Cancer and Metastasis Reviews

, Volume 37, Issue 4, pp 779–790 | Cite as

Cross-talk between lung cancer and bones results in neutrophils that promote tumor progression

  • Patrick O. Azevedo
  • Ana E. Paiva
  • Gabryella S. P. Santos
  • Luiza Lousado
  • Julia P. Andreotti
  • Isadora F. G. Sena
  • Carlos A. Tagliati
  • Akiva Mintz
  • Alexander BirbrairEmail author


Lung cancer is the leading cause of cancer mortality around the world. The lack of detailed understanding of the cellular and molecular mechanisms participating in the lung tumor progression restrains the development of efficient treatments. Recently, by using state-of-the-art technologies, including in vivo sophisticated Cre/loxP technologies in combination with lung tumor models, it was revealed that osteoblasts activate neutrophils that promote tumor growth in the lung. Strikingly, genetic ablation of osteoblasts abolished lung tumor progression via interruption of SiglecFhigh–expressing neutrophils supply to the tumor microenvironment. Interestingly, SiglecFhigh neutrophil signature was associated with worse lung adenocarcinoma patients outcome. This study identifies novel cellular targets for lung cancer treatment. Here, we summarize and evaluate recent advances in our understanding of lung tumor microenvironment.


Osteoblasts Neutrophils Lung Tumor microenvironment 


Funding information

Alexander Birbrair is supported by a grant from Instituto Serrapilheira/Serra-1708-15285, a grant from Pró-reitoria de Pesquisa/Universidade Federal de Minas Gerais (PRPq/UFMG) (Edital 05/2016), a grant from FAPEMIG [Rede Mineira de Engenharia de Tecidos e Terapia Celular (REMETTEC, RED-00570-16)], and a grant from FAPEMIG [Rede De Pesquisa Em Doenças Infecciosas Humanas E Animais Do Estado De Minas Gerais (RED-00313-16)]; Akiva Mintz is supported by the National Institute of Health (1R01CA179072-01A1) and by the American Cancer Society Mentored Research Scholar grant (124443-MRSG-13-121-01-CDD).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Mendes, F., Antunes, C., Abrantes, A. M., Goncalves, A. C., Nobre-Gois, I., Sarmento, A. B., et al. (2015). Lung cancer: the immune system and radiation. British Journal of Biomedical Science, 72(2), 78–84.Google Scholar
  2. 2.
    Chapman, A. M., Sun, K. Y., Ruestow, P., Cowan, D. M., & Madl, A. K. (2016). Lung cancer mutation profile of EGFR, ALK, and KRAS: meta-analysis and comparison of never and ever smokers. Lung Cancer, 102, 122–134. Scholar
  3. 3.
    Skowronek, J. (2015). Brachytherapy in the treatment of lung cancer - a valuable solution. Journal of Contemporary Brachytherapy, 7(4), 297–311. Scholar
  4. 4.
    Birbrair, A., Sattiraju, A., Zhu, D., Zulato, G., Batista, I., Nguyen, V. T., Messi, M. L., Solingapuram Sai, K. K., Marini, F. C., Delbono, O., & Mintz, A. (2017). Novel peripherally derived neural-like stem cells as therapeutic carriers for treating glioblastomas. Stem Cells Translational Medicine, 6(2), 471–481. Scholar
  5. 5.
    Vannucci, L. (2015). Stroma as an active player in the development of the tumor microenvironment. Cancer Microenvironment, 8(3), 159–166. Scholar
  6. 6.
    Junttila, M. R., & de Sauvage, F. J. (2013). Influence of tumour micro-environment heterogeneity on therapeutic response. Nature, 501(7467), 346–354. Scholar
  7. 7.
    Birbrair, A. (2017). Stem cell microenvironments and beyond. Advances in Experimental Medicine and Biology, 1041, 1–3. Scholar
  8. 8.
    Birbrair, A., Zhang, T., Wang, Z. M., Messi, M. L., Olson, J. D., Mintz, A., & Delbono, O. (2014). Type-2 pericytes participate in normal and tumoral angiogenesis. American Journal of Physiology. Cell Physiology, 307(1), C25–C38. Scholar
  9. 9.
    Birbrair, A., Zhang, T., Wang, Z. M., Messi, M. L., Mintz, A., & Delbono, O. (2015). Pericytes at the intersection between tissue regeneration and pathology. Clinical Science (London, England), 128(2), 81–93. Scholar
  10. 10.
    Birbrair, A., Zhang, T., Wang, Z. M., Messi, M. L., Mintz, A., & Delbono, O. (2014). Pericytes: multitasking cells in the regeneration of injured, diseased, and aged skeletal muscle. Frontiers in Aging Neuroscience, 6, 245. Scholar
  11. 11.
    Birbrair, A., Borges, I. D. T., Gilson Sena, I. F., Almeida, G. G., da Silva Meirelles, L., Goncalves, R., et al. (2017). How plastic are pericytes? Stem Cells and Development, 26(14), 1013–1019. Scholar
  12. 12.
