Skip to main content

Advertisement

Log in

Stromal Markers of Breast Cancer Progression: A Review of Recent Findings

  • Breast Cancer Surgery (J Tchou, Section Editor)
  • Published:
Current Surgery Reports Aims and scope Submit manuscript

Abstract

Purpose of the Review

Breast cancer research has long focused on breast epithelium in cancer development. This traditional view is being challenged by more recent work which suggests that stromal components such as fibroblasts, immune cells, endothelial cells, and others may play a central role in cancer development. The purpose of this review is to investigate the elements of the breast stroma and their interaction with the epithelium in creating the necessary pro-tumorigenic environment.

Recent Findings

Several studies have revealed that breast cancer stroma differs significantly from normal breast stroma, with altered cellular and molecular factors that may serve as potential therapeutic targets in breast cancer treatment.

Summary

Studies of the complex interactions within the cancer ecosystem have revealed tumor-associated stromal changes that promote cell growth and invasiveness. They also reveal specific targets for novel strategies to inhibit inflammation, immunosuppression, angiogenesis, and distant invasion.

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

Access this article

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

References

Recently published papers of particular interest have been highlighted as: • Of importance

  1. Gudjonsson T, Magnusson MK. Stem cell biology and the cellular pathways of carcinogenesis. APMIS. 2005;113(11–12):922–9.

    Article  PubMed  Google Scholar 

  2. Gascard P, Tlsty TD. Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev. 2016;30(9):1002–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. • Kaushik S, Pickup MW, Weaver VM. From transformation to metastasis: deconstructing the extracellular matrix in breast cancer. Cancer Metastasis Rev. 2016;35(4):655–67. This review provides a helpful overview of how ECM mechanics and dynamics can contribute to breast cancer progression and metastasis.

  4. Bussard KM, Mutkus L, Stumpf K, Gomez-Manzano C, Marini FC. Tumor-associated stromal cells as key contributors to the tumor microenvironment. Breast Cancer Res. 2016;18(1):84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Conklin MW, Keely PJ. Why the stroma matters in breast cancer: insights into breast cancer patient outcomes through the examination of stromal biomarkers. Cell Adhes Migr. 2012;6(3):249–60.

    Article  Google Scholar 

  6. Rudnick JA, Kuperwasser C. Stromal biomarkers in breast cancer development and progression. Clin Exp Metastasis. 2012;29(7):663–72.

    Article  CAS  PubMed  Google Scholar 

  7. Wu Y, Sarkissyan M, Vadgama JV. Epithelial-mesenchymal transition and breast cancer. J Clin Med. 2016;5(2):13.

    Article  PubMed Central  CAS  Google Scholar 

  8. Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat Med. 2008;14(5):518–27.

    Article  CAS  PubMed  Google Scholar 

  9. Farmer P, Bonnefoi H, Anderle P, Cameron D, Wirapati P, Becette V, et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med. 2009;15(1):68–74.

    Article  CAS  PubMed  Google Scholar 

  10. Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 2007;67(21):10123–8.

    Article  CAS  PubMed  Google Scholar 

  11. Jotzu C, Alt E, Welte G, Li J, Hennessy BT, Devarajan E, et al. Adipose tissue-derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor-derived factors. Anal Cell Pathol (Amst). 2010;33(2):61–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Aboussekhra A. Role of cancer-associated fibroblasts in breast cancer development and prognosis. Int J Dev Biol. 2011;55(7–9):841–9. https://doi.org/10.1387/ijdb.113362aa.

    Article  PubMed  Google Scholar 

  13. Mori L, Bellini A, Stacey MA, Schmidt M, Mattoli S. Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow. Exp Cell Res. 2005;304(1):81–90. https://doi.org/10.1016/j.yexcr.2004.11.011.

    Article  CAS  PubMed  Google Scholar 

  14. Mercier I, Casimiro MC, Wang C, Rosenberg AL, Quong J, Minkeu A, et al. Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: implications for the response to hormonal therapy. Cancer Biol Ther. 2008;7(8):1212–25.

    Article  CAS  PubMed  Google Scholar 

  15. Garin-Chesa P, Old LJ, Rettig WJ. Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci USA. 1990;87(18):7235–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dawood S, Hu R, Homes MD, Collins LC, Schnitt SJ, Connolly J, et al. Defining breast cancer prognosis based on molecular phenotypes: results from a large cohort study. Breast Cancer Res Treat. 2011;126(1):185–92.

    Article  PubMed  Google Scholar 

  17. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121(3):335–48.

    Article  CAS  PubMed  Google Scholar 

  18. Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR18 pathway in cancer. Clin Cancer Res. 2010;16(11):2927–31.

