Int J Immunopharmacol. 1999; 21(4):241-52. DOI: 10.1016/s0192-0561(99)00008-9. View

Almand B, Clark J, Nikitina E, Van Beynen J, English N, Knight S . Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol. 2000; 166(1):678-89. DOI: 10.4049/jimmunol.166.1.678. View

10.

Guy C, Cardiff R, Muller W . Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol. 1992; 12(3):954-61. PMC: 369527. DOI: 10.1128/mcb.12.3.954-961.1992. View

11.

Yamamoto S, Takashima S, Ogawa H, Kuroda T, Yamamoto M, Takeda A . Granulocyte-colony-stimulating-factor-producing hepatocellular carcinoma. J Gastroenterol. 1999; 34(5):640-4. DOI: 10.1007/s005350050387. View

12.

Metcalf D . The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells. Nature. 1989; 339(6219):27-30. DOI: 10.1038/339027a0. View

13.

Yan H, Pickup M, Pang Y, Gorska A, Li Z, Chytil A . Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung. Cancer Res. 2010; 70(15):6139-49. PMC: 4675145. DOI: 10.1158/0008-5472.CAN-10-0706. View

14.

Minn A, Gupta G, Siegel P, Bos P, Shu W, Giri D . Genes that mediate breast cancer metastasis to lung. Nature. 2005; 436(7050):518-24. PMC: 1283098. DOI: 10.1038/nature03799. View

15.

Ryckman C, McColl S, Vandal K, de Medicis R, Lussier A, Poubelle P . Role of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air-pouch model of acute gouty arthritis. Arthritis Rheum. 2003; 48(8):2310-20. DOI: 10.1002/art.11079. View

16.

Shojaei F, Wu X, Malik A, Zhong C, Baldwin M, Schanz S . Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol. 2007; 25(8):911-20. DOI: 10.1038/nbt1323. View

17.

Crawford J, Ozer H, Stoller R, Johnson D, Lyman G, Tabbara I . Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med. 1991; 325(3):164-70. DOI: 10.1056/NEJM199107183250305. View

18.

Daley J, Thomay A, Connolly M, Reichner J, Albina J . Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice. J Leukoc Biol. 2007; 83(1):64-70. DOI: 10.1189/jlb.0407247. View

19.

Erler J, Bennewith K, Cox T, Lang G, Bird D, Koong A . Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell. 2008; 15(1):35-44. PMC: 3050620. DOI: 10.1016/j.ccr.2008.11.012. View

20.

LeCouter J, Zlot C, Tejada M, Peale F, Ferrara N . Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization. Proc Natl Acad Sci U S A. 2004; 101(48):16813-8. PMC: 528996. DOI: 10.1073/pnas.0407697101. View