Cancer Immunology, Immunotherapy

, Volume 66, Issue 8, pp 1059–1067 | Cite as

Common extracellular matrix regulation of myeloid cell activity in the bone marrow and tumor microenvironments

  • Sabina Sangaletti
  • Claudia Chiodoni
  • Claudio Tripodo
  • Mario P. ColomboEmail author
Focussed Research Review


The complex interaction between cells undergoing transformation and the various stromal and immunological cell components of the tumor microenvironment (TME) crucially influences cancer progression and diversification, as well as endowing clinical and prognostic significance. The immunosuppression characterizing the TME depends on the recruitment and activation of different cell types including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Less considered is the non-cellular component of the TME. Here, we focus on the extracellular matrix (ECM) regulatory activities that, within the TME, actively contribute to many aspects of tumor progression, acting on both tumor and immune cells. Particularly, ECM-mediated regulation of tumor-associated immunosuppression occurs through the modulation of myeloid cell expansion, localization, and functional activities. Such regulation is not limited to the TME but occurs also within the bone marrow, wherein matricellular proteins contribute to the maintenance of specialized hematopoietic stem cell niches thereby regulating their homeostasis as well as the generation and expansion of myeloid cells under both physiological and pathological conditions. Highlighting the commonalities among ECM-myeloid cell interactions in bone marrow and TME, in this review we present a picture in which myeloid cells might sense and respond to ECM modifications, providing different ECM-myeloid cell interfaces that may be useful to define prognostic groups and to tailor therapeutic interventions.


Regulatory myeloid suppressor cells SPARC Tumor microenvironment Bone marrow niche Extracellular matrix 



Acute myeloid leukemia


Bone marrow


Diffuse large B cell lymphoma


Extracellular matrix


Epithelial to mesenchymal transition


Hematopoietic stem cell


Interferon gamma




Leukocyte-associated Ig-like receptor




Myelodisplastic syndrome


Myeloid-derived suppressor cell


Neutrophil extracellular traps






Reactive nitrogen species


Reactive oxygen species


Tumor-associated macrophage


Tumor microenvironment


Tumor necrosis factor




Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to declare.


This work was supported by Associazione Italiana per la Ricerca sul Cancro (IG 10137 to Mario P. Colombo, MFAG 12810 to Sabina Sangaletti, IG 17261 to Claudia Chiodoni), and the Italian Ministry of Health (GR-2013-02355637 to Sabina Sangaletti).


