Skip to main content

Advertisement

SpringerLink
Log in

Tumor-associated myeloid cells as guiding forces of cancer cell stemness

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Due to their ability to differentiate into various cell types and to support tissue regeneration, stem cells simultaneously became the holy grail of regenerative medicine and the evil obstacle in cancer therapy. Several studies have investigated niche-related conditions that favor stemness properties and increasingly emphasized their association with an inflammatory environment. Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are major orchestrators of cancer-related inflammation, able to dynamically express different polarized inflammatory programs that promote tumor outgrowth, including tumor angiogenesis, immunosuppression, tissue remodeling and metastasis formation. In addition, these myeloid populations support cancer cell stemness, favoring tumor maintenance and progression, as well as resistance to anticancer treatments. Here, we discuss inflammatory circuits and molecules expressed by TAMs and MDSCs as guiding forces of cancer cell stemness.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

ALDH:

Aldehyde dehydrogenases

CCR2:

C–C chemokine receptor type 2

CSCs:

Cancer stem cells

CtBP2:

C-terminal-binding protein 2

EMT:

Epithelial–mesenchymal transition

EOC:

Epithelial ovarian cancer

HCC:

Hepatocellular carcinoma

HIF-1α:

Hypoxia-inducible factor-1α

IL-1Ra:

Interleukin-1 receptor antagonist

ISG15:

Interferon-stimulated gene 15

MDR1/2:

Multidrug resistance protein 1/2

MDSCs:

Myeloid-derived suppressor cells

MFG-E8:

Milk fat globule-epidermal growth factor-VIII

MSCs:

Mesenchymal stem cells

OXPHOS:

Oxidative phosphorylation

PDAC:

Pancreatic ductal adenocarcinoma

ROS:

Reactive oxygen species

SCF:

Stem cell factor

TAF:

Tumor-associated fibroblast

TAMs:

Tumor-associated macrophages

TIC:

Tumor-initiating cell

TME:

Tumor microenvironment

References

  1. Sica A, Erreni M, Allavena P, Porta C (2015) Macrophage polarization in pathology. Cell Mol Life Sci 72(21):4111–4126. doi:10.1007/s00018-015-1995-y

    Article  CAS  PubMed  Google Scholar 

  2. Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R, Pittet MJ (2009) Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325(5940):612–616. doi:10.1126/science.1175202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sindrilaru A, Peters T, Wieschalka S, Baican C, Baican A, Peter H, Hainzl A, Schatz S, Qi Y, Schlecht A, Weiss JM, Wlaschek M, Sunderkotter C, Scharffetter-Kochanek K (2011) An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Invest 121(3):985–997. doi:10.1172/JCI44490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Anton K, Banerjee D, Glod J (2012) Macrophage-associated mesenchymal stem cells assume an activated, migratory, pro-inflammatory phenotype with increased IL-6 and CXCL10 secretion. PLoS ONE 7(4):e35036. doi:10.1371/journal.pone.0035036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315(26):1650–1659. doi:10.1056/NEJM198612253152606

    Article  CAS  PubMed  Google Scholar 

  6. Shiozawa Y, Nie B, Pienta KJ, Morgan TM, Taichman RS (2013) Cancer stem cells and their role in metastasis. Pharmacol Ther 138(2):285–293. doi:10.1016/j.pharmthera.2013.01.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Malhotra GK, Zhao X, Band H, Band V (2011) Shared signaling pathways in normal and breast cancer stem cells. J Carcinog 10:38. doi:10.4103/1477-3163.91413

    Article  PubMed  PubMed Central  Google Scholar 

  8. Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, Shelton AA, Parmiani G, Castelli C, Clarke MF (2007) Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA 104(24):10158–10163. doi:10.1073/pnas.0703478104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pasto A, Bellio C, Pilotto G, Ciminale V, Silic-Benussi M, Guzzo G, Rasola A, Frasson C, Nardo G, Zulato E, Nicoletto MO, Manicone M, Indraccolo S, Amadori A (2014) Cancer stem cells from epithelial ovarian cancer patients privilege oxidative phosphorylation, and resist glucose deprivation. Oncotarget 5(12):4305–4319. doi:10.18632/oncotarget.2010

    Article  PubMed  PubMed Central  Google Scholar 

  10. Chiou SH, Wang ML, Chou YT, Chen CJ, Hong CF, Hsieh WJ, Chang HT, Chen YS, Lin TW, Hsu HS, Wu CW (2010) Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial–mesenchymal transdifferentiation. Cancer Res 70(24):10433–10444. doi:10.1158/0008-5472.CAN-10-2638

