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Cancer-associated fibroblasts as key regulators of the breast cancer tumor microenvironment

  • J. M. HouthuijzenEmail author
  • J. Jonkers
Article

Abstract

Tumor cells exist in close proximity with non-malignant cells. Extensive and multilayered crosstalk between tumor cells and stromal cells tailors the tumor microenvironment (TME) to support survival, growth, and metastasis. Fibroblasts are one of the largest populations of non-malignant host cells that can be found within the TME of breast, pancreatic, and prostate tumors. Substantial scientific evidence has shown that these cancer-associated fibroblasts (CAFs) are not only associated with tumors by proximity but are also actively recruited to developing tumors where they can influence other cells of the TME as well as influencing tumor cell survival and metastasis. This review discusses the impact of CAFs on breast cancer biology and highlights their heterogeneity, origin and their role in tumor progression, ECM remodeling, therapy resistance, metastasis, and the challenges ahead of targeting CAFs to improve therapy response.

Keywords

Breast cancer Fibroblasts Microenvironment ECM Metastasis Therapy resistance 

References

  1. 1.
    Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674.  https://doi.org/10.1016/j.cell.2011.02.013.CrossRefGoogle Scholar
  2. 2.
    Bainbridge, P. (2013). Wound healing and the role of fibroblasts. Journal of Wound Care, 22(8), 407–408, 410-412.  https://doi.org/10.12968/jowc.2013.22.8.407.CrossRefPubMedGoogle Scholar
  3. 3.
    Kalluri. (2016). The biology and function of fibroblasts in cancer. Nature, 16(9), 582–598.Google Scholar
  4. 4.
    Unsworth, A., Anderson, R., & Britt, K. (2014). Stromal fibroblasts and the immune microenvironment: partners in mammary gland biology and pathology? Journal of Mammary Gland Biology and Neoplasia, 19(2), 169–182.  https://doi.org/10.1007/s10911-014-9326-8.CrossRefPubMedGoogle Scholar
  5. 5.
    Visvader, J. E., & Stingl, J. (2014). Mammary stem cells and the differentiation hierarchy: current status and perspectives. Genes & Development, 28(11), 1143–1158.  https://doi.org/10.1101/gad.242511.114.CrossRefGoogle Scholar
  6. 6.
    Polyak, K., & Kalluri, R. (2010). The role of the microenvironment in mammary gland development and cancer. Cold Spring Harbor Perspectives in Biology, 2(11), a003244.  https://doi.org/10.1101/cshperspect.a003244.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Fleming, J. M., Long, E. L., Ginsburg, E., Gerscovich, D., Meltzer, P. S., & Vonderhaar, B. K. (2008). Interlobular and intralobular mammary stroma: genotype may not reflect phenotype. BMC Cell Biology, 9, 46.  https://doi.org/10.1186/1471-2121-9-46.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Morsing, M., Klitgaard, M. C., Jafari, A., Villadsen, R., Kassem, M., Petersen, O. W., et al. (2016). Evidence of two distinct functionally specialized fibroblast lineages in breast stroma. Breast Cancer Research, 18(1), 108.  https://doi.org/10.1186/s13058-016-0769-2.CrossRefPubMedGoogle Scholar
  9. 9.
    Inman, J. L., Robertson, C., Mott, J. D., & Bissell, M. J. (2015). Mammary gland development: cell fate specification, stem cells and the microenvironment. Development, 142(6), 1028–1042.  https://doi.org/10.1242/dev.087643.CrossRefPubMedGoogle Scholar
  10. 10.
    Bussard, K. M., Mutkus, L., Stumpf, K., Gomez-Manzano, C., & Marini, F. C. (2016). Tumor-associated stromal cells as key contributors to the tumor microenvironment. Breast Cancer Research, 18(1), 84.  https://doi.org/10.1186/s13058-016-0740-2.CrossRefPubMedGoogle Scholar
  11. 11.
    Osterreicher, C. H., Penz-Osterreicher, M., Grivennikov, S. I., Guma, M., Koltsova, E. K., Datz, C., et al. (2011). Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. Proceedings of the National Academy of Sciences of the United States of America, 108(1), 308–313.  https://doi.org/10.1073/pnas.1017547108.CrossRefPubMedGoogle Scholar
  12. 12.
    Lv, F. J., Tuan, R. S., Cheung, K. M., & Leung, V. Y. (2014). Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells, 32(6), 1408–1419.  https://doi.org/10.1002/stem.1681.CrossRefPubMedGoogle Scholar
  13. 13.
    Meng, M. B., Zaorsky, N. G., Deng, L., Wang, H. H., Chao, J., Zhao, L. J., et al. (2015). Pericytes: a double-edged sword in cancer therapy. Future Oncology, 11(1), 169–179.  https://doi.org/10.2217/fon.14.123.CrossRefPubMedGoogle Scholar
  14. 14.
    Su, S., Chen, J., Yao, H., Liu, J., Yu, S., Lao, L., et al. (2018). CD10(+)GPR77(+) cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell, 172(4), 841–856.e816.  https://doi.org/10.1016/j.cell.2018.01.009.CrossRefPubMedGoogle Scholar
  15. 15.