  1. 1.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. doi: 10.1016/j.cell.2011.02.013 CrossRefPubMedGoogle Scholar
  2. 2.
    Acerbi I, Cassereau L, Dean I et al (2015) Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr Biol (Camb) 7:1120–1134. doi: 10.1039/c5ib00040h CrossRefGoogle Scholar
  3. 3.
    Afik R, Zigmond E, Vugman M et al (2016) Tumor macrophages are pivotal constructors of tumor collagenous matrix. J Exp Med 213:2315–2331. doi: 10.1084/jem.20151193 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Sangaletti S, Stoppacciaro A, Guiducci C, Torrisi MR, Colombo MP (2003) Leukocyte, rather than tumor-produced SPARC, determines stroma and collagen type IV deposition in mammary carcinoma. J Exp Med 198:1475–1485. doi: 10.1084/jem.20030202 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Sangaletti S, Di Carlo E, Gariboldi S et al (2008) Macrophage-derived SPARC bridges tumor cell-extracellular matrix interactions toward metastasis. Cancer Res 68:9050–9059. doi: 10.1158/0008-5472.CAN-08-1327 CrossRefPubMedGoogle Scholar
  6. 6.
    Pickup MW, Mouw JK, Weaver VM (2014) The extracellular matrix modulates the hallmarks of cancer. EMBO Rep 15:1243–1253. doi: 10.15252/embr.201439246 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Levental KR, Yu HM, Kass L et al (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891–906. doi: 10.1016/j.cell.2009.10.027 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bergamaschi A, Tagliabue E, Sørlie T et al (2008) Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome. J Pathol 214:357–367. doi: 10.1002/path.2278 CrossRefPubMedGoogle Scholar
  9. 9.
    Triulzi T, Casalini P, Sandri M et al (2013) Neoplastic and stromal cells contribute to an extracellular matrix gene expression profile defining a breast cancer subtype likely to progress. PLoS One 8:e56761. doi: 10.1371/journal.pone.0056761 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Sangaletti S, Tripodo C, Santangelo A et al (2016) Mesenchymal transition of high-grade breast carcinomas depends on extracellular matrix control of myeloid suppressor cell activity. Cell Rep 17:233–248. doi: 10.1016/j.celrep.2016.08.075 CrossRefPubMedGoogle Scholar
  11. 11.
    Helleman J, Jansen MP, Ruigrok-Ritstier K et al (2008) Association of an extracellular matrix gene cluster with breast cancer prognosis and endocrine therapy response. Clin Cancer Res 14:5555–5564. doi: 10.1158/1078-0432.Ccr-08-0555 CrossRefPubMedGoogle Scholar
  12. 12.
    Guttlein LN, Benedetti LG, Fresno C et al (2017) Predictive outcomes for HER2-enriched cancer using growth and metastasis signatures driven by SPARC. Mol Cancer Res 15:304–316. doi: 10.1158/1541-7786.MCR-16-0243-T CrossRefPubMedGoogle Scholar
  13. 13.
    Cheon DJ, Tong YG, Sim MS et al (2014) A collagen-remodeling gene signature regulated by TGF-beta signaling is associated with metastasis and poor survival in serous ovarian cancer. Clin Cancer Res 20:711–723. doi: 10.1158/1078-0432.Ccr-13-1256 CrossRefPubMedGoogle Scholar
  14. 14.
    Zhang W, Ota T, Shridhar V, Chien J, Wu BL, Kuang R (2013) Network-based survival analysis reveals subnetwork signatures for predicting outcomes of ovarian cancer treatment. PLoS Comput Biol 9:e1002975. doi: 10.1371/journal.pcbi.1002975 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Naba A, Clauser KR, Whittaker CA, Carr SA, Tanabe KK, Hynes RO (2014) Extracellular matrix signatures of human primary metastatic colon cancers and their metastases to liver. BMC Cancer 14:518. doi: 10.1186/1471-2407-14-518 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Lenz G, Wright G, Dave SS et al (2008) Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 359:2313–2323. doi: 10.1056/NEJMoa0802885 CrossRefPubMedGoogle Scholar
  17. 17.
    Jain P, Fayad LE, Rosenwald A, Young KH, O’Brien S (2013) Recent advances in de novo CD5(+) diffuse large B cell lymphoma. Am J Hematol 88:798–802. doi: 10.1002/ajh.23467 CrossRefPubMedGoogle Scholar
  18. 18.
    Sangaletti S, Tripodo C, Vitali C et al (2014) Defective stromal remodeling and neutrophil extracellular traps in lymphoid tissues favor the transition from autoimmunity to lymphoma. Cancer Discov 4:110–129. doi: 10.1158/2159-8290.Cd-13-0276 CrossRefPubMedGoogle Scholar
  19. 19.
    Galon J, Costes A, Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964. doi: 10.1126/science.1129139 CrossRefPubMedGoogle Scholar
  20. 20.
    Newman AM, Liu CL, Green MR et al (2015) Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 12:453–457. doi: 10.1038/nmeth.3337 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Gentles AJ, Newman AM, Liu CL et al (2015) The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med 21:938–945. doi: 10.1038/nm.3909 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Becht E, Giraldo NA, Lacroix L et al (2016) Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol 17:218. doi: 10.1186/s13059-016-1070-5 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Salmon H, Franciszkiewicz K, Damotte D et al (2012) Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Invest 122:899–910. doi: 10.1172/Jci45817 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lu TY, Gabrilovich DI (2012) Molecular pathways: tumor-infiltrating myeloid cells and reactive oxygen species in regulation of tumor microenvironment. Clin Cancer Res 18:4877–4882. doi: 10.1158/1078-0432.CCR-11-2939 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    De Sanctis F, Sandri S, Ferrarini G et al (2014) The emerging immunological role of post-translational modifications by reactive nitrogen species in cancer microenvironment. Front Immunol 5:69. doi: 10.3389/fimmu.2014.00069 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Smith CK, Kaplan MJ (2015) The role of neutrophils in the pathogenesis of systemic lupus erythematosus. Curr Opin Rheumatol 27:448–453. doi: 10.1097/Bor.0000000000000197 CrossRefPubMedGoogle Scholar
  27. 27.
    Kaplan G (1983) In vitro differentiation of human monocytes. Monocytes cultured on glass are cytotoxic to tumor cells but monocytes cultured on collagen are not. J Exp Med 157:2061–2072CrossRefPubMedGoogle Scholar