    Article  CAS  PubMed  Google Scholar 

  11. Anido J, Saez-Borderias A, Gonzalez-Junca A, Rodon L, Folch G, Carmona MA, Prieto-Sanchez RM, Barba I, Martinez-Saez E, Prudkin L, Cuartas I, Raventos C, Martinez-Ricarte F, Poca MA, Garcia-Dorado D, Lahn MM, Yingling JM, Rodon J, Sahuquillo J, Baselga J, Seoane J (2010) TGF-beta receptor inhibitors target the CD44(high)/Id1(high) glioma-initiating cell population in human glioblastoma. Cancer Cell 18(6):655–668. doi:10.1016/j.ccr.2010.10.023

    Article  CAS  PubMed  Google Scholar 

  12. Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, Bernasconi S, Saccani S, Nebuloni M, Vago L, Mantovani A, Melillo G, Sica A (2003) Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med 198(9):1391–1402. doi:10.1084/jem.20030267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hsieh CH, Shyu WC, Chiang CY, Kuo JW, Shen WC, Liu RS (2011) NADPH oxidase subunit 4-mediated reactive oxygen species contribute to cycling hypoxia-promoted tumor progression in glioblastoma multiforme. PLoS ONE 6(9):e23945. doi:10.1371/journal.pone.0023945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Blaylock RL (2015) Cancer microenvironment, inflammation and cancer stem cells: a hypothesis for a paradigm change and new targets in cancer control. Surg Neurol Int 6:92. doi:10.4103/2152-7806.157890

    Article  PubMed  PubMed Central  Google Scholar 

  15. Bonde AK, Tischler V, Kumar S, Soltermann A, Schwendener RA (2012) Intratumoral macrophages contribute to epithelial–mesenchymal transition in solid tumors. BMC Cancer 12:35. doi:10.1186/1471-2407-12-35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, Lagutina I, Grosveld GC, Osawa M, Nakauchi H, Sorrentino BP (2001) The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 7(9):1028–1034. doi:10.1038/nm0901-1028

    Article  CAS  PubMed  Google Scholar 

  17. Bourguignon LY, Peyrollier K, Xia W, Gilad E (2008) Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells. J Biol Chem 283(25):17635–17651. doi:10.1074/jbc.M800109200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fatrai S, van Schelven SJ, Ubink I, Govaert KM, Raats D, Koster J, Verheem A, Borel Rinkes IH, Kranenburg O (2015) Maintenance of clonogenic KIT(+) human colon tumor cells requires secretion of stem cell factor by differentiated tumor cells. Gastroenterology 149(3):692–704. doi:10.1053/j.gastro.2015.05.003

    Article  CAS  PubMed  Google Scholar 

  19. Schilder RJ, Sill MW, Lee RB, Shaw TJ, Senterman MK, Klein-Szanto AJ, Miner Z, Vanderhyden BC (2008) Phase II evaluation of imatinib mesylate in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 26(20):3418–3425. doi:10.1200/JCO.2007.14.3420

    Article  CAS  PubMed  Google Scholar 

  20. Matassa DS, Amoroso MR, Lu H, Avolio R, Arzeni D, Procaccini C, Faicchia D, Maddalena F, Simeon V, Agliarulo I, Zanini E, Mazzoccoli C, Recchi C, Stronach E, Marone G, Gabra H, Matarese G, Landriscina M, Esposito F (2016) Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer. Cell Death Differ 23(9):1542–1554. doi:10.1038/cdd.2016.39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331(6024):1565–1570. doi:10.1126/science.1203486

    Article  CAS  PubMed  Google Scholar 

  22. Belli C, Piemonti L, D’Incalci M, Zucchetti M, Porcu L, Cappio S, Doglioni C, Allavena P, Ceraulo D, Maggiora P, Dugnani E, Cangi MG, Garassini G, Reni M (2016) Phase II trial of salvage therapy with trabectedin in metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol 77(3):477–484. doi:10.1007/s00280-015-2932-3