    Birbrair, A., & Delbono, O. (2015). Pericytes are essential for skeletal muscle formation. Stem Cell Reviews, 11(4), 547–548. Scholar
  13. 13.
    Birbrair, A., Zhang, T., Files, D. C., Mannava, S., Smith, T., Wang, Z. M., et al. (2014). Type-1 pericytes accumulate after tissue injury and produce collagen in an organ-dependent manner. Stem Cell Research & Therapy, 5(6), 122. Scholar
  14. 14.
    Birbrair, A., Zhang, T., Wang, Z. M., Messi, M. L., Enikolopov, G. N., Mintz, A., & Delbono, O. (2013). Skeletal muscle pericyte subtypes differ in their differentiation potential. Stem Cell Research, 10(1), 67–84. S1873-5061(12)00089-X [pii].Google Scholar
  15. 15.
    Birbrair, A., Zhang, T., Wang, Z. M., Messi, M. L., Enikolopov, G. N., Mintz, A., & Delbono, O. (2013). Role of pericytes in skeletal muscle regeneration and fat accumulation. Stem Cells and Development, 22(16), 2298–2314. Scholar
  16. 16.
    Birbrair, A., Zhang, T., Wang, Z. M., Messi, M. L., Mintz, A., & Delbono, O. (2013). Type-1 pericytes participate in fibrous tissue deposition in aged skeletal muscle. American Journal of Physiology. Cell Physiology, 305(11), C1098–C1113. Scholar
  17. 17.
    Almeida, V. M., Paiva, A. E., Sena, I. F. G., Mintz, A., Magno, L. A. V., & Birbrair, A. (2017). Pericytes make spinal cord breathless after injury. Neuroscientist.
  18. 18.
    Prazeres, P., Almeida, V. M., Lousado, L., Andreotti, J. P., Paiva, A. E., Santos, G. S. P., et al. (2017). Macrophages generate pericytes in the developing brain. Cellular and Molecular Neurobiology, 38, 777–782. Scholar
  19. 19.
    Dias Moura Prazeres, P. H., Sena, I. F. G., Borges, I. D. T., de Azevedo, P. O., Andreotti, J. P., de Paiva, A. E., de Almeida, V. M., de Paula Guerra, D. A., Pinheiro dos Santos, G. S., Mintz, A., Delbono, O., & Birbrair, A. (2017). Pericytes are heterogeneous in their origin within the same tissue. Developmental Biology, 427(1), 6–11. Scholar
  20. 20.
    Guerra, D. A. P., Paiva, A. E., Sena, I. F. G., Azevedo, P. O., Batista Jr., M. L., Mintz, A., & Birbrair, A. (2017). Adipocytes role in the bone marrow niche. Cytometry. Part A, 93, 167–171. Scholar
  21. 21.
    Costa, M. A., Paiva, A. E., Andreotti, J. P., Cardoso, M. V., Cardoso, C. D., Mintz, A., & Birbrair, A. (2018). Pericytes constrict blood vessels after myocardial ischemia. Journal of Molecular and Cellular Cardiology, 116, 1–4. Scholar
  22. 22.
    Azevedo, P. O., Sena, I. F. G., Andreotti, J. P., Carvalho-Tavares, J., Alves-Filho, J. C., Cunha, T. M., et al. (2018). Pericytes modulate myelination in the central nervous system. Journal of Cellular Physiology, 233(8), 5523–5529.
  23. 23.
    Santos, G. S. P., Prazeres, P., Mintz, A., & Birbrair, A. (2017). Role of pericytes in the retina. Eye (London, England), 32, 483–486. Scholar
  24. 24.
    Asada, N., Kunisaki, Y., Pierce, H., Wang, Z., Fernandez, N. F., Birbrair, A., Ma’ayan, A., & Frenette, P. S. (2017). Differential cytokine contributions of perivascular haematopoietic stem cell niches. Nature Cell Biology, 19(3), 214–223. Scholar
  25. 25.
    Khan, J. A., Mendelson, A., Kunisaki, Y., Birbrair, A., Kou, Y., Arnal-Estape, A., Pinho, S., Ciero, P., Nakahara, F., Maayan, A., Bergman, A., Merad, M., & Frenette, P. S. (2016). Fetal liver hematopoietic stem cell niches associate with portal vessels. Science, 351(6269), 176–180. Scholar
  26. 26.
    Birbrair, A., Wang, Z. M., Messi, M. L., Enikolopov, G. N., & Delbono, O. (2011). Nestin-GFP transgene reveals neural precursor cells in adult skeletal muscle. PLoS One, 6(2), e16816. Scholar
  27. 27.
    Birbrair, A., Zhang, T., Wang, Z. M., Messi, M. L., Enikolopov, G. N., Mintz, A., & Delbono, O. (2013). Skeletal muscle neural progenitor cells exhibit properties of NG2-glia. Experimental Cell Research, 319(1), 45–63, doi:S0014-4827(12)00400-4 [pii]. Scholar
  28. 28.
    Prazeres, P. H. D. M., Turquetti, A. O. M., Azevedo, P. O., Barreto, R. S. N., Miglino, M. A., Mintz, A., Delbono, O., & Birbrair, A. (2018). Perivascular cell αv integrins as a target to treat skeletal muscle fibrosis. The International Journal of Biochemistry & Cell Biology, 99, 109–113.Google Scholar
  29. 29.
