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Human breast cancer biopsies induce eosinophil recruitment and enhance adjacent cancer cell proliferation

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Abstract

Chronic inflammation is known to facilitate cancer progression and metastasis. Less is known about the effect of acute inflammation within the tumor microenvironment, resulting from standard invasive procedures. Recent studies in mouse models have shown that the acute inflammatory response triggered by a biopsy in mammary cancer increases the frequency of distal metastases. Although tumor biopsies are part of the standard clinical practice in breast cancer diagnosis, no studies have reported their effect on inflammatory response. The objective of this study is to (1) determine whether core needle biopsies in breast cancer patients trigger an inflammatory response, (2) characterize the type of inflammatory response present, and (3) evaluate the potential effect of any acute inflammatory response on residual tumor cells. The biopsy wound site was identified in the primary tumor resection tissue samples from breast cancer patients. The inflammatory response in areas adjacent (i.e., immediately around previous biopsy site) and distant to the wound biopsy was investigated by histology and immunohistochemistry analysis. Proliferation of tumor cells was also assayed. We demonstrate that diagnostic core needle biopsies trigger a selective recruitment of inflammatory cells at the site of the biopsy, and they persist for extended periods of time. While macrophages were part of the inflammatory response, an unexpected accumulation of eosinophils at the edge of the biopsy wound was also identified. Importantly, we show that biopsy causes an increase in the proliferation rate of tumor cells located in the area adjacent to the biopsy wound. Diagnostic core needle biopsies in breast cancer patients do induce a unique acute inflammatory response within the tumor microenvironment and have an effect on the surrounding tumor cells. Therefore, biopsy-induced inflammation could have an impact on residual tumor cell progression and/or metastasis in human breast cancer. These findings may carry relevance in the clinical management of breast cancer.

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Abbreviations

H&E:

Hematoxylin and eosin

IHC:

Immunohistochemistry

CD (from CD45 or CD68):

Cluster of differentiation (cluster of differentiation 45 and cluster of differentiation 68)

References

  1. Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, et al (2015) SEER Cancer Statistics Review, 1975–2012, National Cancer Institute. Bethesda. http://www.seercancergov/csr/1975_2012/ based on November 2014 SEER data submission, posted to the SEER web site, April 2015

  2. Shiao SL, Ganesan AP, Rugo HS, Coussens LM (2011) Immune microenvironments in solid tumors: new targets for therapy. Genes Dev 25:2559–2572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Shalapour S, Karin M (2015) Immunity, inflammation, and cancer: an eternal fight between good and evil. J Clin Invest 125:3347–3355

    Article  PubMed  Google Scholar 

  4. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bhatelia K, Singh K, Singh R (2014) TLRs: linking inflammation and breast cancer. Cell Signal 26:2350–2357

    Article  CAS  PubMed  Google Scholar 

  6. Demaria S, Pikarsky E, Karin M, Coussens LM, Chen YC, El-Omar EM, Trinchieri G, Dubinett SM, Mao JT, Szabo E et al (2010) Cancer and inflammation: promise for biologic therapy. J Immunother 33:335–351

    Article  PubMed  PubMed Central  Google Scholar 

  7. Grivennikov SI, Karin M (2011) Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann Rheum Dis 70(Suppl 1):i104–i108

    Article  CAS  PubMed  Google Scholar 

  8. Multhoff G, Molls M, Radons J (2011) Chronic inflammation in cancer development. Front Immunol 2:98

    PubMed  Google Scholar 

  9. Coussens LM, Pollard JW (2011) Leukocytes in mammary development and cancer. Cold Spring Harb Perspect Biol 3:a003285

    Article  PubMed  PubMed Central  Google Scholar 

  10. Szalayova G, James TA, Rincon M (2015) A framework for the role of acute inflammation in tumor progression. Breast Cancer Res Treat 151:235–238

    Article  CAS  PubMed  Google Scholar 

  11. Arnold KM, Opdenaker LM, Flynn D, Sims-Mourtada J (2015) Wound healing and cancer stem cells: inflammation as a driver of treatment resistance in breast cancer. Cancer Growth Metastas 8:1–13

    Google Scholar 

  12. Ceelen W, Pattyn P, Mareel M (2014) Surgery, wound healing, and metastasis: recent insights and clinical implications. Crit Rev Oncol Hematol 89:16–26

