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The lung metastatic niche

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Abstract

Cancer cells that succeed in forming lung metastases need to survive in a foreign microenvironment and to protect themselves against immune surveillance. Lung metastatic niches facilitate this process. They can develop as pre-metastatic niches by inflammatory events that are provoked by primary tumors before tumor cell arrival, and/or they can be post-formed by reciprocal signaling between metastasizing tumor cells and local non-tumor cells. Primary tumor-derived factors induce expression of chemokines in the lungs to which bone marrow-derived myeloid cells are recruited. These cells work in concert with lung-specific resident cells to establish pre-metastatic niches. The role of the endogenous TLR4-dependent innate immune system in pre-metastatic niche formation illustrates this point. During lung infection, endotoxin induces inflammation by increasing vascular permeability and leukocyte mobilization to the lungs through the endotoxin receptor TLR4 that is expressed in endothelial cells and leukocytes, respectively. This innate immune system can be hijacked by primary tumors to generate a pre-metastatic niche. Specifically, primary tumor-produced chemokine CCL2 works in an endocrine manner to induce pulmonary overexpression of endogenous TLR4 ligands such as S100A8 and SAA3 resulting in lung inflammation similar to that caused by endotoxin. An endotoxin analog Eritoran inhibits pre-metastatic niche formation in this system.

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References

  1. Schofield R (1978) The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4:7–25

    CAS  PubMed  Google Scholar 

  2. Shiozawa Y, Pedersen EA, Havens AM, Jung Y, Mishra A, Joseph J, Kim JK, Patel LR, Ying C, Ziegler AM et al (2011) Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest 121:1298–1312

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Irwin RS, Augustyn N, French CT, Rice J, Tedeschi V, Welch SJ (2013) Spread the word about the journal in 2013: from citation manipulation to invalidation of patient-reported outcomes measures to renaming the Clara cell to new journal features. Chest 143:1–4

    Article  PubMed  Google Scholar 

  4. Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, Bronson RT, Jacks T (2005) Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121:823–835

    Article  CAS  PubMed  Google Scholar 

  5. Nicolson G, Nakajima M, Irimura T (1986) Invasion of vascular endothelium and organ tissue in vitro by B16 melanoma variants. In: Honn K, Powers W, Sloane B (eds) Mechanisms of cancer metastasis. Springer, USA, pp 275–297

    Chapter  Google Scholar 

  6. Bocklage T, Leslie K, Yousem S, Colby T (2001) Extracutaneous angiosarcomas metastatic to the lungs: clinical and pathologic features of twenty-one cases. Mod Pathol 14:1216–1225

    Article  CAS  PubMed  Google Scholar 

  7. Kaplan RN, Rafii S, Lyden D (2006) Preparing the "soil": the premetastatic niche. Cancer Res 66:11089–11093

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Tomita T, Sakurai Y, Ishibashi S, Maru Y (2011) Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis. Oncogene 30:3429–3439

    Article  CAS  PubMed  Google Scholar 

  9. Hiratsuka S, Watanabe A, Aburatani H, Maru Y (2006) Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8:1369–1375

    Article  CAS  PubMed  Google Scholar 

  10. Tomita T, Ieguchi K, Deguchi A, Takita M, Tsukaha F, Hiratsuka S, Maru Y (2015) Tumor cell lung recruitment assay. J Vis Exp (in press)

  11. Vadrevu SK, Chintala NK, Sharma SK, Sharma P, Cleveland C, Riediger L, Manne S, Fairlie DP, Gorczyca W, Almanza O et al (2014) Complement c5a receptor facilitates cancer metastasis by altering T-cell responses in the metastatic niche. Cancer Res 74:3454–3465

    Article  CAS  PubMed  Google Scholar 

  12. Sharma SK, Chintala NK, Vadrevu SK, Patel J, Karbowniczek M, Markiewski MM (2015) Pulmonary alveolar macrophages contribute to the premetastatic niche by suppressing antitumor T cell responses in the lungs. J Immunol 194:5529–5538

    Article  CAS  PubMed  Google Scholar 

  13. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  14. Deguchi A, Tomita T, Omori T, Komatsu A, Ohto U, Takahashi S, Tanimura N, Akashi-Takamura S, Miyake K, Maru Y (2013) Serum amyloid A3 binds MD-2 to activate p38 and NF-κB pathways in a MyD88-dependent manner. J Immunol 191:1856–1864

    Article  CAS  PubMed  Google Scholar 

  15. Maus UA, Wellmann S, Hampl C, Kuziel WA, Srivastava M, Mack M, Everhart MB, Blackwell TS, Christman JW, Schlondorff D et al (2005) CCR2-positive monocytes recruited to inflamed lungs downregulate local CCL2 chemokine levels. Am J Physiol Lung Cell Mol Physiol 288:L350–L358

    Article  CAS  PubMed  Google Scholar 

  16. Bessede A, Gargaro M, Pallotta MT, Matino D, Servillo G, Brunacci C, Bicciato S, Mazza EM, Macchiarulo A, Vacca C et al (2014) Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature 511:184–190