    Brechbuhl, H. M., Finlay-Schultz, J., Yamamoto, T. M., Gillen, A. E., Cittelly, D. M., Tan, A. C., et al. (2017). Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen. Clinical Cancer Research, 23(7), 1710–1721.  https://doi.org/10.1158/1078-0432.ccr-15-2851.CrossRefPubMedGoogle Scholar
  16. 16.
    Tchou, J., Kossenkov, A. V., Chang, L., Satija, C., Herlyn, M., Showe, L. C., et al. (2012). Human breast cancer associated fibroblasts exhibit subtype specific gene expression profiles. BMC Medical Genomics, 5, 39–39.  https://doi.org/10.1186/1755-8794-5-39.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Busch, S., Andersson, D., Bom, E., Walsh, C., Stahlberg, A., & Landberg, G. (2017). Cellular organization and molecular differentiation model of breast cancer-associated fibroblasts. Molecular Cancer, 16(1), 73.  https://doi.org/10.1186/s12943-017-0642-7.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Jotzu, C., Alt, E., Welte, G., Li, J., Hennessy, B. T., Devarajan, E., et al. (2011). Adipose tissue derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor derived factors. Cellular Oncology (Dordrecht), 34(1), 55–67.  https://doi.org/10.1007/s13402-011-0012-1.CrossRefGoogle Scholar
  19. 19.
    Cho, J. A., Park, H., Lim, E. H., & Lee, K. W. (2012). Exosomes from breast cancer cells can convert adipose tissue-derived mesenchymal stem cells into myofibroblast-like cells. International Journal of Oncology, 40(1), 130–138.  https://doi.org/10.3892/ijo.2011.1193.CrossRefPubMedGoogle Scholar
  20. 20.
    Weber, C. E., Kothari, A. N., Wai, P. Y., Li, N. Y., Driver, J., Zapf, M. A., et al. (2015). Osteopontin mediates an MZF1-TGF-beta1-dependent transformation of mesenchymal stem cells into cancer-associated fibroblasts in breast cancer. Oncogene, 34(37), 4821–4833.  https://doi.org/10.1038/onc.2014.410.CrossRefPubMedGoogle Scholar
  21. 21.
    Avgustinova, A., Iravani, M., Robertson, D., Fearns, A., Gao, Q., Klingbeil, P., et al. (2016). Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness. Nature Communications, 7, 10305.  https://doi.org/10.1038/ncomms10305.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Chen, J. Y., Li, C. F., Kuo, C. C., Tsai, K. K., Hou, M. F., & Hung, W. C. (2014). Cancer/stroma interplay via cyclooxygenase-2 and indoleamine 2,3-dioxygenase promotes breast cancer progression. Breast Cancer Research, 16(4), 410.  https://doi.org/10.1186/s13058-014-0410-1.CrossRefPubMedGoogle Scholar
  23. 23.
    Mishra, P. J., Mishra, P. J., Humeniuk, R., Medina, D. J., Alexe, G., Mesirov, J. P., et al. (2008). Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Research, 68(11), 4331–4339.  https://doi.org/10.1158/0008-5472.can-08-0943.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kidd, S., Spaeth, E., Watson, K., Burks, J., Lu, H., Klopp, A., et al. (2012). Origins of the tumor microenvironment: quantitative assessment of adipose-derived and bone marrow-derived stroma. PLoS One, 7(2), e30563.  https://doi.org/10.1371/journal.pone.0030563.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Dirat, B., Bochet, L., Dabek, M., Daviaud, D., Dauvillier, S., Majed, B., et al. (2011). Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Research, 71(7), 2455–2465.  https://doi.org/10.1158/0008-5472.can-10-3323.CrossRefPubMedGoogle Scholar
  26. 26.
    Bochet, L., Lehuede, C., Dauvillier, S., Wang, Y. Y., Dirat, B., Laurent, V., et al. (2013). Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Research, 73(18), 5657–5668.  https://doi.org/10.1158/0008-5472.can-13-0530.CrossRefPubMedGoogle Scholar
  27. 27.