    Andreotti, J. P., Paiva, A. E., Prazeres, P., Guerra, D. A. P., Silva, W. N., Vaz, R. S., et al. (2018). The role of natural killer cells in the uterine microenvironment during pregnancy. Cellular & Molecular Immunology.
  30. 30.
    Andreotti, J. P., Prazeres, P. H. D. M., Magno, L. A. V., Romano-Silva, M. A., Mintz, A., & Birbrair, A. (2018). Neurogenesis in the postnatal cerebellum after injury. International Journal of Developmental Neuroscience, 67, 33–36.Google Scholar
  31. 31.
    Guerra, D. A. P., Paiva, A. E., Sena, I. F. G., Azevedo, P. O., Silva, W. N., Mintz, A., & Birbrair, A. (2018). Targeting glioblastoma-derived pericytes improves chemotherapeutic outcome. Angiogenesis.
  32. 32.
    Guerra, D. A. P., Paiva, A. E., Sena, I. F. G., Azevedo, P. O., Batista Jr., M. L., Mintz, A., & Birbrair, A. (2018). Adipocytes role in the bone marrow niche. Cytometry. Part A, 93(2), 167–171. Scholar
  33. 33.
    Sena, I. F. G., Paiva, A. E., Prazeres, P., Azevedo, P. O., Lousado, L., Bhutia, S. K., et al. (2018). Glioblastoma-activated pericytes support tumor growth via immunosuppression. Cancer Medicine, 7, 1232–1239. Scholar
  34. 34.
    Coatti, G. C., Frangini, M., Valadares, M. C., Gomes, J. P., Lima, N. O., Cavacana, N., et al. (2017). Pericytes extend survival of ALS SOD1 mice and induce the expression of antioxidant enzymes in the murine model and in IPSCs derived neuronal cells from an ALS patient. Stem Cell Reviews, 13, 686–698. Scholar
  35. 35.
    Pereira, L. X., Viana, C. T. R., Orellano, L. A. A., Almeida, S. A., Vasconcelos, A. C., Goes, A. M., et al. (2017). Synthetic matrix of polyether-polyurethane as a biological platform for pancreatic regeneration. Life Sciences, 176, 67–74. Scholar
  36. 36.
    Quail, D. F., & Joyce, J. A. (2013). Microenvironmental regulation of tumor progression and metastasis. Nature Medicine, 19(11), 1423–1437. Scholar
  37. 37.
    Egeblad, M., Nakasone, E. S., & Werb, Z. (2010). Tumors as organs: complex tissues that interface with the entire organism. Developmental Cell, 18(6), 884–901. Scholar
  38. 38.
    Zilio, S., & Serafini, P. (2016). Neutrophils and granulocytic MDSC: the Janus god of cancer immunotherapy. Vaccines (Basel), 4(3).
  39. 39.
    Aulakh, G. K. (2017). Neutrophils in the lung: “the first responders”. Cell and Tissue Research, 371, 577–588. Scholar
  40. 40.
    Nicolas-Avila, J. A., Adrover, J. M., & Hidalgo, A. (2017). Neutrophils in homeostasis, immunity, and cancer. Immunity, 46(1), 15–28. Scholar
  41. 41.
    Fridlender, Z. G., Sun, J., Kim, S., Kapoor, V., Cheng, G., Ling, L., Worthen, G. S., & Albelda, S. M. (2009). Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell, 16(3), 183–194. Scholar
  42. 42.
    Engblom, C., Pfirschke, C., Zilionis, R., Da Silva Martins, J., Bos, S. A., Courties, G., et al. (2017). Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF(high) neutrophils. Science, 358(6367), eaal5081. Scholar
  43. 43.
    Vanneman, M., & Dranoff, G. (2012). Combining immunotherapy and targeted therapies in cancer treatment. Nature Reviews. Cancer, 12(4), 237–251. Scholar
  44. 44.
    Lewis, C. E., Leek, R., Harris, A., & McGee, J. O. (1995). Cytokine regulation of angiogenesis in breast cancer: the role of tumor-associated macrophages. Journal of Leukocyte Biology, 57(5), 747–751.Google Scholar
  45. 45.
    Hanahan, D., & Coussens, L. M. (2012). Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell, 21(3), 309–322. Scholar
  46. 46.
    Smyth, M. J., Cretney, E., Kershaw, M. H., & Hayakawa, Y. (2004). Cytokines in cancer immunity and immunotherapy. Immunological Reviews, 202, 275–293. Scholar
  47. 47.
    McAllister, S. S., & Weinberg, R. A. (2014). The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nature Cell Biology, 16(8), 717–727. Scholar
  48. 48.
    Wculek, S. K., & Malanchi, I. (2015). Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature, 528(7582), 413–417. Scholar
  49. 49.
    Liotta, L. A., & Kohn, E. C. (2001). The microenvironment of the tumour-host interface. Nature, 411(6835), 375–379. Scholar
  50. 50.