  28. 28.
    Lebbink RJ, de Ruiter T, Adelmeijer J et al (2006) Collagens are functional, high affinity ligands for the inhibitory immune receptor LAIR-1. J Exp Med 203:1419–1425. doi: 10.1084/jem.20052554 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Solito S, Falisi E, Diaz-Montero CM et al (2011) A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood 118:2254–2265. doi: 10.1182/blood-2010-12-325753 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Mantovani A, Cassatella MA, Costantini C, Jaillon S (2011) Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11:519–531. doi: 10.1038/nri3024 CrossRefPubMedGoogle Scholar
  31. 31.
    Marigo I, Bosio E, Solito S et al (2010) Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity 32:790–802. doi: 10.1016/j.immuni.2010.05.010 CrossRefPubMedGoogle Scholar
  32. 32.
    Lyons TR, O’Brien J, Borges VF et al (2011) Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nat Med 17:1109–1115. doi: 10.1038/nm.2416 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Esbona K, Inman D, Saha S, Jeffery J, Schedin P, Wilke L, Keely P (2016) COX-2 modulates mammary tumor progression in response to collagen density. Breast Cancer Res 18:35. doi: 10.1186/s13058-016-0695-3 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Knipper JA, Willenborg S, Brinckmann J et al (2015) Interleukin-4 receptor alpha signaling in myeloid cells controls collagen fibril assembly in skin repair. Immunity 43:803–816. doi: 10.1016/j.immuni.2015.09.005 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Basu A, Kligman LH, Samulewicz SJ, Howe CC (2001) Impaired wound healing in mice deficient in a matricellular protein SPARC (osteonectin, BM-40). BMC Cell Biol 2:15. doi: 10.1186/1471-2121-2-15 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Murphy-Ullrich JE, Sage EH (2014) Revisiting the matricellular concept. Matrix Biol 37:1–14. doi: 10.1016/j.matbio.2014.07.005 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ehninger A, Boch T, Medyouf H, Müdder K, Orend G, Trumpp A (2014) Loss of SPARC protects hematopoietic stem cells from chemotherapy toxicity by accelerating their return to quiescence. Blood 123:4054–4063. doi: 10.1182/blood-2013-10-533711 CrossRefPubMedGoogle Scholar
  38. 38.
    Tripodo C, Sangaletti S, Guarnotta C et al (2012) Stromal SPARC contributes to the detrimental fibrotic changes associated with myeloproliferation whereas its deficiency favors myeloid cell expansion. Blood 120:3541–3554. doi: 10.1182/blood-2011-12-398537 CrossRefPubMedGoogle Scholar
  39. 39.
    Sangaletti S, Tripodo C, Portararo P et al (2014) Stromal niche communalities underscore the contribution of the matricellular protein SPARC to B-cell development and lymphoid malignancies. Oncoimmunology 3:e28989. doi: 10.4161/onci.28989 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Nilsson SK, Johnston HM, Whitty GA et al (2005) Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood 106:1232–1239. doi: 10.1182/blood-2004-11-4422 CrossRefPubMedGoogle Scholar
  41. 41.
    Giallongo C, La Cava P, Tibullo D et al (2013) SPARC expression in CML is associated to imatinib treatment and to inhibition of leukemia cell proliferation. BMC Cancer 13:60. doi: 10.1186/1471-2407-13-60 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Pellagatti A, Cazzola M, Giagounidis A et al (2007) Expression profiling of CD34+ cells in patients with myelodysplastic syndromes: differences between early and advanced cases and analysis of apoptosis-related genes. Leuk Res 31:S35-S. doi: 10.1016/S0145-2126(07)70061-9 CrossRefGoogle Scholar
  43. 43.
    Alachkar H, Santhanam R, Maharry K et al (2014) SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome. J Clin Invest 124:1512–1524. doi: 10.1172/JCI70921 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Powell JA, Thomas D, Barry EF et al (2009) Expression profiling of a hemopoietic cell survival transcriptome implicates osteopontin as a functional prognostic factor in AML. Blood 114:4859–4870. doi: 10.1182/blood-2009-02-204818 CrossRefPubMedGoogle Scholar
  45. 45.
    Nakamura-Ishizu A, Okuno Y, Omatsu Y et al (2012) Extracellular matrix protein tenascin-C is required in the bone marrow microenvironment primed for hematopoietic regeneration. Blood 119:5429–5437. doi: 10.1182/blood-2011-11-393645 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Kim EK, Jeon I, Seo H et al (2014) Tumor-derived osteopontin suppresses antitumor immunity by promoting extramedullary myelopoiesis. Cancer Res 74:6705–6716. doi: 10.1158/0008-5472.CAN-14-1482 CrossRefPubMedGoogle Scholar
  47. 47.
    Wang Z, Xiong S, Mao Y et al (2016) Periostin promotes immunosuppressive premetastatic niche formation to facilitate breast tumour metastasis. J Pathol 239:484–495. doi: 10.1002/path.4747 CrossRefPubMedGoogle Scholar
  48. 48.
    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. Cancer Res 72(Suppl):SY28-02. doi:10.1158/1538-7445.Am2012-Sy28-02Google Scholar
  49. 49.
    Sangaletti S, Tripodo C, Sandri S et al (2014) Osteopontin shapes immunosuppression in the metastatic niche. Cancer Res 74:4706–4719. doi: 10.1158/0008-5472.CAN-13-3334 CrossRefPubMedGoogle Scholar
  50. 50.
    Condamine T, Dominguez GA, Youn JI, et al (2016) Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Science Immunol 1:aaf8943. doi: 10.1126/sciimmunol.aaf8943
  51. 51.
    Catena R, Bhattacharya N, El Rayes T et al (2013) Bone marrow-derived Gr1 + cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. Cancer Discov 3:578–589. doi: 10.1158/2159-8290.CD-12.0476 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Sabina Sangaletti
    • 1
  • Claudia Chiodoni
    • 1
  • Claudio Tripodo
    • 2
  • Mario P. Colombo
    • 1
    Email author
  1. 1.Molecular Immunology Unit, Department of Experimental Oncology and Molecular MedicineFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
  2. 2.Tumor Immunology UnitUniversity of PalermoPalermoItaly

Personalised recommendations