    Kojima, Y., Acar, A., Eaton, E. N., Mellody, K. T., Scheel, C., Ben-Porath, I., et al. (2010). Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proceedings of the National Academy of Sciences of the United States of America, 107(46), 20009–20014.  https://doi.org/10.1073/pnas.1013805107.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Nair, N., Calle, A. S., Zahra, M. H., Prieto-Vila, M., Oo, A. K. K., Hurley, L., et al. (2017). A cancer stem cell model as the point of origin of cancer-associated fibroblasts in tumor microenvironment. Scientific Reports, 7(1), 6838.  https://doi.org/10.1038/s41598-017-07144-5.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    LeBleu, V. S., Taduri, G., O'Connell, J., Teng, Y., Cooke, V. G., Woda, C., et al. (2013). Origin and function of myofibroblasts in kidney fibrosis. Nature Medicine, 19(8), 1047–1053.  https://doi.org/10.1038/nm.3218.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Zarzynska, J. M. (2014). Two faces of TGF-beta1 in breast cancer. Mediators of Inflammation, 2014, 141747.  https://doi.org/10.1155/2014/141747.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kakarla, S., Song, X.-T., & Gottschalk, S. (2012). Cancer-associated fibroblasts as targets for immunotherapy. Immunotherapy, 4(11), 1129–1138.  https://doi.org/10.2217/imt.12.112.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Shangguan, L., Ti, X., Krause, U., Hai, B., Zhao, Y., Yang, Z., et al. (2012). Inhibition of TGF-beta/Smad signaling by BAMBI blocks differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and abolishes their protumor effects. Stem Cells, 30(12), 2810–2819.  https://doi.org/10.1002/stem.1251.CrossRefPubMedGoogle Scholar
  33. 33.
    Gao, M. Q., Kim, B. G., Kang, S., Choi, Y. P., Yoon, J. H., & Cho, N. H. (2013). Human breast cancer-associated fibroblasts enhance cancer cell proliferation through increased TGF-alpha cleavage by ADAM17. Cancer Letters, 336(1), 240–246.  https://doi.org/10.1016/j.canlet.2013.05.011.CrossRefPubMedGoogle Scholar
  34. 34.
    Guido, C., Whitaker-Menezes, D., Capparelli, C., Balliet, R., Lin, Z., Pestell, R. G., et al. (2012). Metabolic reprogramming of cancer-associated fibroblasts by TGF-beta drives tumor growth: connecting TGF-beta signaling with "Warburg-like" cancer metabolism and L-lactate production. Cell Cycle, 11(16), 3019–3035.  https://doi.org/10.4161/cc.21384.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Martinez-Outschoorn, U. E., Prisco, M., Ertel, A., Tsirigos, A., Lin, Z., Pavlides, S., et al. (2011). Ketones and lactate increase cancer cell "stemness," driving recurrence, metastasis and poor clinical outcome in breast cancer: achieving personalized medicine via Metabolo-Genomics. Cell Cycle, 10(8), 1271–1286.  https://doi.org/10.4161/cc.10.8.15330.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Zhang, D., Wang, Y., Shi, Z., Liu, J., Sun, P., Hou, X., et al. (2015). Metabolic reprogramming of cancer-associated fibroblasts by IDH3alpha downregulation. Cell Reports, 10(8), 1335–1348.  https://doi.org/10.1016/j.celrep.2015.02.006.CrossRefPubMedGoogle Scholar
  37. 37.
    Yan, W., Wu, X., Zhou, W., Fong, M. Y., Cao, M., Liu, J., et al. (2018). Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells. Nature Cell Biology, 20(5), 597–609.  https://doi.org/10.1038/s41556-018-0083-6.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Donnarumma, E., Fiore, D., Nappa, M., Roscigno, G., Adamo, A., Iaboni, M., et al. (2017). Cancer-associated fibroblasts release exosomal microRNAs that dictate an aggressive phenotype in breast cancer. Oncotarget, 8(12), 19592–19608.  https://doi.org/10.18632/oncotarget.14752.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001). Stem cells, cancer, and cancer stem cells. Nature, 414(6859), 105–111.  https://doi.org/10.1038/35102167.CrossRefGoogle Scholar
  40. 40.
    Peiris-Pages, M., Sotgia, F., & Lisanti, M. P. (2015). Chemotherapy induces the cancer-associated fibroblast phenotype, activating paracrine Hedgehog-GLI signalling in breast cancer cells. Oncotarget, 6(13), 10728–10745.  https://doi.org/10.18632/oncotarget.3828.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Zhao, X. L., Lin, Y., Jiang, J., Tang, Z., Yang, S., Lu, L., et al. (2017). High-mobility group box 1 released by autophagic cancer-associated fibroblasts maintains the stemness of luminal breast cancer cells. The Journal of Pathology, 243(3), 376–389.  https://doi.org/10.1002/path.4958.CrossRefPubMedGoogle Scholar
  42. 42.
    Tsuyada, A., Chow, A., Wu, J., Somlo, G., Chu, P., Loera, S., et al. (2012). CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer Research, 72(11), 2768–2779.  https://doi.org/10.1158/0008-5472.can-11-3567.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Cazet, A. S., Hui, M. N., Elsworth, B. L., Wu, S. Z., Roden, D., Chan, C. L., et al. (2018). Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer. Nature Communications, 9(1), 2897.  https://doi.org/10.1038/s41467-018-05220-6.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Boesch, M., Onder, L., Cheng, H.-W., Novkovic, M., Mörbe, U., Sopper, S., et al. (2018). Interleukin 7-expressing fibroblasts promote breast cancer growth through sustenance of tumor cell stemness. OncoImmunology, 7(4), e1414129.  https://doi.org/10.1080/2162402X.2017.1414129.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Sansone, P., Savini, C., Kurelac, I., Chang, Q., Amato, L. B., Strillacci, A., et al. (2017). Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 114(43), E9066–e9075.  https://doi.org/10.1073/pnas.1704862114.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    De Wever, O., Van Bockstal, M., Mareel, M., Hendrix, A., & Bracke, M. (2014). Carcinoma-associated fibroblasts provide operational flexibility in metastasis. Seminars in Cancer Biology, 25, 33–46.  https://doi.org/10.1016/j.semcancer.2013.12.009.CrossRefPubMedGoogle Scholar
  47. 47.