    Article  CAS  PubMed  Google Scholar 

  23. Nishio N, Fujita M, Tanaka Y, Maki H, Zhang R, Hirosawa T, Demachi-Okamura A, Uemura Y, Taguchi O, Takahashi Y, Kojima S, Kuzushima K (2012) Zoledronate sensitizes neuroblastoma-derived tumor-initiating cells to cytolysis mediated by human gammadelta T cells. J Immunother 35(8):598–606. doi:10.1097/CJI.0b013e31826a745a

    Article  CAS  PubMed  Google Scholar 

  24. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. doi:10.1038/nrc3239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mantovani A, Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22(2):231–237. doi:10.1016/j.coi.2010.01.009

    Article  CAS  PubMed  Google Scholar 

  26. Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122(3):787–795. doi:10.1172/JCI59643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Raggi C, Mousa HS, Correnti M, Sica A, Invernizzi P (2016) Cancer stem cells and tumor-associated macrophages: a roadmap for multitargeting strategies. Oncogene 35(6):671–682. doi:10.1038/onc.2015.132

    Article  CAS  PubMed  Google Scholar 

  28. Gallucci RM, Simeonova PP, Matheson JM, Kommineni C, Guriel JL, Sugawara T, Luster MI (2000) Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice. FASEB J 14(15):2525–2531. doi:10.1096/fj.00-0073com

    Article  CAS  PubMed  Google Scholar 

  29. Sano S, Itami S, Takeda K, Tarutani M, Yamaguchi Y, Miura H, Yoshikawa K, Akira S, Takeda J (1999) Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J 18(17):4657–4668. doi:10.1093/emboj/18.17.4657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yu H, Lee H, Herrmann A, Buettner R, Jove R (2014) Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 14(11):736–746. doi:10.1038/nrc3818

    Article  CAS  PubMed  Google Scholar 

  31. Wan S, Zhao E, Kryczek I, Vatan L, Sadovskaya A, Ludema G, Simeone DM, Zou W, Welling TH (2014) Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147(6):1393–1404. doi:10.1053/j.gastro.2014.08.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Won C, Kim BH, Yi EH, Choi KJ, Kim EK, Jeong JM, Lee JH, Jang JJ, Yoon JH, Jeong WI, Park IC, Kim TW, Bae SS, Factor VM, Ma S, Thorgeirsson SS, Lee YH, Ye SK (2015) Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma. Hepatology 62(4):1160–1173. doi:10.1002/hep.27968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jinushi M, Chiba S, Yoshiyama H, Masutomi K, Kinoshita I, Dosaka-Akita H, Yagita H, Takaoka A, Tahara H (2011) Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc Natl Acad Sci USA 108(30):12425–12430. doi:10.1073/pnas.1106645108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE, Belaygorod L, Carpenter D, Collins L, Piwnica-Worms D, Hewitt S, Udupi GM, Gallagher WM, Wegner C, West BL, Wang-Gillam A, Goedegebuure P, Linehan DC, DeNardo DG (2013) Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 73(3):1128–1141. doi:10.1158/0008-5472.CAN-12-2731

    Article  CAS  PubMed  Google Scholar 

  35. Iliopoulos D, Hirsch HA, Struhl K (2009) An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139(4):693–706. doi:10.1016/j.cell.2009.10.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ward R, Sims AH, Lee A, Lo C, Wynne L, Yusuf H, Gregson H, Lisanti MP, Sotgia F, Landberg G, Lamb R (2015) Monocytes and macrophages, implications for breast cancer migration and stem cell-like activity and treatment. Oncotarget 6(16):14687–14699. doi:10.18632/oncotarget.4189

    Article  PubMed  PubMed Central  Google Scholar 

  37. Wolfe AR, Trenton NJ, Debeb BG, Larson R, Ruffell B, Chu K, Hittelman W, Diehl M, Reuben JM, Ueno NT, Woodward WA (2016) Mesenchymal stem cells and macrophages interact through IL-6 to promote inflammatory breast cancer in pre-clinical models. Oncotarget 7(50):82482–82492. doi:10.18632/oncotarget.12694

    PubMed  PubMed Central  Google Scholar 

  38. Yang J, Liao D, Chen C, Liu Y, Chuang TH, Xiang R, Markowitz D, Reisfeld RA, Luo Y (2013) Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway. Stem Cells 31(2):248–258. doi:10.1002/stem.1281

    Article  CAS  PubMed  Google Scholar 

  39. Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, Forster I, Akira S (1999) Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10(1):39–49