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Hiratsuka S, Watanabe A, Sakurai Y, Akashi-Takamura S, Ishibashi S, Miyake K, Shibuya M, Akira S, Aburatani H, Maru Y (2008) The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol 10:1349–1355

    Article  CAS  PubMed  Google Scholar 

  18. He Q, Zhang C, Wang L, Zhang P, Ma D, Lv J, Liu F (2015) Inflammatory signaling regulates hematopoietic stem and progenitor cell emergence in vertebrates. Blood 125:1098–1106

    Article  CAS  PubMed  Google Scholar 

  19. Shi C, Jia T, Mendez-Ferrer S, Hohl Tobias M, Serbina Natalya V, Lipuma L, Leiner I, Li Ming O, Frenette Paul S, Pamer Eric G (2011) Bone marrow mesenchymal stem and progenitor cells induce monocyte emigration in response to circulating toll-like receptor ligands. Immunity 34:590–601

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Bugl S, Wirths S, Radsak MP, Schild H, Stein P, Andre MC, Muller MR, Malenke E, Wiesner T, Marklin M et al (2013) Steady-state neutrophil homeostasis is dependent on TLR4/TRIF signaling. Blood 121:723–733

    Article  CAS  PubMed  Google Scholar 

  21. Deguchi A, Tomita T, Ohto U, Takemura K, Kitao A, Akashi-Takamura S, Miyake K, Maru Y (2015) Eritoran inhibits S100A8-mediated TLR4/MD-2 activation and tumor growth by changing the immune microenvironment. Oncogene. doi:10.1038/onc.2015.211

    PubMed  Google Scholar 

  22. Kim HM, Park BS, Kim JI, Kim SE, Lee J, Oh SC, Enkhbayar P, Matsushima N, Lee H, Yoo OJ et al (2007) Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell 130:906–917

    Article  CAS  PubMed  Google Scholar 

  23. Hiratsuka S, Ishibashi S, Tomita T, Watanabe A, Akashi-Takamura S, Murakami M, Kijima H, Miyake K, Aburatani H, Maru Y (2013) Primary tumours modulate innate immune signalling to create pre-metastatic vascular hyperpermeability foci. Nat Commun 4:1853

    Article  PubMed Central  PubMed  Google Scholar 

  24. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ (2009) Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15:35–44

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Chen Q, Zhang XH, Massague J (2011) Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell 20:538–549

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Gao D, Joshi N, Choi H, Ryu S, Hahn M, Catena R, Sadik H, Argani P, Wagner P, Vahdat LT et al (2012) Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Res 72:1384–1394

    Article  CAS  PubMed  Google Scholar 

  28. Hiratsuka S, Nakamura K, Iwai S, Murakami M, Itoh T, Kijima H, Shipley JM, Senior RM, Shibuya M (2002) MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2:289–300

    Article  CAS  PubMed  Google Scholar 

  29. Yan HH, Pickup M, Pang Y, Gorska AE, Li Z, Chytil A, Geng Y, Gray JW, Moses HL, Yang L (2010) Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung. Cancer Res 70:6139–6149

    Article  CAS  PubMed  Google Scholar 

  30. Hsu MY, Rovinsky SA, Lai CY, Qasem S, Liu X, How J, Engelhardt JF, Murphy GF (2008) Aggressive melanoma cells escape from BMP7-mediated autocrine growth inhibition through coordinated Noggin upregulation. Lab Investig 88:842–855

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Gao H, Chakraborty G, Lee-Lim AP, Mo Q, Decker M, Vonica A, Shen R, Brogi E, Brivanlou AH, Giancotti FG (2012) The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 150:764–779

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Oskarsson T, Acharyya S, Zhang XH, Vanharanta S, Tavazoie SF, Morris PG, Downey RJ, Manova-Todorova K, Brogi E, Massague J (2011) Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med 17:867–874

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Saupe F, Schwenzer A, Jia Y, Gasser I, Spenle C, Langlois B, Kammerer M, Lefebvre O, Hlushchuk R, Rupp T et al (2013) Tenascin-C downregulates wnt inhibitor dickkopf-1, promoting tumorigenesis in a neuroendocrine tumor model. Cell Rep 5:482–492

    Article  CAS  PubMed  Google Scholar 

  34. Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N (1995) Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 95:1789–1797

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Bais C, Wu X, Yao J, Yang S, Crawford Y, McCutcheon K, Tan C, Kolumam G, Vernes JM, Eastham-Anderson J et al (2010) PlGF blockade does not inhibit angiogenesis during primary tumor growth. Cell 141:166–177

    Article  CAS  PubMed  Google Scholar 

  36. Garmy-Susini B, Avraamides CJ, Desgrosellier JS, Schmid MC, Foubert P, Ellies LG, Lowy AM, Blair SL, Vandenberg SR, Datnow B et al (2013) PI3Kα activates integrin α4β1 to establish a metastatic niche in lymph nodes. Proc Natl Acad Sci U S A 110:9042–9047

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, Frenette PS (2013) Autonomic nerve development contributes to prostate cancer progression. Science 341:1236361