    Article  CAS  PubMed  Google Scholar 

  19. DiMeo TA, Anderson K, Phadke P, Fan C, Feng C, Perou CM, et al. A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial-mesenchymal transition in basal-like breast cancer. Cancer Res. 2009;69(13):5364–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hazan RB, Qiao R, Keren R, Badano I, Suyama K. Cadherin switch in tumor progression. Ann N Y Acad Sci. 2004;1014:155–63.

    Article  CAS  PubMed  Google Scholar 

  21. Angelucci C, Maulucci G, Lama G, Proietti G, Colabianchi A, Papi M, et al. Epithelial-stromal interactions in human breast cancer: effects on adhesion, plasma membrane fluidity and migration speed and directness. PLoS ONE. 2012;7(12):e50804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lee J, Hong BS, Ryu HS, Lee HB, Lee M, Park IA, et al. Transition into inflammatory cancer-associated adipocytes in breast cancer microenvironment requires microRNA regulatory mechanism. PLoS ONE. 2017;12(3):e0174126.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Xiong Y, McDonald LT, Russell DL, Kelly RR, Wilson KR, Mehrotra M, et al. Hematopoietic stem cell-derived adipocytes and fibroblasts in the tumor microenvironment. World J Stem Cells. 2015;7(2):253–65.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Duong MN, Geneste A, Fallone F, Li X, Dumontet C, Muller C. The fat and the bad: mature adipocytes, key actors in tumor progression and resistance. Oncotarget. 2017;8(34):57622–41. https://doi.org/10.18632/oncotarget.18038.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011;17(11):1498–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG, et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell. 2012;150(1):165–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yadav A, Kumar B, Yu JG, Old M, Teknos TN, Kumar P. Tumor-associated endothelial cells promote tumor metastasis by chaperoning circulating tumor cells and protecting them from anoikis. PLoS ONE. 2015;10(10):e0141602.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10(9):942–9.

    Article  CAS  PubMed  Google Scholar 

  29. Medrek C, Pontén F, Jirström K, Leandersson K. The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer. 2012;12:306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Acerbi I, Cassereau L, Dean I, Shi Q, Au A, Park C, et al. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr Biol (Camb). 2015;7(10):1120–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  32. DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 2011;1(1):54–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bruno A, Ferlazzo G, Albini A, Noonan DM. A think tank of TINK/TANKs: tumor-infiltrating/tumor-associated natural killer cells in tumor progression and angiogenesis. J Natl Cancer Inst. 2014;106(8):dju200.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Man YG, Sang QX. The significance of focal myoepithelial cell layer disruptions in human breast tumor invasion: a paradigm shift from the “protease-centered” hypothesis. Exp Cell Res. 2004;301(2):103–18.

    Article  CAS  PubMed  Google Scholar 

  35. DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, et al. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell. 2009;16(2):91–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mantovani A, Sica A, Locati M. New vistas on macrophage differentiation and activation. Eur J Immunol. 2007;37(1):14–6.

    Article  CAS  PubMed  Google Scholar 

  37. Place AE, Jin Huh S, Polyak K. The microenvironment in breast cancer progression: biology and implications for treatment. Breast Cancer Res. 2011;13(6):227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Deryugina EI, Quigley JP. Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature. Matrix Biol. 2015;44–46:94–112.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. • Oskarsson T. Extracellular matrix components in breast cancer progression and metastasis. Breast. 2013;22(Suppl 2):S66–72. https://doi.org/10.1016/j.breast.2013.07.012. This work explores the roles of various ECM proteins that may play a role in breast cancer progression and matrix therapeutic resistance.

  40. Wang K, Wu F, Seo BR, Fischbach C, Chen W, Hsu L, et al. Breast cancer cells alter the dynamics of stromal fibronectin-collagen interactions. Matrix Biol. 2017;60–61:86–95. https://doi.org/10.1016/j.matbio.2016.08.001.

    Article  CAS  PubMed  Google Scholar 

  41. Carey SP, Martin KE, Reinhart-King CA. Three-dimensional collagen matrix induces a mechanosensitive invasive epithelial phenotype. Sci Rep. 2017;7:42088. https://doi.org/10.1038/srep42088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Xing F, Saidou J, Watabe K. Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front Biosci. 2010;15:166–79.

    Article  CAS  PubMed Central  Google Scholar 

  43. Cirri P, Chiarugi P. Cancer associated fibroblasts: the dark side of the coin. Am J Cancer Res. 2011;1(4):482–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Pyke C, Graem N, Ralfkiaer E, Rønne E, Høyer-Hansen G, Brünner N, et al. Receptor for urokinase is present in tumor-associated macrophages in ductal breast carcinoma. Cancer Res. 1993;53(8):1911–5.

    CAS  PubMed  Google Scholar 

  45. Stetler-Stevenson WG. Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Invest. 1999;103(9):1237–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu SC, Yang SF, Yeh KT, Yeh CM, Chiou HL, Lee CY, et al. Relationships between the level of matrix metalloproteinase-2 and tumor size of breast cancer. Clin Chim Acta. 2006;371(1–2):92–6.