    Article  CAS  PubMed  Google Scholar 

  40. Lang R (2005) Tuning of macrophage responses by Stat3-inducing cytokines: molecular mechanisms and consequences in infection. Immunobiology 210(2–4):63–76. doi:10.1016/j.imbio.2005.05.001

    Article  CAS  PubMed  Google Scholar 

  41. Sica A, Saccani A, Bottazzi B, Polentarutti N, Vecchi A, van Damme J, Mantovani A (2000) Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages. J Immunol 164(2):762–767

    Article  CAS  PubMed  Google Scholar 

  42. Kang YJ, Yang SJ, Park G, Cho B, Min CK, Kim TY, Lee JS, Oh IH (2007) A novel function of interleukin-10 promoting self-renewal of hematopoietic stem cells. Stem Cells 25(7):1814–1822. doi:10.1634/stemcells.2007-0002

    Article  CAS  PubMed  Google Scholar 

  43. Tuccitto A, Tazzari M, Beretta V, Rini F, Miranda C, Greco A, Santinami M, Patuzzo R, Vergani B, Villa A, Manenti G, Cleris L, Giardiello D, Alison M, Rivoltini L, Castelli C, Perego M (2016) Immunomodulatory factors control the fate of melanoma tumor initiating cells. Stem Cells 34(10):2449–2460. doi:10.1002/stem.2413

    Article  CAS  PubMed  Google Scholar 

  44. Xu L, Wang X, Wang J, Liu D, Wang Y, Huang Z, Tan H (2016) Hypoxia-induced secretion of IL-10 from adipose-derived mesenchymal stem cell promotes growth and cancer stem cell properties of Burkitt lymphoma. Tumour Biol 37(6):7835–7842. doi:10.1007/s13277-015-4664-8

    Article  CAS  PubMed  Google Scholar 

  45. Sainz B Jr, Martin B, Tatari M, Heeschen C, Guerra S (2014) ISG15 is a critical microenvironmental factor for pancreatic cancer stem cells. Cancer Res 74(24):7309–7320. doi:10.1158/0008-5472.CAN-14-1354

    Article  CAS  PubMed  Google Scholar 

  46. Sainz B Jr, Alcala S, Garcia E, Sanchez-Ripoll Y, Azevedo MM, Cioffi M, Tatari M, Miranda-Lorenzo I, Hidalgo M, Gomez-Lopez G, Canamero M, Erkan M, Kleeff J, Garcia-Silva S, Sancho P, Hermann PC, Heeschen C (2015) Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment. Gut 64(12):1921–1935. doi:10.1136/gutjnl-2014-308935

    Article  CAS  PubMed  Google Scholar 

  47. Lu H, Clauser KR, Tam WL, Frose J, Ye X, Eaton EN, Reinhardt F, Donnenberg VS, Bhargava R, Carr SA, Weinberg RA (2014) A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol 16(11):1105–1117. doi:10.1038/ncb3041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Weber CE, Li NY, Wai PY, Kuo PC (2012) Epithelial-mesenchymal transition, TGF-beta, and osteopontin in wound healing and tissue remodeling after injury. J Burn Care Res 33(3):311–318. doi:10.1097/BCR.0b013e318240541e

    Article  PubMed  PubMed Central  Google Scholar 

  49. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008) The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715. doi:10.1016/j.cell.2008.03.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Fazilaty H, Gardaneh M, Bahrami T, Salmaninejad A, Behnam B (2013) Crosstalk between breast cancer stem cells and metastatic niche: Emerging molecular metastasis pathway? Tumour Biol 34(4):2019–2030. doi:10.1007/s13277-013-0831-y

    Article  CAS  PubMed  Google Scholar 

  51. Rennekampff HO, Hansbrough JF, Kiessig V, Dore C, Sticherling M, Schroder JM (2000) Bioactive interleukin-8 is expressed in wounds and enhances wound healing. J Surg Res 93(1):41–54. doi:10.1006/jsre.2000.5892

    Article  CAS  PubMed  Google Scholar 

  52. Singh JK, Farnie G, Bundred NJ, Simoes BM, Shergill A, Landberg G, Howell SJ, Clarke RB (2013) Targeting CXCR1/2 significantly reduces breast cancer stem cell activity and increases the efficacy of inhibiting HER2 via HER2-dependent and -independent mechanisms. Clin Cancer Res 19(3):643–656. doi:10.1158/1078-0432.CCR-12-1063