    Headley, M. B., Bins, A., Nip, A., Roberts, E. W., Looney, M. R., Gerard, A., & Krummel, M. F. (2016). Visualization of immediate immune responses to pioneer metastatic cells in the lung. Nature, 531(7595), 513–517. Scholar
  51. 51.
    Erler, J. T., Bennewith, K. L., Cox, T. R., Lang, G., Bird, D., Koong, A., le, Q. T., & Giaccia, A. J. (2009). Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell, 15(1), 35–44. Scholar
  52. 52.
    Kaplan, R. N., Riba, R. D., Zacharoulis, S., Bramley, A. H., Vincent, L., Costa, C., MacDonald, D. D., Jin, D. K., Shido, K., Kerns, S. A., Zhu, Z., Hicklin, D., Wu, Y., Port, J. L., Altorki, N., Port, E. R., Ruggero, D., Shmelkov, S. V., Jensen, K. K., Rafii, S., & Lyden, D. (2005). VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature, 438(7069), 820–827. Scholar
  53. 53.
    Coffelt, S. B., Kersten, K., Doornebal, C. W., Weiden, J., Vrijland, K., Hau, C. S., Verstegen, N. J. M., Ciampricotti, M., Hawinkels, L. J. A. C., Jonkers, J., & de Visser, K. E. (2015). IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. Nature, 522(7556), 345–348. Scholar
  54. 54.
    Chow, A., Zhou, W., Liu, L., Fong, M. Y., Champer, J., Van Haute, D., et al. (2014). Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-kappaB. Scientific Reports, 4, 5750. Scholar
  55. 55.
    Nielsen, S. R., Quaranta, V., Linford, A., Emeagi, P., Rainer, C., Santos, A., Ireland, L., Sakai, T., Sakai, K., Kim, Y. S., Engle, D., Campbell, F., Palmer, D., Ko, J. H., Tuveson, D. A., Hirsch, E., Mielgo, A., & Schmid, M. C. (2016). Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nature Cell Biology, 18(5), 549–560. Scholar
  56. 56.
    van Deventer, H. W., Palmieri, D. A., Wu, Q. P., McCook, E. C., & Serody, J. S. (2013). Circulating fibrocytes prepare the lung for cancer metastasis by recruiting Ly-6C+ monocytes via CCL2. Journal of Immunology, 190(9), 4861–4867. Scholar
  57. 57.
    Brambilla, E., Le Teuff, G., Marguet, S., Lantuejoul, S., Dunant, A., Graziano, S., et al. (2016). Prognostic effect of tumor lymphocytic infiltration in resectable non-small-cell lung cancer. Journal of Clinical Oncology, 34(11), 1223–1230. Scholar
  58. 58.
    Welsh, T. J., Green, R. H., Richardson, D., Waller, D. A., O'Byrne, K. J., & Bradding, P. (2005). Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. Journal of Clinical Oncology, 23(35), 8959–8967. Scholar
  59. 59.
    Dieu-Nosjean, M. C., Antoine, M., Danel, C., Heudes, D., Wislez, M., Poulot, V., Rabbe, N., Laurans, L., Tartour, E., de Chaisemartin, L., Lebecque, S., Fridman, W. H., & Cadranel, J. (2008). Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. Journal of Clinical Oncology, 26(27), 4410–4417. Scholar
  60. 60.
    Lavin, Y., Kobayashi, S., Leader, A., Amir, E. D., Elefant, N., Bigenwald, C., Remark, R., Sweeney, R., Becker, C. D., Levine, J. H., Meinhof, K., Chow, A., Kim-Shulze, S., Wolf, A., Medaglia, C., Li, H., Rytlewski, J. A., Emerson, R. O., Solovyov, A., Greenbaum, B. D., Sanders, C., Vignali, M., Beasley, M. B., Flores, R., Gnjatic, S., Pe’er, D., Rahman, A., Amit, I., & Merad, M. (2017). Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell, 169(4), 750–765 e717. Scholar
  61. 61.
    Boyle, W. J., Simonet, W. S., & Lacey, D. L. (2003). Osteoclast differentiation and activation. Nature, 423(6937), 337–342. Scholar
  62. 62.
    Kingsley, L. A., Fournier, P. G., Chirgwin, J. M., & Guise, T. A. (2007). Molecular biology of bone metastasis. Molecular Cancer Therapeutics, 6(10), 2609–2617. Scholar
  63. 63.
    Lin, S. C., Lee, Y. C., Yu, G., Cheng, C. J., Zhou, X., Chu, K., Murshed, M., le, N. T., Baseler, L., Abe, J. I., Fujiwara, K., deCrombrugghe, B., Logothetis, C. J., Gallick, G. E., Yu-Lee, L. Y., Maity, S. N., & Lin, S. H. (2017). Endothelial-to-osteoblast conversion generates osteoblastic metastasis of prostate cancer. Developmental Cell, 41(5), 467–480 e463. Scholar
  64. 64.