    Article  PubMed  Google Scholar 

  13. Fitzal F, Sporn EP, Draxler W, Mittlbock M, Taucher S, Rudas M, Riedl O, Helbich TH, Jakesz R, Gnant M (2006) Preoperative core needle biopsy does not increase local recurrence rate in breast cancer patients. Breast Cancer Res Treat 97:9–15

    Article  PubMed  Google Scholar 

  14. Chen AM, Haffty BG, Lee CH (2002) Local recurrence of breast cancer after breast conservation therapy in patients examined by means of stereotactic core-needle biopsy. Radiology 225:707–712

    Article  PubMed  Google Scholar 

  15. King TA, Hayes DH, Cederbom GJ, Champaign JL, Smetherman DH, Farr GH, Bolton JS, Fuhrman GM (2001) Biopsy technique has no impact on local recurrence after breast-conserving therapy. Breast J 7:19–24

    Article  CAS  PubMed  Google Scholar 

  16. Hoorntje LE, Schipper ME, Kaya A, Verkooijen HM, Klinkenbijl JG, Borel Rinkes IH (2004) Tumour cell displacement after 14G breast biopsy. Eur J Surg Oncol 30:520–525

    Article  CAS  PubMed  Google Scholar 

  17. Thurfjell MG, Jansson T, Nordgren H, Bergh J, Lindgren A, Thurfjell E (2000) Local breast cancer recurrence caused by mammographically guided punctures. Acta Radiol 41:435–440

    Article  CAS  PubMed  Google Scholar 

  18. Chao C, Torosian MH, Boraas MC, Sigurdson ER, Hoffman JP, Eisenberg BL, Fowble B (2001) Local recurrence of breast cancer in the stereotactic core needle biopsy site: case reports and review of the literature. Breast J 7:124–127

    Article  CAS  PubMed  Google Scholar 

  19. Hobson J, Gummadidala P, Silverstrim B, Grier D, Bunn J, James T, Rincon M (2013) Acute inflammation induced by the biopsy of mouse mammary tumors promotes the development of metastasis. Breast Cancer Res Treat 139:391–401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pollard JW (2008) Macrophages define the invasive microenvironment in breast cancer. J Leukoc Biol 84:623–630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56:4625–4629

    CAS  PubMed  Google Scholar 

  22. Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605–612

    Article  CAS  PubMed  Google Scholar 

  23. Ham M, Moon A (2013) Inflammatory and microenvironmental factors involved in breast cancer progression. Arch Pharmacal Res 36:1419–1431

    Article  CAS  Google Scholar 

  24. Butowski N, Colman H, De Groot JF, Omuro AM, Nayak L, Wen PY, Cloughesy TF, Marimuthu A, Haidar S, Perry A et al (2015) Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study. Neuro-oncology 18(4):557–564

    Article  PubMed  Google Scholar 

  25. von Tresckow B, Morschhauser F, Ribrag V, Topp MS, Chien C, Seetharam S, Aquino R, Kotoulek S, de Boer CJ, Engert A (2015) An Open-Label, Multicenter, Phase I/II Study of JNJ-40346527, a CSF-1R inhibitor, in patients with relapsed or refractory hodgkin lymphoma. Clin Cancer Res 21:1843–1850

    Article  Google Scholar 

  26. Zhang YJ, Wei L, Li J, Zheng YQ, Li XR (2013) Status quo and development trend of breast biopsy technology. Gland Surg 2:15–24

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Azab B, Bhatt VR, Phookan J, Murukutla S, Kohn N, Terjanian T, Widmann WD (2012) Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients. Ann Surg Oncol 19:217–224

    Article  PubMed  Google Scholar 

  28. Nozawa H, Chiu C, Hanahan D (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci USA 103:12493–12498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bald T, Quast T, Landsberg J, Rogava M, Glodde N, Lopez-Ramos D, Kohlmeyer J, Riesenberg S, van den Boorn-Konijnenberg D, Homig-Holzel C et al (2014) Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507:109–113

    Article  CAS  PubMed  Google Scholar 

  30. Ravin KA, Loy M (2016) The eosinophil in infection. Clin Rev Allerg Immunol 50(2):214–227

  31. Stone KD, Prussin C, Metcalfe DD (2010) IgE, mast cells, basophils, and eosinophils. J Allerg Clin Immunol 125:S73–S80