    Article  CAS  PubMed  Google Scholar 

  53. Ginestier C, Liu S, Diebel ME, Korkaya H, Luo M, Brown M, Wicinski J, Cabaud O, Charafe-Jauffret E, Birnbaum D, Guan JL, Dontu G, Wicha MS (2010) CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest 120(2):485–497. doi:10.1172/JCI39397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ma C, Komohara Y, Ohnishi K, Shimoji T, Kuwahara N, Sakumura Y, Matsuishi K, Fujiwara Y, Motoshima T, Takahashi W, Yamada S, Kitada S, Fujimoto N, Nakayama T, Eto M, Takeya M (2016) Infiltration of tumor-associated macrophages is involved in CD44 expression in clear cell renal cell carcinoma. Cancer Sci 107(5):700–707. doi:10.1111/cas.12917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tham M, Tan KW, Keeble J, Wang X, Hubert S, Barron L, Tan NS, Kato M, Prevost-Blondel A, Angeli V, Abastado JP (2014) Melanoma-initiating cells exploit M2 macrophage TGFbeta and arginase pathway for survival and proliferation. Oncotarget 5(23):12027–12042. doi:10.18632/oncotarget.2482

    Article  PubMed  PubMed Central  Google Scholar 

  56. Tham M, Khoo K, Yeo KP, Kato M, Prevost-Blondel A, Angeli V, Abastado JP (2015) Macrophage depletion reduces postsurgical tumor recurrence and metastatic growth in a spontaneous murine model of melanoma. Oncotarget 6(26):22857–22868. doi:10.18632/oncotarget.3127

    Article  PubMed  PubMed Central  Google Scholar 

  57. Zhou W, Ke SQ, Huang Z, Flavahan W, Fang X, Paul J, Wu L, Sloan AE, McLendon RE, Li X, Rich JN, Bao S (2015) Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat Cell Biol 17(2):170–182. doi:10.1038/ncb3090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Raggi C, Correnti M, Sica A, Andersen JB, Cardinale V, Alvaro D, Chiorino G, Forti E, Glaser S, Alpini G, Destro A, Sozio F, Di Tommaso L, Roncalli M, Banales JM, Coulouarn C, Bujanda L, Torzilli G, Invernizzi P (2017) Cholangiocarcinoma stem-like subset shapes tumor-initiating niche by educating associated macrophages. J Hepatol 66(1):102–115. doi:10.1016/j.jhep.2016.08.012

    Article  CAS  PubMed  Google Scholar 

  59. Lee TK, Cheung VC, Lu P, Lau EY, Ma S, Tang KH, Tong M, Lo J, Ng IO (2014) Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma. Hepatology 60(1):179–191. doi:10.1002/hep.27070

    Article  CAS  PubMed  Google Scholar 

  60. Cioffi M, Trabulo S, Hidalgo M, Costello E, Greenhalf W, Erkan M, Kleeff J, Sainz B Jr, Heeschen C (2015) Inhibition of CD47 effectively targets pancreatic cancer stem cells via dual mechanisms. Clin Cancer Res 21(10):2325–2337. doi:10.1158/1078-0432.CCR-14-1399

    Article  CAS  PubMed  Google Scholar 

  61. Panni RZ, Sanford DE, Belt BA, Mitchem JB, Worley LA, Goetz BD, Mukherjee P, Wang-Gillam A, Link DC, Denardo DG, Goedegebuure SP, Linehan DC (2014) Tumor-induced STAT3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancer. Cancer Immunol Immunother 63(5):513–528. doi:10.1007/s00262-014-1527-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12(4):253–268. doi:10.1038/nri3175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Peng D, Tanikawa T, Li W, Zhao L, Vatan L, Szeliga W, Wan S, Wei S, Wang Y, Liu Y, Staroslawska E, Szubstarski F, Rolinski J, Grywalska E, Stanislawek A, Polkowski W, Kurylcio A, Kleer C, Chang AE, Wicha M, Sabel M, Zou W, Kryczek I (2016) Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH cross-talk signaling. Cancer Res 76(11):3156–3165. doi:10.1158/0008-5472.CAN-15-2528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cui TX, Kryczek I, Zhao L, Zhao E, Kuick R, Roh MH, Vatan L, Szeliga W, Mao Y, Thomas DG, Kotarski J, Tarkowski R, Wicha M, Cho K, Giordano T, Liu R, Zou W (2013) Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. Immunity 39(3):611–621. doi:10.1016/j.immuni.2013.08.025

