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Cellular and Molecular Biology

Intratumoural haematopoietic stem and progenitor cell differentiation into M2 macrophages facilitates the regrowth of solid tumours after radiation therapy

British Journal of Cancer volume 126, pages 927–936 (2022)Cite this article

Subjects

Abstract

Background

Bone-marrow-derived haematopoietic stem and progenitor cells (HSPCs) are a prominent part of the highly complex tumour microenvironment (TME) where they localise within tumours and maintain haematopoietic potency. Understanding the role HSPCs play in tumour growth and response to radiation therapy (RT) may lead to improved patient treatments and outcomes.

Methods

We used a mouse model of non-small cell lung carcinoma where tumours were exposed to RT regimens alone or in combination with GW2580, a pharmacological inhibitor of colony stimulating factor (CSF)-1 receptor. RT-PCR, western blotting and immunohistochemistry were used to quantify expression levels of factors that affect HSPC differentiation. DsRed+ HSPC intratumoural activity was tracked using flow cytometry and confocal microscopy.

Results

We demonstrated that CSF-1 is enhanced in the TME following exposure to RT. CSF-1 signaling induced intratumoural HSPC differentiation into M2 polarised tumour-associated macrophages (TAMs), aiding in post-RT tumour survival and regrowth. In contrast, hyperfractionated/pulsed radiation therapy (PRT) and GW2580 ablated this process resulting in improved tumour killing and mouse survival.

Conclusions

Tumours coopt intratumoural HSPC fate determination via CSF-1 signaling to overcome the effects of RT. Thus, limiting intratumoural HSPC activity represents an attractive strategy for improving the clinical treatment of solid tumours.

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Fig. 1: SRT modulates tumour growth and levels of intratumoural HSPCs and M2 macrophages.
Fig. 2: SRT induces TME alterations that favour HSPC differentiation into M2 macrophages.
Fig. 3: HSPCs can directly differentiate into M2 macrophages in response to SRT.
Fig. 4: Use of the CSF-1R active inhibitor GW2580 prevents differentiation of HSPCs into M2 macrophages after RT reducing tumour regrowth.
Fig. 5: Use of fractionated RT decreases HSPC migration and differentiation into M2 macrophages reducing tumour growth.
Fig. 6: Augmentative treatment with GW2580 enhances RT effects and abrogates HSPC activity in the TME.

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Data availability

All data are included in this published article and are available (GJM) upon reasonable request.

References

  1. Kane J, Krueger SA, Dilworth JT, Torma JT, Wilson GD, Marples B, et al. Hematopoietic stem and progenitor cell migration after hypofractionated radiation therapy in a murine model. Int J Radiat Oncol Biol Phys. 2013;87:1162–70.

    Article  Google Scholar 

  2. Bissell MJ, Hines WC. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med. 2011;17:320–9.

    Article  CAS  Google Scholar 

  3. Liu Y, Cao X. The origin and function of tumor-associated macrophages. Cell Mol Immunol. 2015;12:1–4.

    Article  Google Scholar 

  4. Kim J, Bae JS. Tumor-associated macrophages and neutrophils in tumor microenvironment. Mediators Inflamm. 2016;2016:6058147.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002;196:254–65.

    Article  CAS  Google Scholar 

  6. Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66:605–12.

    Article  CAS  Google Scholar 

  7. Quatromoni JG, Eruslanov E. Tumor-associated macrophages: function, phenotype, and link to prognosis in human lung cancer. Am J Transl Res. 2012;4:376–89.

    PubMed  PubMed Central  Google Scholar 

  8. Jeannin P, Paolini L, Adam C, Delneste Y. The roles of CSFs on the functional polarization of tumor-associated macrophages. FEBS J. 2018;285:680–99.

    Article  CAS  Google Scholar 

  9. Ohri CM, Shikotra A, Green RH, Waller DA, Bradding P. Macrophages within NSCLC tumour islets are predominantly of a cytotoxic M1 phenotype associated with extended survival. Eur Respir J. 2009;33:118–26.

    Article  CAS  Google Scholar 

  10. Chung FT, Lee KY, Wang CW, Heh CC, Chan YF, Chen HW, et al. Tumor-associated macrophages correlate with response to epidermal growth factor receptor-tyrosine kinase inhibitors in advanced non-small cell lung cancer. Int J Cancer. 2012;131:E227–235.