    Article  Google Scholar 

  32. Spencer LA, Bonjour K, Melo RC, Weller PF (2014) Eosinophil secretion of granule-derived cytokines. Front Immunol 5:496

    Article  PubMed  PubMed Central  Google Scholar 

  33. Amini RM, Aaltonen K, Nevanlinna H, Carvalho R, Salonen L, Heikkila P, Blomqvist C (2007) Mast cells and eosinophils in invasive breast carcinoma. BMC Cancer 7:165

    Article  PubMed  PubMed Central  Google Scholar 

  34. Dethlefsen C, Hojfeldt G, Hojman P (2013) The role of intratumoral and systemic IL-6 in breast cancer. Breast Cancer Res Treat 138:657–664

    Article  CAS  PubMed  Google Scholar 

  35. Tawara K, Oxford JT, Jorcyk CL (2011) Clinical significance of interleukin (IL)-6 in cancer metastasis to bone: potential of anti-IL-6 therapies. Cancer Manag Res 3:177–189

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Conze D, Weiss L, Regen PS, Bhushan A, Weaver D, Johnson P, Rincon M (2001) Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells. Cancer Res 61:8851–8858

    CAS  PubMed  Google Scholar 

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Acknowledgments

We wish to thank the staff of the Pathology Facility at the University of Vermont Medical Center for their assistance in retrieving archives tissue samples and providing the unstaining tissue slide section. We also thank Phani Gummadidala for technical support. This work was funded by the Virginia Wellington Cabot Foundation (M.R), Lake Champlain Cancer Research Organization (LLCRO) (T.J.) and NIH P30 RR031158 (M.R.).

Authors’ contribution

GS and AO contributed to the performance of experiments (e.g., immunostaining, identification of the biopsy area, manual quantification of number of cells in each area, etc.), the design of the study, acquisition of data, analysis and interpretation of the results, and involved in the drafting of the manuscript. BS and JW contributed to the performance of experiments (e.g., immunostaining, identification of the biopsy area, manual quantification of number of cells in each area, etc.), the design of the study, acquisition of data, analysis, and interpretation of the results. JB performed all final statistical analysis in the manuscript, and as involved in the drafting of the manuscript. AA (pathologist), he identified the eligible patients, verified the identification of the biopsy wound or identified the wound, verified the results from the immunostaining, participated in the interpretation of the data, and involved in the drafting of the manuscript. TJ contributed to the design of the study, evaluated the results, and involved in the drafting of the manuscript. MR contributed the design of the study, wrote the IRB protocol, participated in the identification of the biopsy area, evaluated the immunostaining results, participated in the analysis and interpretation of the results, and did most of the writing of the manuscript.

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    Authors and Affiliations

    1. Department of Surgery, University of Vermont, Burlington, VT, 05405, USA

      Gabriela Szalayova, Aleksandra Ogrodnik, Brianna Spencer, Jacqueline Wade & Ted James

    2. Department of Surgery, Danbury Hospital, Danbury, CT, 06810, USA

      Gabriela Szalayova & Aleksandra Ogrodnik

    3. Division of Immunobiology, Department of Medicine, University of Vermont, Given C331, 89 Beaumont Avenue, Burlington, VT, 05405, USA

      Gabriela Szalayova, Aleksandra Ogrodnik, Brianna Spencer, Jacqueline Wade & Mercedes Rincon

    4. Department of Mathematics and Statistics, University of Vermont, Burlington, VT, 05405, USA

      Janice Bunn

    5. Department of Pathology, University of Vermont, Burlington, VT, 05405, USA

      Abiy Ambaye

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    1. Gabriela Szalayova
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    Correspondence to Ted James or Mercedes Rincon.

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    Gabriela Szalayova and Aleksandra Ogrodnik are co-first authors and contributed equally to this work.

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    Szalayova, G., Ogrodnik, A., Spencer, B. et al. Human breast cancer biopsies induce eosinophil recruitment and enhance adjacent cancer cell proliferation. Breast Cancer Res Treat 157, 461–474 (2016). https://doi.org/10.1007/s10549-016-3839-3

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