    Paiva, A. E., Lousado, L., Almeida, V. M., Andreotti, J. P., Santos, G. S. P., Azevedo, P. O., Sena, I. F. G., Prazeres, P. H. D. M., Borges, I. T., Azevedo, V., Mintz, A., & Birbrair, A. (2017). Endothelial cells as precursors for osteoblasts in the metastatic prostate cancer bone. Neoplasia, 19(11), 928–931. Scholar
  65. 65.
    Long, F. (2011). Building strong bones: molecular regulation of the osteoblast lineage. Nature Reviews. Molecular Cell Biology, 13(1), 27–38. Scholar
  66. 66.
    Olsen, B. R., Reginato, A. M., & Wang, W. (2000). Bone development. Annual Review of Cell and Developmental Biology, 16, 191–220. Scholar
  67. 67.
    Helms, J. A., & Schneider, R. A. (2003). Cranial skeletal biology. Nature, 423(6937), 326–331. Scholar
  68. 68.
    Liu, H., Guo, J., Wang, L., Chen, N., Karaplis, A., Goltzman, D., & Miao, D. (2009). Distinctive anabolic roles of 1,25-dihydroxyvitamin D(3) and parathyroid hormone in teeth and mandible versus long bones. The Journal of Endocrinology, 203(2), 203–213. Scholar
  69. 69.
    Kishi, T., Hagino, H., Kishimoto, H., & Nagashima, H. (1998). Bone responses at various skeletal sites to human parathyroid hormone in ovariectomized rats: effects of long-term administration, withdrawal, and readministration. Bone, 22(5), 515–522.Google Scholar
  70. 70.
    Long, F., Chung, U. I., Ohba, S., McMahon, J., Kronenberg, H. M., & McMahon, A. P. (2004). Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton. Development, 131(6), 1309–1318. Scholar
  71. 71.
    Wang, Y., Wan, C., Deng, L., Liu, X., Cao, X., Gilbert, S. R., Bouxsein, M. L., Faugere, M. C., Guldberg, R. E., Gerstenfeld, L. C., Haase, V. H., Johnson, R. S., Schipani, E., & Clemens, T. L. (2007). The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. The Journal of Clinical Investigation, 117(6), 1616–1626. Scholar
  72. 72.
    Sodek, K. L., Tupy, J. H., Sodek, J., & Grynpas, M. D. (2000). Relationships between bone protein and mineral in developing porcine long bone and calvaria. Bone, 26(2), 189–198.Google Scholar
  73. 73.
    van den Bos, T., Speijer, D., Bank, R. A, Bromme, D., & Everts, V. (2008). Differences in matrix composition between calvaria and long bone in mice suggest differences in biomechanical properties and resorption: special emphasis on collagen. Bone, 43(3), 459–468. Scholar
  74. 74.
    Komori, T. (2008). Regulation of bone development and maintenance by Runx2. Frontiers in Bioscience, 13, 898–903.Google Scholar
  75. 75.
    Lian, J. B., McKee, M. D., Todd, A. M., & Gerstenfeld, L. C. (1993). Induction of bone-related proteins, osteocalcin and osteopontin, and their matrix ultrastructural localization with development of chondrocyte hypertrophy in vitro. Journal of Cellular Biochemistry, 52(2), 206–219. Scholar
  76. 76.
    Pockwinse, S. M., Lawrence, J. B., Singer, R. H., Stein, J. L., Lian, J. B., & Stein, G. S. (1993). Gene expression at single cell resolution associated with development of the bone cell phenotype: ultrastructural and in situ hybridization analysis. Bone, 14(3), 347–352.Google Scholar
  77. 77.
    Nakase, T., Takaoka, K., Hirakawa, K., Hirota, S., Takemura, T., Onoue, H., Takebayashi, K., Kitamura, Y., & Nomura, S. (1994). Alterations in the expression of osteonectin, osteopontin and osteocalcin mRNAs during the development of skeletal tissues in vivo. Bone and Mineral, 26(2), 109–122.Google Scholar
  78. 78.
    Ikeda, T., Nomura, S., Yamaguchi, A., Suda, T., & Yoshiki, S. (1992). In situ hybridization of bone matrix proteins in undecalcified adult rat bone sections. The Journal of Histochemistry and Cytochemistry, 40(8), 1079–1088. Scholar
  79. 79.
    Thiede, M. A., Smock, S. L., Petersen, D. N., Grasser, W. A., Thompson, D. D., & Nishimoto, S. K. (1994). Presence of messenger ribonucleic acid encoding osteocalcin, a marker of bone turnover, in bone marrow megakaryocytes and peripheral blood platelets. Endocrinology, 135(3), 929–937. Scholar
  80. 80.
    Fleet, J. C., & Hock, J. M. (1994). Identification of osteocalcin mRNA in nonosteoid tissue of rats and humans by reverse transcription-polymerase chain reaction. Journal of Bone and Mineral Research, 9(10), 1565–1573. Scholar
  81. 81.
    Zhang, J., & Link, D. C. (2016). Targeting of mesenchymal stromal cells by Cre-recombinase transgenes commonly used to target osteoblast lineage cells. Journal of Bone and Mineral Research, 31(11), 2001–2007. Scholar
  82. 82.