    Article  CAS  PubMed  Google Scholar 

  47. Fang J, Xiao L, Joo KI, Liu Y, Zhang C, Liu S, et al. A potent immunotoxin targeting fibroblast activation protein for treatment of breast cancer in mice. Int J Cancer. 2016;138(4):1013–23.

    Article  CAS  PubMed  Google Scholar 

  48. Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 2010;330(6005):827–30. https://doi.org/10.1126/science.1195300.

    Article  CAS  PubMed  Google Scholar 

  49. Wang LC, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res. 2014;2(2):154–66. https://doi.org/10.1158/2326-6066.CIR-13-0027.

    Article  CAS  PubMed  Google Scholar 

  50. Brennen WN, Rosen DM, Wang H, Isaacs JT, Denmeade SR. Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug. J Natl Cancer Inst. 2012;104(17):1320–34. https://doi.org/10.1093/jnci/djs336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tran E, Chinnasamy D, Yu Z, Morgan RA, Lee CC, Restifo NP, et al. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J Exp Med. 2013;210(6):1125–35. https://doi.org/10.1084/jem.20130110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Dua I, Tan A. Immunotherapy for triple-negative breast cancer: a focus on immune checkpoint inhibitors. AJHO. 2017;13(4):20–7.

    Google Scholar 

  53. Vikas P, Borcherding N, Zhang W. The clinical promise of immunotherapy in triple-negative breast cancer. Cancer Manag Res. 2018;10:6823–33. https://doi.org/10.2147/CMAR.S185176.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Solinas C, Gombos A, Latifyan S, Piccart-Gebhart M, Kok M, Buisseret L. Targeting immune checkpoints in breast cancer: an update of early results. ESMO Open. 2017;2(5):e000255. https://doi.org/10.1136/esmoopen-2017-000255.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Yang L, Pang Y, Moses HL. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 2010;31(6):220–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ohmori T, Yang JL, Price JO, Arteaga CL. Blockade of tumor cell transforming growth factor-betas enhances cell cycle progression and sensitizes human breast carcinoma cells to cytotoxic chemotherapy. Exp Cell Res. 1998;245(2):350–9.

    Article  CAS  PubMed  Google Scholar 

  57. Bhola NE, Balko JM, Dugger TC, Kuba MG, Sánchez V, Sanders M, et al. TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest. 2013;123(3):1348–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sparano JA, Bernardo P, Stephenson P, Gradishar WJ, Ingle JN, Zucker S, et al. Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group trial E2196. J Clin Oncol. 2004;22(23):4683–90.

    Article  CAS  PubMed  Google Scholar 

  59. Devy L, Huang L, Naa L, Yanamandra N, Pieters H, Frans N, et al. Selective inhibition of matrix metalloproteinase-14 blocks tumor growth, invasion, and angiogenesis. Cancer Res. 2009;69(4):1517–26.

    Article  CAS  PubMed  Google Scholar 

  60. Radisky ES, Raeeszadeh-Sarmazdeh M, Radisky DC. Therapeutic potential of matrix metalloproteinase inhibition in breast cancer. J Cell Biochem. 2017;118(11):3531–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhou J, Chen Y, Lang JY, Lu JJ, Ding J. Salvicine inactivates beta 1 integrin and inhibits adhesion of MDA-MB-435 cells to fibronectin via reactive oxygen species signaling. Mol Cancer Res. 2008;6(2):194–204.

    Article  PubMed  CAS  Google Scholar 

  62. Bäuerle T, Komljenovic D, Merz M, Berger MR, Goodman SL, Semmler W. Cilengitide inhibits progression of experimental breast cancer bone metastases as imaged noninvasively using VCT, MRI and DCE-MRI in a longitudinal in vivo study. Int J Cancer. 2011;128(10):2453–62.

    Article  PubMed  CAS  Google Scholar 

  63. Lautenschlaeger T, Perry J, Peereboom D, Li B, Ibrahim A, Huebner A, et al. In vitro study of combined cilengitide and radiation treatment in breast cancer cell lines. Radiat Oncol. 2013;8:246.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Schmitt M, Harbeck N, Brünner N, Jänicke F, Meisner C, Mühlenweg B, et al. Cancer therapy trials employing level-of-evidence-1 disease forecast cancer biomarkers uPA and its inhibitor PAI-1. Expert Rev Mol Diagn. 2011;11(6):617–34.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Swati Kulkarni.

Ethics declarations

Conflict of interest

The authors have no potential conflicts of interest to declare.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical collection on Breast Cancer Surgery.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tata, N., Al-Zubeidy, B. & Kulkarni, S. Stromal Markers of Breast Cancer Progression: A Review of Recent Findings. Curr Surg Rep 7, 22 (2019). https://doi.org/10.1007/s40137-019-0242-0

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s40137-019-0242-0

Keywords

Navigation