    Article  CAS  Google Scholar 

  11. Ohtaki Y, Ishii G, Nagai K, Ashimine S, Kuwata T, Hishida T, et al. Stromal macrophage expressing CD204 is associated with tumor aggressiveness in lung adenocarcinoma. J Thorac Oncol. 2010;5:1507–15.

    Article  Google Scholar 

  12. Zhang B, Yao G, Zhang Y, Gao J, Yang B, Rao Z, et al. M2-polarized tumor-associated macrophages are associated with poor prognoses resulting from accelerated lymphangiogenesis in lung adenocarcinoma. Clinics (Sao Paulo). 2011;66:1879–86.

    Article  Google Scholar 

  13. Azzam EI, Jay-Gerin JP, Pain D. Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury. Cancer Lett. 2012;327:48–60.

    Article  CAS  Google Scholar 

  14. Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegue E, et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell. 2008;13:206–20.

    Article  CAS  Google Scholar 

  15. Klopp AH, Spaeth EL, Dembinski JL, Woodward WA, Munshi A, Meyn RE, et al. Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment. Cancer Res. 2007;67:11687–95.

    Article  CAS  Google Scholar 

  16. Bigoni-Ordonez GD, Czarnowski D, Parsons T, Madlambayan GJ, Villa-Diaz LG. Integrin alpha6 (CD49f), the microenvironment and cancer stem cells. Curr Stem Cell Res Ther. 2019;14:428–36.

    Article  CAS  Google Scholar 

  17. Jourdan MM, Lopez A, Olasz EB, Duncan NE, Demara M, Kittipongdaja W, et al. Laminin 332 deposition is diminished in irradiated skin in an animal model of combined radiation and wound skin injury. Radiat Res. 2011;176:636–48.

    Article  CAS  Google Scholar 

  18. Cristofaro B, Emanueli C. Possible novel targets for therapeutic angiogenesis. Curr Opin Pharmacol. 2009;9:102–8.

    Article  CAS  Google Scholar 

  19. Bakkenist CJ, Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003;421:499–506.

    Article  CAS  Google Scholar 

  20. Dilworth JT, Krueger SA, Dabjan M, Grills IS, Torma J, Wilson GD, et al. Pulsed low-dose irradiation of orthotopic glioblastoma multiforme (GBM) in a pre-clinical model: effects on vascularization and tumor control. Radiother Oncol. 2013;108:149–54.

    Article  Google Scholar 

  21. Kane JL, Krueger SA, Hanna A, Raffel TR, Wilson GD, Madlambayan GJ, et al. Effect of irradiation on tumor microenvironment and bone marrow cell migration in a preclinical tumor model. Int J Radiat Oncol Biol Phys. 2016;96:170–8.

    Article  CAS  Google Scholar 

  22. Almahariq MF, Quinn TJ, Arden JD, Roskos PT, Wilson GD, Marples B, et al. Pulsed radiation therapy for the treatment of newly diagnosed glioblastoma. Neuro Oncol. 2020. https://doi.org/10.1093/neuonc/noaa165.

    Article  PubMed Central  Google Scholar 

  23. Madlambayan GJ, Butler JM, Hosaka K, Jorgensen M, Fu D, Guthrie SM, et al. Bone marrow stem and progenitor cell contribution to neovasculogenesis is dependent on model system with SDF-1 as a permissive trigger. Blood. 2009;114:4310–9.

    Article  CAS  Google Scholar 

  24. Iyer G, Wang AR, Brennan SR, Bourgeois S, Armstrong E, Shah P, et al. Identification of stable housekeeping genes in response to ionizing radiation in cancer research. Sci Rep. 2017;7:43763.

    Article  Google Scholar 

  25. A Package for Survival Analysis in R [computer program]. Version 3.2-7. 2020. https://CRAN.R-project.org/package=survival2020.

  26. Arndt K, Grinenko T, Mende N, Reichert D, Portz M, Ripich T, et al. CD133 is a modifier of hematopoietic progenitor frequencies but is dispensable for the maintenance of mouse hematopoietic stem cells. Proc Natl Acad Sci USA. 2013;110:5582–7.