    Dacquin, R., Starbuck, M., Schinke, T., & Karsenty, G. (2002). Mouse alpha1(I)-collagen promoter is the best known promoter to drive efficient Cre recombinase expression in osteoblast. Developmental Dynamics, 224(2), 245–251. Scholar
  83. 83.
    Lefrancais, E., Ortiz-Munoz, G., Caudrillier, A., Mallavia, B., Liu, F., Sayah, D. M., et al. (2017). The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature, 544(7648), 105–109. Scholar
  84. 84.
    Borges, I., Sena, I., Azevedo, P., Andreotti, J., Almeida, V., Paiva, A., Santos, G., Guerra, D., Prazeres, P., Mesquita, L. L., Silva, L. S. B., Leonel, C., Mintz, A., & Birbrair, A. (2017). Lung as a niche for hematopoietic progenitors. Stem Cell Reviews, 13(5), 567–574. Scholar
  85. 85.
    Lousado, L., Prazeres, P., Andreotti, J. P., Paiva, A. E., Azevedo, P. O., Santos, G. S. P., et al. (2017). Schwann cell precursors as a source for adrenal gland chromaffin cells. Cell Death & Disease, 8(10), e3072. Scholar
  86. 86.
    Azevedo, P. O., Lousado, L., Paiva, A. E., Andreotti, J. P., Santos, G. S. P., Sena, I. F. G., Prazeres, P. H. D. M., Filev, R., Mintz, A., & Birbrair, A. (2017). Endothelial cells maintain neural stem cells quiescent in their niche. Neuroscience, 363, 62–65. Scholar
  87. 87.
    Schofield, R. (1978). The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells, 4(1–2), 7–25.Google Scholar
  88. 88.
    Birbrair, A., & Frenette, P. S. (2016). Niche heterogeneity in the bone marrow. Annals of the New York Academy of Sciences, 1370(1), 82–96. Scholar
  89. 89.
    Andreotti, J. P., Lousado, L., Magno, L. A. V., & Birbrair, A. (2017). Hypothalamic neurons take center stage in the neural stem cell niche. Cell Stem Cell, 21(3), 293–294. Scholar
  90. 90.
    Sena, I. F. G., Prazeres, P., Santos, G. S. P., Borges, I. T., Azevedo, P. O., Andreotti, J. P., et al. (2017). Identity of Gli1+ cells in the bone marrow. Experimental Hematology, 54, 12–16. Scholar
  91. 91.
    Sena, I. F. G., Borges, I. T., Lousado, L., Azevedo, P. O., Andreotti, J. P., Almeida, V. M., Paiva, A. E., Santos, G. S. P., Guerra, D. A. P., Prazeres, P. H. D. M., Souto, L., Mintz, A., & Birbrair, A. (2017). LepR+ cells dispute hegemony with Gli1+ cells in bone marrow fibrosis. Cell Cycle, 16, 1–5. Scholar
  92. 92.
    Alvarenga, E. C., Silva, W. N., Vasconcellos, R., Paredes-Gamero, E. J., Mintz, A., & Birbrair, A. (2018). Promyelocytic leukemia protein in mesenchymal stem cells is essential for leukemia progression. Annals of Hematology., 97(10), 1749–1755.Google Scholar
  93. 93.
    Silva, W. N., Leonel, C., Prazeres, P., Sena, I. F. G., Guerra, D. A. P., Heller, D., et al. (2018). Role of Schwann cells in cutaneous wound healing. Wound Repair Regeneration.
  94. 94.
    Silva, M. T., & Correia-Neves, M. (2012). Neutrophils and macrophages: the main partners of phagocyte cell systems. Frontiers in Immunology, 3, 174. Scholar
  95. 95.
    Silva, W. N., Prazeres, P., Paiva, A. E., Lousado, L., Turquetti, A. O. M., Barreto, R. S. N., et al. (2018). Macrophage-derived GPNMB accelerates skin healing. Experimental Dermatology, 27, 630–635. Scholar
  96. 96.
    Cho, H. J., Jung, J. I., Lim, D. Y., Kwon, G. T., Her, S., Park, J. H., & Park, J. H. Y. (2012). Bone marrow-derived, alternatively activated macrophages enhance solid tumor growth and lung metastasis of mammary carcinoma cells in a Balb/C mouse orthotopic model. Breast Cancer Research, 14(3), R81. Scholar
  97. 97.
    Cortez-Retamozo, V., Etzrodt, M., Newton, A., Rauch, P. J., Chudnovskiy, A., Berger, C., Ryan, R. J. H., Iwamoto, Y., Marinelli, B., Gorbatov, R., Forghani, R., Novobrantseva, T. I., Koteliansky, V., Figueiredo, J. L., Chen, J. W., Anderson, D. G., Nahrendorf, M., Swirski, F. K., Weissleder, R., & Pittet, M. J. (2012). Origins of tumor-associated macrophages and neutrophils. Proceedings of the National Academy of Sciences of the United States of America, 109(7), 2491–2496. Scholar
  98. 98.
    Crocker, P. R., Clark, E. A., Filbin, M., Gordon, S., Jones, Y., Kehrl, J. H., et al. (1998). Siglecs: a family of sialic-acid binding lectins. Glycobiology, 8(2), v.Google Scholar
  99. 99.