    Dittmer, A., & Dittmer, J. (2018). Long-term exposure to carcinoma-associated fibroblasts makes breast cancer cells addictive to integrin beta1. Oncotarget, 9(31), 22079–22094.  https://doi.org/10.18632/oncotarget.25183.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Orimo, A., Gupta, P. B., Sgroi, D. C., Arenzana-Seisdedos, F., Delaunay, T., Naeem, R., et al. (2005). Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell, 121(3), 335–348.  https://doi.org/10.1016/j.cell.2005.02.034.CrossRefPubMedGoogle Scholar
  49. 49.
    Al-Rakan, M. A., Colak, D., Hendrayani, S. F., Al-Bakheet, A., Al-Mohanna, F. H., Kaya, N., et al. (2013). Breast stromal fibroblasts from histologically normal surgical margins are pro-carcinogenic. The Journal of Pathology, 231(4), 457–465.  https://doi.org/10.1002/path.4256.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Chen, L. C., Tu, S. H., Huang, C. S., Chen, C. S., Ho, C. T., Lin, H. W., et al. (2012). Human breast cancer cell metastasis is attenuated by lysyl oxidase inhibitors through down-regulation of focal adhesion kinase and the paxillin-signaling pathway. Breast Cancer Research and Treatment, 134(3), 989–1004.  https://doi.org/10.1007/s10549-012-1986-8.CrossRefPubMedGoogle Scholar
  51. 51.
    Tyan, S. W., Hsu, C. H., Peng, K. L., Chen, C. C., Kuo, W. H., Lee, E. Y., et al. (2012). Breast cancer cells induce stromal fibroblasts to secrete ADAMTS1 for cancer invasion through an epigenetic change. PLoS One, 7(4), e35128.  https://doi.org/10.1371/journal.pone.0035128.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Pinto, M. P., Dye, W. W., Jacobsen, B. M., & Horwitz, K. B. (2014). Malignant stroma increases luminal breast cancer cell proliferation and angiogenesis through platelet-derived growth factor signaling. BMC Cancer, 14, 735.  https://doi.org/10.1186/1471-2407-14-735.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Adams, E. F., Newton, C. J., Braunsberg, H., Shaikh, N., Ghilchik, M., & James, V. H. (1988). Effects of human breast fibroblasts on growth and 17 beta-estradiol dehydrogenase activity of MCF-7 cells in culture. Breast Cancer Research and Treatment, 11(2), 165–172.CrossRefGoogle Scholar
  54. 54.
    Cheng, G., Fan, X., Hao, M., Wang, J., Zhou, X., & Sun, X. (2016). Higher levels of TIMP-1 expression are associated with a poor prognosis in triple-negative breast cancer. Molecular Cancer, 15(1), 30.  https://doi.org/10.1186/s12943-016-0515-5.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Rasmussen, A. A., & Cullen, K. J. (1998). Paracrine/autocrine regulation of breast cancer by the insulin-like growth factors. Breast Cancer Research and Treatment, 47(3), 219–233.CrossRefGoogle Scholar
  56. 56.
    Bernard, S., Myers, M., Fang, W. B., Zinda, B., Smart, C., Lambert, D., et al. (2018). CXCL1 derived from mammary fibroblasts promotes progression of mammary lesions to invasive carcinoma through CXCR2 dependent mechanisms. Journal of Mammary Gland Biology and Neoplasia.  https://doi.org/10.1007/s10911-018-9407-1.CrossRefGoogle Scholar
  57. 57.
    Jin, K., Pandey, N. B., & Popel, A. S. (2017). Crosstalk between stromal components and tumor cells of TNBC via secreted factors enhances tumor growth and metastasis. Oncotarget, 8(36), 60210–60222.  https://doi.org/10.18632/oncotarget.19417.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Pickup, M. W., Mouw, J. K., & Weaver, V. M. (2014). The extracellular matrix modulates the hallmarks of cancer. EMBO Reports, 15(12), 1243–1253.  https://doi.org/10.15252/embr.201439246.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Bergamaschi, A., Tagliabue, E., Sørlie, T., Naume, B., Triulzi, T., Orlandi, R., et al. (2008). Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome. The Journal of Pathology, 214(3), 357–367.  https://doi.org/10.1002/path.2278.CrossRefPubMedGoogle Scholar
  60. 60.
    Robertson, C. (2016). The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking. Experimental Cell Research, 343(1), 73–81.  https://doi.org/10.1016/j.yexcr.2015.11.009.CrossRefPubMedGoogle Scholar
  61. 61.