    Article  CAS  PubMed  Google Scholar 

  65. Di Mitri D, Toso A, Chen JJ, Sarti M, Pinton S, Jost TR, D’Antuono R, Montani E, Garcia-Escudero R, Guccini I, Da Silva-Alvarez S, Collado M, Eisenberger M, Zhang Z, Catapano C, Grassi F, Alimonti A (2014) Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature 515(7525):134–137. doi:10.1038/nature13638

    Article  PubMed  Google Scholar 

  66. Wei J, Barr J, Kong LY, Wang Y, Wu A, Sharma AK, Gumin J, Henry V, Colman H, Priebe W, Sawaya R, Lang FF, Heimberger AB (2010) Glioblastoma cancer-initiating cells inhibit T-cell proliferation and effector responses by the signal transducers and activators of transcription 3 pathway. Mol Cancer Ther 9(1):67–78. doi:10.1158/1535-7163.MCT-09-0734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Otvos B, Silver DJ, Mulkearns-Hubert EE, Alvarado AG, Turaga SM, Sorensen MD, Rayman P, Flavahan WA, Hale JS, Stoltz K, Sinyuk M, Wu Q, Jarrar A, Kim SH, Fox PL, Nakano I, Rich JN, Ransohoff RM, Finke J, Kristensen BW, Vogelbaum MA, Lathia JD (2016) Cancer stem cell-secreted macrophage migration inhibitory factor stimulates myeloid derived suppressor cell function and facilitates glioblastoma immune evasion. Stem Cells 34(8):2026–2039. doi:10.1002/stem.2393

    Article  CAS  PubMed  Google Scholar 

  68. Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496(7446):445–455. doi:10.1038/nature12034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Strauss L, Sangaletti S, Consonni FM, Szebeni G, Morlacchi S, Totaro MG, Porta C, Anselmo A, Tartari S, Doni A, Zitelli F, Tripodo C, Colombo MP, Sica A (2015) RORC1 regulates tumor-promoting “emergency” granulo-monocytopoiesis. Cancer Cell 28(2):253–269. doi:10.1016/j.ccell.2015.07.006

    Article  CAS  PubMed  Google Scholar 

  70. Mantovani A, Allavena P (2015) The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med 212(4):435–445. doi:10.1084/jem.20150295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41(1):49–61. doi:10.1016/j.immuni.2014.06.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Buque A, Bloy N, Aranda F, Cremer I, Eggermont A, Fridman WH, Fucikova J, Galon J, Spisek R, Tartour E, Zitvogel L, Kroemer G, Galluzzi L (2016) Trial watch-small molecules targeting the immunological tumor microenvironment for cancer therapy. Oncoimmunology 5(6):e1149674. doi:10.1080/2162402X.2016.1149674

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by Associazione Italiana Ricerca sul Cancro (AIRC), project #15585, #14032 Italy; Fondazione Cariplo, Italy; Ministero Università Ricerca (MIUR), Italy, (Grant Numbers: RBAU01PTYW; RBNE01XHB2_002; RBAP11H2R9_005); Ministero della Salute (GR-2011-02349580); Istituto Oncologico Veneto 5x1000 grant.

Author information

Author notes

  1. Antonio Sica, Chiara Porta, Alberto Amadori, Anna Pastò have equally contributed to the work.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Università del Piemonte Orientale “Amedeo Avogadro”, Via Bovio 6, 28100, Novara, Italy

    Antonio Sica & Chiara Porta

  2. Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy

    Antonio Sica

  3. Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy

    Alberto Amadori

  4. Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy

    Alberto Amadori & Anna Pastò

Authors
  1. Antonio Sica
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chiara Porta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alberto Amadori
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Pastò
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Antonio Sica.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Additional information

This paper is a Focussed Research Review based on a presentation given at the conference Regulatory Myeloid Suppressor Cells: From Basic Discovery to Therapeutic Application which was hosted by the Wistar Institute in Philadelphia, PA, USA, 16th–19th June, 2016. It is part of a Cancer Immunology, Immunotherapy series of Focussed Research Reviews.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sica, A., Porta, C., Amadori, A. et al. Tumor-associated myeloid cells as guiding forces of cancer cell stemness. Cancer Immunol Immunother 66, 1025–1036 (2017). https://doi.org/10.1007/s00262-017-1997-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-017-1997-8

Keywords

Search

Navigation