    Kelm, S., Pelz, A., Schauer, R., Filbin, M. T., Tang, S., de Bellard, M. E., et al. (1994). Sialoadhesin, myelin-associated glycoprotein and CD22 define a new family of sialic acid-dependent adhesion molecules of the immunoglobulin superfamily. Current Biology, 4(11), 965–972.Google Scholar
  100. 100.
    Macauley, M. S., Crocker, P. R., & Paulson, J. C. (2014). Siglec-mediated regulation of immune cell function in disease. Nature Reviews. Immunology, 14(10), 653–666. Scholar
  101. 101.
    Brinkman-Van der Linden, E. C., Hurtado-Ziola, N., Hayakawa, T., Wiggleton, L., Benirschke, K., Varki, A., et al. (2007). Human-specific expression of Siglec-6 in the placenta. Glycobiology, 17(9), 922–931. Scholar
  102. 102.
    Mitra, N., Banda, K., Altheide, T. K., Schaffer, L., Johnson-Pais, T. L., Beuten, J., Leach, R. J., Angata, T., Varki, N., & Varki, A. (2011). SIGLEC12, a human-specific segregating (pseudo)gene, encodes a signaling molecule expressed in prostate carcinomas. The Journal of Biological Chemistry, 286(26), 23003–23011. Scholar
  103. 103.
    Ali, S. R., Fong, J. J., Carlin, A. F., Busch, T. D., Linden, R., Angata, T., Areschoug, T., Parast, M., Varki, N., Murray, J., Nizet, V., & Varki, A. (2014). Siglec-5 and Siglec-14 are polymorphic paired receptors that modulate neutrophil and amnion signaling responses to group B streptococcus. The Journal of Experimental Medicine, 211(6), 1231–1242. Scholar
  104. 104.
    Rochereau, N., Drocourt, D., Perouzel, E., Pavot, V., Redelinghuys, P., Brown, G. D., Tiraby, G., Roblin, X., Verrier, B., Genin, C., Corthésy, B., & Paul, S. (2013). Dectin-1 is essential for reverse transcytosis of glycosylated SIgA-antigen complexes by intestinal M cells. PLoS Biology, 11(9), e1001658. Scholar
  105. 105.
    Angata, T., Nycholat, C. M., & Macauley, M. S. (2015). Therapeutic targeting of Siglecs using antibody- and glycan-based approaches. Trends in Pharmacological Sciences, 36(10), 645–660. Scholar
  106. 106.
    Kiwamoto, T., Katoh, T., Evans, C. M., Janssen, W. J., Brummet, M. E., Hudson, S. A., Zhu, Z., Tiemeyer, M., & Bochner, B. S. (2015). Endogenous airway mucins carry glycans that bind Siglec-F and induce eosinophil apoptosis. The Journal of Allergy and Clinical Immunology, 135(5), 1329–1340 e1329. Scholar
  107. 107.
    Zhang, M., Angata, T., Cho, J. Y., Miller, M., Broide, D. H., & Varki, A. (2007). Defining the in vivo function of Siglec-F, a CD33-related Siglec expressed on mouse eosinophils. Blood, 109(10), 4280–4287. Scholar
  108. 108.
    Kirby, A. C., Coles, M. C., & Kaye, P. M. (2009). Alveolar macrophages transport pathogens to lung draining lymph nodes. Journal of Immunology, 183(3), 1983–1989. Scholar
  109. 109.
    Suzukawa, M., Miller, M., Rosenthal, P., Cho, J. Y., Doherty, T. A., Varki, A., & Broide, D. (2013). Sialyltransferase ST3Gal-III regulates Siglec-F ligand formation and eosinophilic lung inflammation in mice. Journal of Immunology, 190(12), 5939–5948. Scholar
  110. 110.
    Tateno, H., Crocker, P. R., & Paulson, J. C. (2005). Mouse Siglec-F and human Siglec-8 are functionally convergent paralogs that are selectively expressed on eosinophils and recognize 6′-sulfo-sialyl Lewis X as a preferred glycan ligand. Glycobiology, 15(11), 1125–1135. Scholar
  111. 111.
    Bochner, B. S. (2009). Siglec-8 on human eosinophils and mast cells, and Siglec-F on murine eosinophils, are functionally related inhibitory receptors. Clinical and Experimental Allergy, 39(3), 317–324. Scholar
  112. 112.
    Tam, X. H., Shiu, S. W., Leng, L., Bucala, R., Betteridge, D. J., & Tan, K. C. (2011). Enhanced expression of receptor for advanced glycation end-products is associated with low circulating soluble isoforms of the receptor in type 2 diabetes. Clinical Science (London, England), 120(2), 81–89. Scholar
  113. 113.
    Weidle, U. H., Birzele, F., Kollmorgen, G., & Ruger, R. (2016). Molecular basis of lung tropism of metastasis. Cancer Genomics Proteomics, 13(2), 129–139.Google Scholar
  114. 114.
    Liu, Y., & Cao, X. (2016). Characteristics and significance of the pre-metastatic niche. Cancer Cell, 30(5), 668–681. Scholar
  115. 115.