    Boraschi-Diaz, I., Wang, J., Mort, J. S., & Komarova, S. V. (2017). Collagen type I as a ligand for receptor-mediated signaling. [Review]. Frontiers in Physics, 5(12).  https://doi.org/10.3389/fphy.2017.00012.
  62. 62.
    Heino, J. (2014). Cellular signaling by collagen-binding integrins. Advances in Experimental Medicine and Biology, 819, 143–155.  https://doi.org/10.1007/978-94-017-9153-3_10.CrossRefPubMedGoogle Scholar
  63. 63.
    Bhogal, R. K., Stoica, C. M., McGaha, T. L., & Bona, C. A. (2005). Molecular aspects of regulation of collagen gene expression in fibrosis. Journal of Clinical Immunology, 25(6), 592–603.  https://doi.org/10.1007/s10875-005-7827-3.CrossRefPubMedGoogle Scholar
  64. 64.
    Bates, A. L., Pickup, M. W., Hallett, M. A., Dozier, E. A., Thomas, S., & Fingleton, B. (2015). Stromal matrix metalloproteinase 2 regulates collagen expression and promotes the outgrowth of experimental metastases. The Journal of Pathology, 235(5), 773–783.  https://doi.org/10.1002/path.4493.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Kim, S. H., Lee, H. Y., Jung, S. P., Kim, S., Lee, J. E., Nam, S. J., et al. (2014). Role of secreted type I collagen derived from stromal cells in two breast cancer cell lines. Oncology Letters, 8(2), 507–512.  https://doi.org/10.3892/ol.2014.2199.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Liu, J., Shen, J. X., Wu, H. T., Li, X. L., Wen, X. F., Du, C. W., et al. (2018). Collagen 1A1 (COL1A1) promotes metastasis of breast cancer and is a potential therapeutic target. Discovery Medicine, 25(139), 211–223.PubMedGoogle Scholar
  67. 67.
    Krishnamachary, B., Stasinopoulos, I., Kakkad, S., Penet, M. F., Jacob, D., Wildes, F., et al. (2017). Breast cancer cell cyclooxygenase-2 expression alters extracellular matrix structure and function and numbers of cancer associated fibroblasts. Oncotarget, 8(11), 17981–17994.  https://doi.org/10.18632/oncotarget.14912.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Badaoui, M., Mimsy-Julienne, C., Saby, C., Van Gulick, L., Peretti, M., Jeannesson, P., et al. (2018). Collagen type 1 promotes survival of human breast cancer cells by overexpressing Kv10.1 potassium and Orai1 calcium channels through DDR1-dependent pathway. Oncotarget, 9(37), 24653–24671.  https://doi.org/10.18632/oncotarget.19065.CrossRefPubMedGoogle Scholar
  69. 69.
    Barcus, C. E., O'Leary, K. A., Brockman, J. L., Rugowski, D. E., Liu, Y., Garcia, N., et al. (2017). Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells. Breast Cancer Research, 19(1), 9.  https://doi.org/10.1186/s13058-017-0801-1.CrossRefPubMedGoogle Scholar
  70. 70.
    Conklin, M. W., Eickhoff, J. C., Riching, K. M., Pehlke, C. A., Eliceiri, K. W., Provenzano, P. P., et al. (2011). Aligned collagen is a prognostic signature for survival in human breast carcinoma. The American Journal of Pathology, 178(3), 1221–1232.  https://doi.org/10.1016/j.ajpath.2010.11.076.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Morris, B. A., Burkel, B., Ponik, S. M., Fan, J., Condeelis, J. S., Aguirre-Ghiso, J. A., et al. (2016). Collagen matrix density drives the metabolic shift in breast cancer cells. EBioMedicine, 13, 146–156.  https://doi.org/10.1016/j.ebiom.2016.10.012.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Xiong, G., Deng, L., Zhu, J., Rychahou, P. G., & Xu, R. (2014). Prolyl-4-hydroxylase alpha subunit 2 promotes breast cancer progression and metastasis by regulating collagen deposition. BMC Cancer, 14, 1.  https://doi.org/10.1186/1471-2407-14-1.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Karousou, E., D'Angelo, M. L., Kouvidi, K., Vigetti, D., Viola, M., Nikitovic, D., et al. (2014). Collagen VI and hyaluronan: the common role in breast cancer. BioMed Research International, 2014, 606458.  https://doi.org/10.1155/2014/606458.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Castro-Sanchez, L., Soto-Guzman, A., Navarro-Tito, N., Martinez-Orozco, R., & Salazar, E. P. (2010). Native type IV collagen induces cell migration through a CD9 and DDR1-dependent pathway in MDA-MB-231 breast cancer cells. European Journal of Cell Biology, 89(11), 843–852.  https://doi.org/10.1016/j.ejcb.2010.07.004.CrossRefPubMedGoogle Scholar
  75. 75.