    Article  CAS  Google Scholar 

  27. Jablonski KA, Amici SA, Webb LM, Ruiz-Rosado Jde D, Popovich PG, Partida-Sanchez S, et al. Novel markers to delineate murine M1 and M2 macrophages. PLoS ONE. 2015;10:e0145342.

    Article  Google Scholar 

  28. Priceman SJ, Sung JL, Shaposhnik Z, Burton JB, Torres-Collado AX, Moughon DL, et al. Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy. Blood. 2010;115:1461–71.

    Article  CAS  Google Scholar 

  29. Hu Y, He MY, Zhu LF, Yang CC, Zhou ML, Wang Q, et al. Tumor-associated macrophages correlate with the clinicopathological features and poor outcomes via inducing epithelial to mesenchymal transition in oral squamous cell carcinoma. J Exp Clin Cancer Res. 2016;35:12.

    Article  Google Scholar 

  30. Klug F, Prakash H, Huber PE, Seibel T, Bender N, Halama N, et al. Low-dose irradiation programs macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell. 2013;24:589–602.

    Article  CAS  Google Scholar 

  31. Jayasingam SD, Citartan M, Thang TH, Mat Zin AA, Ang KC, Ch’ng ES. Evaluating the polarization of tumor-associated macrophages into M1 and M2 phenotypes in human cancer tissue: technicalities and challenges in routine clinical practice. Front Oncol. 2019;9:1512.

    Article  Google Scholar 

  32. Ostuni R, Kratochvill F, Murray PJ, Natoli G. Macrophages and cancer: from mechanisms to therapeutic implications. Trends Immunol. 2015;36:229–39.

    Article  CAS  Google Scholar 

  33. Ding L, Saunders TL, Enikolopov G, Morrison SJ. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012;481:457–62.

    Article  CAS  Google Scholar 

  34. Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19:1264–72.

    Article  CAS  Google Scholar 

  35. Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74:5057–69.

    Article  CAS  Google Scholar 

  36. Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest. 2010;120:694–705.

    Article  CAS  Google Scholar 

  37. Szilvassy SJ, Meyerrose TE, Ragland PL, Grimes B. Differential homing and engraftment properties of hematopoietic progenitor cells from murine bone marrow, mobilized peripheral blood, and fetal liver. Blood. 2001;98:2108–15.

    Article  CAS  Google Scholar 

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Acknowledgements

The BRI animal facility staff and SG assisted with animal husbandry and tumour inoculations.

Funding

This work was supported by an OU Center for Biomedical Research grant (GJM) and OU Provost grant (TMP). Flow cytometry was performed in the OU Flow Cytometry Core, supported in part by a NSF-MRI (NSF-1919572) grant (LGV-D and GJM).

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Authors and Affiliations

  1. Department of Biological Sciences, Oakland University, Rochester, MI, USA

    Tyler M. Parsons, Marisa A. Brake, Crystal Poma, Sarah E. Hosch, Randal J. Westrick, Luis G. Villa-Diaz & Gerard J. Madlambayan

  2. Department of Radiation Oncology, Beaumont Research Institute, Royal Oak, MI, USA

    Tyler M. Parsons, Katie L. Buelow, Alaa Hanna & George D. Wilson

  3. Department of Bioengineering, Oakland University, Rochester, MI, USA

    Randal J. Westrick, Luis G. Villa-Diaz & Gerard J. Madlambayan

  4. Oakland University Center for Data Science and Big Data Analytics, Rochester, MI, USA

    Randal J. Westrick

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Contributions

GJM, GW, LGV-D and TMP conceived the project. TMP, KLB, AH and CP performed the experiments. TMP, KLB, MAB, SEH, RJW, LGV-D, GW and GJM provided resources and analysed data. TMP, GW, LGV-D and GJM were responsible for project management and compliance protocols. GJM, TMP, SEH, RJW and LGV-D wrote the paper. GW and KLB edited the manuscript.

Corresponding author

Correspondence to Gerard J. Madlambayan.

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Animal experiments were approved by the BRI IACUC.

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The authors declare no competing interests.

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Parsons, T.M., Buelow, K.L., Hanna, A. et al. Intratumoural haematopoietic stem and progenitor cell differentiation into M2 macrophages facilitates the regrowth of solid tumours after radiation therapy. Br J Cancer 126, 927–936 (2022). https://doi.org/10.1038/s41416-021-01652-y

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