    Paiva, A. E., Lousado, L., Guerra, D. A. P., Azevedo, P. O., Sena, I. F. G., Andreotti, J. P., Santos, G. S. P., Gonçalves, R., Mintz, A., & Birbrair, A. (2018). Pericytes in the premetastatic niche. Cancer Research, 78, 2779–2786. Scholar
  116. 116.
    Murgai, M., Ju, W., Eason, M., Kline, J., Beury, D. W., Kaczanowska, S., Miettinen, M. M., Kruhlak, M., Lei, H., Shern, J. F., Cherepanova, O. A., Owens, G. K., & Kaplan, R. N. (2017). KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis. Nature Medicine, 23(10), 1176–1190. Scholar
  117. 117.
    Gartrell, B. A., & Saad, F. (2014). Managing bone metastases and reducing skeletal related events in prostate cancer. Nature Reviews. Clinical Oncology, 11(6), 335–345. Scholar
  118. 118.
    Travis, W. D. (2012). Update on small cell carcinoma and its differentiation from squamous cell carcinoma and other non-small cell carcinomas. Modern Pathology, 25(Suppl 1), S18–S30. Scholar
  119. 119.
    Schnabel, P. A., & Junker, K. (2015). Pulmonary neuroendocrine tumors in the new WHO 2015 classification: start of breaking new grounds? Pathologe, 36(3), 283–292. Scholar
  120. 120.
    Hanna, J. M., & Onaitis, M. W. (2013). Cell of origin of lung cancer. Journal of Carcinogenesis, 12, 6. Scholar
  121. 121.
    Muller, K. M. (1984). Histological classification and histogenesis of lung cancer. European Journal of Respiratory Diseases, 65(1), 4–19.Google Scholar
  122. 122.
    O'Byrne, K. J., & Dalgleish, A. G. (2001). Chronic immune activation and inflammation as the cause of malignancy. British Journal of Cancer, 85(4), 473–483. Scholar
  123. 123.
    Kim, V., Rogers, T. J., & Criner, G. J. (2008). New concepts in the pathobiology of chronic obstructive pulmonary disease. Proceedings of the American Thoracic Society, 5(4), 478–485. Scholar
  124. 124.
    Samet, J. M. (2000). Does idiopathic pulmonary fibrosis increase lung cancer risk? American Journal of Respiratory and Critical Care Medicine, 161(1), 1–2. Scholar
  125. 125.
    Kasagi, S., & Chen, W. (2013). TGF-beta1 on osteoimmunology and the bone component cells. Cell & Bioscience, 3(1), 4. Scholar
  126. 126.
    Osta, B., Benedetti, G., & Miossec, P. (2014). Classical and paradoxical effects of TNF-alpha on bone homeostasis. Frontiers in Immunology, 5, 48. Scholar
  127. 127.
    Nakanishi, M., & Rosenberg, D. W. (2013). Multifaceted roles of PGE2 in inflammation and cancer. Seminars in Immunopathology, 35(2), 123–137. Scholar
  128. 128.
    Coudriet, G. M., He, J., Trucco, M., Mars, W. M., & Piganelli, J. D. (2010). Hepatocyte growth factor modulates interleukin-6 production in bone marrow derived macrophages: implications for inflammatory mediated diseases. PLoS One, 5(11), e15384. Scholar
  129. 129.
    Kennedy, D. E., & Knight, K. L. (2017). Inflammatory changes in bone marrow microenvironment associated with declining B lymphopoiesis. Journal of Immunology, 198(9), 3471–3479. Scholar
  130. 130.
    Wong, J., Tran, L. T., Magun, E. A., Magun, B. E., & Wood, L. J. (2014). Production of IL-1beta by bone marrow-derived macrophages in response to chemotherapeutic drugs: synergistic effects of doxorubicin and vincristine. Cancer Biology & Therapy, 15(10), 1395–1403. Scholar
  131. 131.
    Niccoli, T., & Partridge, L. (2012). Ageing as a risk factor for disease. Current Biology, 22(17), R741–R752. Scholar
  132. 132.
    Kuranda, K., Vargaftig, J., de la Rochere, P., Dosquet, C., Charron, D., Bardin, F., Tonnelle, C., Bonnet, D., & Goodhardt, M. (2011). Age-related changes in human hematopoietic stem/progenitor cells. Aging Cell, 10(3), 542–546. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Patrick O. Azevedo
    • 1
  • Ana E. Paiva
    • 1
  • Gabryella S. P. Santos
    • 1
  • Luiza Lousado
    • 1
  • Julia P. Andreotti
    • 1
  • Isadora F. G. Sena
    • 1
  • Carlos A. Tagliati
    • 2
  • Akiva Mintz
    • 3
  • Alexander Birbrair
    • 1
    • 3
    Email author
  1. 1.Department of PathologyFederal University of Minas GeraisBelo HorizonteBrazil
  2. 2.Department of Clinical and Toxicological AnalysisFederal University of Minas GeraisBelo HorizonteBrazil
  3. 3.Department of RadiologyColumbia University Medical CenterNew YorkUSA

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