    Mazouni, C., Arun, B., Andre, F., Ayers, M., Krishnamurthy, S., Wang, B., et al. (2008). Collagen IV levels are elevated in the serum of patients with primary breast cancer compared to healthy volunteers. British Journal of Cancer, 99(1), 68–71.  https://doi.org/10.1038/sj.bjc.6604443.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Brodsky, A. S., Xiong, J., Yang, D., Schorl, C., Fenton, M. A., Graves, T. A., et al. (2016). Identification of stromal ColXalpha1 and tumor-infiltrating lymphocytes as putative predictive markers of neoadjuvant therapy in estrogen receptor-positive/HER2-positive breast cancer. BMC Cancer, 16, 274.  https://doi.org/10.1186/s12885-016-2302-5.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Wang, J. P., & Hielscher, A. (2017). Fibronectin: how its aberrant expression in tumors may improve therapeutic targeting. Journal of Cancer, 8(4), 674–682.  https://doi.org/10.7150/jca.16901.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Insua-Rodriguez, J., & Oskarsson, T. (2016). The extracellular matrix in breast cancer. Advanced Drug Delivery Reviews, 97, 41–55.  https://doi.org/10.1016/j.addr.2015.12.017.CrossRefPubMedGoogle Scholar
  79. 79.
    Multhaupt, H. A., Leitinger, B., Gullberg, D., & Couchman, J. R. (2016). Extracellular matrix component signaling in cancer. Advanced Drug Delivery Reviews, 97, 28–40.  https://doi.org/10.1016/j.addr.2015.10.013.CrossRefPubMedGoogle Scholar
  80. 80.
    Rybak, J. N., Roesli, C., Kaspar, M., Villa, A., & Neri, D. (2007). The extra-domain A of fibronectin is a vascular marker of solid tumors and metastases. Cancer Research, 67(22), 10948–10957.  https://doi.org/10.1158/0008-5472.can-07-1436.CrossRefPubMedGoogle Scholar
  81. 81.
    Ignotz, R. A., & Massague, J. (1986). Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. The Journal of Biological Chemistry, 261(9), 4337–4345.PubMedGoogle Scholar
  82. 82.
    Mulsow, J. J., Watson, R. W., Fitzpatrick, J. M., & O'Connell, P. R. (2005). Transforming growth factor-beta promotes pro-fibrotic behavior by serosal fibroblasts via PKC and ERK1/2 mitogen activated protein kinase cell signaling. Annals of Surgery, 242(6), 880–887 discussion 887-889.CrossRefGoogle Scholar
  83. 83.
    Czaja, M. J., Weiner, F. R., Eghbali, M., Giambrone, M. A., Eghbali, M., & Zern, M. A. (1987). Differential effects of gamma-interferon on collagen and fibronectin gene expression. The Journal of Biological Chemistry, 262(27), 13348–13351.PubMedGoogle Scholar
  84. 84.
    Erdogan, B., Ao, M., White, L. M., Means, A. L., Brewer, B. M., Yang, L., et al. (2017). Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. The Journal of Cell Biology, 216(11), 3799–3816.  https://doi.org/10.1083/jcb.201704053.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Yao, E. S., Zhang, H., Chen, Y. Y., Lee, B., Chew, K., Moore, D., et al. (2007). Increased beta1 integrin is associated with decreased survival in invasive breast cancer. Cancer Research, 67(2), 659–664.  https://doi.org/10.1158/0008-5472.can-06-2768.CrossRefPubMedGoogle Scholar
  86. 86.
    Li, C. L., Yang, D., Cao, X., Wang, F., Hong, D. Y., Wang, J., et al. (2017). Fibronectin induces epithelial-mesenchymal transition in human breast cancer MCF-7 cells via activation of calpain. Oncology Letters, 13(5), 3889–3895.  https://doi.org/10.3892/ol.2017.5896.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Balanis, N., Wendt, M. K., Schiemann, B. J., Wang, Z., Schiemann, W. P., & Carlin, C. R. (2013). Epithelial to mesenchymal transition promotes breast cancer progression via a fibronectin-dependent STAT3 signaling pathway. The Journal of Biological Chemistry, 288(25), 17954–17967.  https://doi.org/10.1074/jbc.M113.475277.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Hong, H., Zhou, T., Fang, S., Jia, M., Xu, Z., Dai, Z., et al. (2014). Pigment epithelium-derived factor (PEDF) inhibits breast cancer metastasis by down-regulating fibronectin. Breast Cancer Research and Treatment, 148(1), 61–72.  https://doi.org/10.1007/s10549-014-3154-9.CrossRefPubMedGoogle Scholar
  89. 89.
    He, Z. H., Lei, Z., Zhen, Y., Gong, W., Huang, B., Yuan, Y., et al. (2014). Adeno-associated virus-mediated expression of recombinant CBD-HepII polypeptide of human fibronectin inhibits metastasis of breast cancer. Breast Cancer Research and Treatment, 143(1), 33–45.  https://doi.org/10.1007/s10549-013-2783-8.CrossRefPubMedGoogle Scholar
  90. 90.