    Article  PubMed  Google Scholar 

  38. Ferjancic S, Gil-Bernabe AM, Hill SA, Allen PD, Richardson P, Sparey T, Savory E, McGuffog J, Muschel RJ (2013) VCAM-1 and VAP-1 recruit myeloid cells that promote pulmonary metastasis in mice. Blood 121:3289–3297

    Article  CAS  PubMed  Google Scholar 

  39. Palumbo JS, Kombrinck KW, Drew AF, Grimes TS, Kiser JH, Degen JL, Bugge TH (2000) Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells. Blood 96:3302–3309

    CAS  PubMed  Google Scholar 

  40. Palumbo JS, Potter JM, Kaplan LS, Talmage K, Jackson DG, Degen JL (2002) Spontaneous hematogenous and lymphatic metastasis, but not primary tumor growth or angiogenesis, is diminished in fibrinogen-deficient mice. Cancer Res 62:6966–6972

    CAS  PubMed  Google Scholar 

  41. Kim S, Takahashi H, Lin WW, Descargues P, Grivennikov S, Kim Y, Luo JL, Karin M (2009) Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457:102–106

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Liu J, Liao S, Diop-Frimpong B, Chen W, Goel S, Naxerova K, Ancukiewicz M, Boucher Y, Jain RK, Xu L (2012) TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proc Natl Acad Sci U S A 109:16618–16623

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Bandyopadhyay A, Agyin JK, Wang L, Tang Y, Lei X, Story BM, Cornell JE, Pollock BH, Mundy GR, Sun LZ (2006) Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-β type I receptor kinase inhibitor. Cancer Res 66:6714–6721

    Article  CAS  PubMed  Google Scholar 

  44. Kowanetz M, Wu X, Lee J, Tan M, Hagenbeek T, Qu X, Yu L, Ross J, Korsisaari N, Cao T et al (2010) Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc Natl Acad Sci U S A 107:21248–21255

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Contador-Troca M, Alvarez-Barrientos A, Barrasa E, Rico-Leo EM, Catalina-Fernandez I, Menacho-Marquez M, Bustelo XR, Garcia-Borron JC, Gomez-Duran A, Saenz-Santamaria J et al (2013) The dioxin receptor has tumor suppressor activity in melanoma growth and metastasis. Carcinogenesis 34:2683–2693

    Article  CAS  PubMed  Google Scholar 

  46. Malanchi I, Santamaria-Martinez A, Susanto E, Peng H, Lehr HA, Delaloye JF, Huelsken J (2012) Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481:85–89

    Article  CAS  Google Scholar 

  47. Laubli H, Spanaus KS, Borsig L (2009) Selectin-mediated activation of endothelial cells induces expression of CCL5 and promotes metastasis through recruitment of monocytes. Blood 114:4583–4591

    Article  CAS  PubMed  Google Scholar 

  48. D'Alterio C, Barbieri A, Portella L, Palma G, Polimeno M, Riccio A, Ierano C, Franco R, Scognamiglio G, Bryce J et al (2012) Inhibition of stromal CXCR4 impairs development of lung metastases. Cancer Immunol Immunother 61:1713–1720

    Article  PubMed Central  PubMed  Google Scholar 

  49. Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP et al (2014) The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507:508–512

    Article  CAS  PubMed  Google Scholar 

  50. Bandapalli OR, Ehrmann F, Ehemann V, Gaida M, Macher-Goeppinger S, Wente M, Schirmacher P, Brand K (2012) Down-regulation of CXCL1 inhibits tumor growth in colorectal liver metastasis. Cytokine 57:46–53

    Article  CAS  PubMed  Google Scholar 

  51. Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG, Manova-Todorova K, Leversha M, Hogg N, Seshan VE et al (2012) A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150:165–178

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Podsypanina K, Du YC, Jechlinger M, Beverly LJ, Hambardzumyan D, Varmus H (2008) Seeding and propagation of untransformed mouse mammary cells in the lung. Science 321:1841–1844

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Maru Y (2007) Which came first, tumor cells or macrophages? Cell Adhes Migr 1:107–109

    Article  Google Scholar 

  54. Ellwood-Yen K, Graeber TG, Wongvipat J, Iruela-Arispe ML, Zhang J, Matusik R, Thomas GV, Sawyers CL (2003) Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 4:223–238

    Article  CAS  PubMed  Google Scholar 

  55. Simon RH, Lovett EJ 3rd, Tomaszek D, Lundy J (1980) Electrical stimulation of the midbrain mediates metastatic tumor growth. Science 209:1132–1133

    Article  CAS  PubMed  Google Scholar 

  56. Volpert OV, Lawler J, Bouck NP (1998) A human fibrosarcoma inhibits systemic angiogenesis and the growth of experimental metastases via thrombospondin-1. Proc Natl Acad Sci U S A 95:6343–6348

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220–231

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15:232–239

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

The study was supported by Grants-in-Aid for Scientific Research from Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan (21117008) to YM.

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  1. Department of Pharmacology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan

    Yoshiro Maru

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Maru, Y. The lung metastatic niche. J Mol Med 93, 1185–1192 (2015). https://doi.org/10.1007/s00109-015-1355-2

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