    Park, C. C., Zhang, H., Pallavicini, M., Gray, J. W., Baehner, F., Park, C. J., et al. (2006). Beta1 integrin inhibitory antibody induces apoptosis of breast cancer cells, inhibits growth, and distinguishes malignant from normal phenotype in three dimensional cultures and in vivo. Cancer Research, 66(3), 1526–1535.  https://doi.org/10.1158/0008-5472.can-05-3071.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Sampayo, R. G., Toscani, A. M., Rubashkin, M. G., Thi, K., Masullo, L. A., Violi, I. L., et al. (2018). Fibronectin rescues estrogen receptor alpha from lysosomal degradation in breast cancer cells. The Journal of Cell Biology, 217(8), 2777–2798.  https://doi.org/10.1083/jcb.201703037.CrossRefPubMedGoogle Scholar
  92. 92.
    Tucker, R. P., & Chiquet-Ehrismann, R. (2009). The regulation of tenascin expression by tissue microenvironments. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1793(5), 888–892.  https://doi.org/10.1016/j.bbamcr.2008.12.012.CrossRefGoogle Scholar
  93. 93.
    Hancox, R. A., Allen, M. D., Holliday, D. L., Edwards, D. R., Pennington, C. J., Guttery, D. S., et al. (2009). Tumour-associated tenascin-C isoforms promote breast cancer cell invasion and growth by matrix metalloproteinase-dependent and independent mechanisms. Breast Cancer Research, 11(2), R24.  https://doi.org/10.1186/bcr2251.CrossRefPubMedGoogle Scholar
  94. 94.
    Yang, Z., Ni, W., Cui, C., Fang, L., & Xuan, Y. (2017). Tenascin C is a prognostic determinant and potential cancer-associated fibroblasts marker for breast ductal carcinoma. Experimental and Molecular Pathology, 102(2), 262–267.  https://doi.org/10.1016/j.yexmp.2017.02.012.CrossRefPubMedGoogle Scholar
  95. 95.
    Adams, M., Jones, J. L., Walker, R. A., Pringle, J. H., & Bell, S. C. (2002). Changes in tenascin-C isoform expression in invasive and preinvasive breast disease. Cancer Research, 62(11), 3289–3297.PubMedGoogle Scholar
  96. 96.
    Oskarsson, T., Acharyya, S., Zhang, X. H. F., Vanharanta, S., Tavazoie, S. F., Morris, P. G., et al. (2011). Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. [Article]. Nature Medicine, 17, 867.  https://doi.org/10.1038/nm.2379.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Degen, M., Brellier, F., Schenk, S., Driscoll, R., Zaman, K., Stupp, R., et al. (2008). Tenascin-W, a new marker of cancer stroma, is elevated in sera of colon and breast cancer patients. International Journal of Cancer, 122(11), 2454–2461.  https://doi.org/10.1002/ijc.23417.CrossRefPubMedGoogle Scholar
  98. 98.
    Degen, M., Brellier, F., Kain, R., Ruiz, C., Terracciano, L., Orend, G., et al. (2007). Tenascin-W is a novel marker for activated tumor stroma in low-grade human breast cancer and influences cell behavior. Cancer Research, 67(19), 9169–9179.  https://doi.org/10.1158/0008-5472.can-07-0666.CrossRefPubMedGoogle Scholar
  99. 99.
    Brellier, F., Martina, E., Degen, M., Heuze-Vourc'h, N., Petit, A., Kryza, T., et al. (2012). Tenascin-W is a better cancer biomarker than tenascin-C for most human solid tumors. BMC Clinical Pathology, 12, 14.  https://doi.org/10.1186/1472-6890-12-14.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Chiovaro, F., Martina, E., Bottos, A., Scherberich, A., Hynes, N. E., & Chiquet-Ehrismann, R. (2015). Transcriptional regulation of tenascin-W by TGF-beta signaling in the bone metastatic niche of breast cancer cells. International Journal of Cancer, 137(8), 1842–1854.  https://doi.org/10.1002/ijc.29565.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Baker, A. M., Bird, D., Lang, G., Cox, T. R., & Erler, J. T. (2013). Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK. Oncogene, 32(14), 1863–1868.  https://doi.org/10.1038/onc.2012.202.CrossRefPubMedGoogle Scholar
  102. 102.
    Provenzano, P. P., Cuevas, C., Chang, A. E., Goel, V. K., Von Hoff, D. D., & Hingorani, S. R. (2012). Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell, 21(3), 418–429.  https://doi.org/10.1016/j.ccr.2012.01.007.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Provenzano, P. P., Eliceiri, K. W., Campbell, J. M., Inman, D. R., White, J. G., & Keely, P. J. (2006). Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Medicine, 4(1), 38.  https://doi.org/10.1186/1741-7015-4-38.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Levental, K. R., Yu, H., Kass, L., Lakins, J. N., Egeblad, M., Erler, J. T., et al. (2009). Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell, 139(5), 891–906.  https://doi.org/10.1016/j.cell.2009.10.027.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Wells, R. G. (2008). The role of matrix stiffness in regulating cell behavior. Hepatology, 47(4), 1394–1400.  https://doi.org/10.1002/hep.22193.CrossRefPubMedGoogle Scholar
  106. 106.
    Mouw, J. K., Yui, Y., Damiano, L., Bainer, R. O., Lakins, J. N., Acerbi, I., et al. (2014). Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nature Medicine, 20(4), 360–367.  https://doi.org/10.1038/nm.3497.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Pickup, M. W., Laklai, H., Acerbi, I., Owens, P., Gorska, A. E., Chytil, A., et al. (2013). Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-beta-deficient mouse mammary carcinomas. Cancer Research, 73(17), 5336–5346.  https://doi.org/10.1158/0008-5472.can-13-0012.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Erler, J. T., Bennewith, K. L., Nicolau, M., Dornhofer, N., Kong, C., Le, Q. T., et al. (2006). Lysyl oxidase is essential for hypoxia-induced metastasis. Nature, 440(7088), 1222–1226.  https://doi.org/10.1038/nature04695.CrossRefPubMedGoogle Scholar
  109. 109.
    Tang, X., Hou, Y., Yang, G., Wang, X., Tang, S., Du, Y. E., et al. (2016). Stromal miR-200s contribute to breast cancer cell invasion through CAF activation and ECM remodeling. Cell Death and Differentiation, 23(1), 132–145.  https://doi.org/10.1038/cdd.2015.78.CrossRefPubMedGoogle Scholar
  110. 110.
    El-Mohri, H., Wu, Y., Mohanty, S., & Ghosh, G. (2017). Impact of matrix stiffness on fibroblast function. Materials Science & Engineering. C, Materials for Biological Applications, 74, 146–151.  https://doi.org/10.1016/j.msec.2017.02.001.CrossRefGoogle Scholar
  111. 111.
    Asano, S., Ito, S., Takahashi, K., Furuya, K., Kondo, M., Sokabe, M., et al. (2017). Matrix stiffness regulates migration of human lung fibroblasts. Physiological Reports, 5(9).  https://doi.org/10.14814/phy2.13281.CrossRefGoogle Scholar
  112. 112.
    Basset, P., Bellocq, J. P., Wolf, C., Stoll, I., Hutin, P., Limacher, J. M., et al. (1990). A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature, 348(6303), 699–704.  https://doi.org/10.1038/348699a0.CrossRefPubMedGoogle Scholar
  113. 113.
    Têtu, B., Brisson, J., Wang, C. S., Lapointe, H., Beaudry, G., Blanchette, C., et al. (2006). The influence of MMP-14, TIMP-2 and MMP-2 expression on breast cancer prognosis. [journal article]. Breast Cancer Research, 8(3), R28.  https://doi.org/10.1186/bcr1503.CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Radisky, E. S., & Radisky, D. C. (2015). Matrix metalloproteinases as breast cancer drivers and therapeutic targets. Frontiers in Bioscience (Landmark edition), 20, 1144–1163.CrossRefGoogle Scholar
  115. 115.
    Stuelten, C. H., DaCosta Byfield, S., Arany, P. R., Karpova, T. S., Stetler-Stevenson, W. G., & Roberts, A. B. (2005). Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-alpha and TGF-beta. Journal of Cell Science, 118(Pt 10), 2143–2153.  https://doi.org/10.1242/jcs.02334.CrossRefPubMedGoogle Scholar
  116. 116.
    Saad, S., Gottlieb, D. J., Bradstock, K. F., Overall, C. M., & Bendall, L. J. (2002). Cancer cell-associated fibronectin induces release of matrix metalloproteinase-2 from normal fibroblasts. Cancer Research, 62, 283–289.PubMedGoogle Scholar
  117. 117.
    Lochter, A., Galosy, S., Muschler, J., Freedman, N., Werb, Z., & Bissell, M. J. (1997). Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. The Journal of Cell Biology, 139(7), 1861–1872.CrossRefGoogle Scholar
  118. 118.
    Xu, H., Li, M., Zhou, Y., Wang, F., Li, X., Wang, L., et al. (2016). S100A4 participates in epithelial-mesenchymal transition in breast cancer via targeting MMP2. Tumour Biology, 37(3), 2925–2932.  https://doi.org/10.1007/s13277-015-3709-3.CrossRefPubMedGoogle Scholar
  119. 119.
    Liss, M., Sreedhar, N., Keshgegian, A., Sauter, G., Chernick, M. R., Prendergast, G. C., et al. (2009). Tissue inhibitor of metalloproteinase-4 is elevated in early-stage breast cancers with accelerated progression and poor clinical course. The American Journal of Pathology, 175(3), 940–946.  https://doi.org/10.2353/ajpath.2009.081094.CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Gong, Y., Scott, E., Lu, R., Xu, Y., Oh, W. K., & Yu, Q. (2013). TIMP-1 promotes accumulation of cancer associated fibroblasts and cancer progression. PLoS One, 8(10), e77366.  https://doi.org/10.1371/journal.pone.0077366.CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Song, T., Dou, C., Jia, Y., Tu, K., & Zheng, X. (2015). TIMP-1 activated carcinoma-associated fibroblasts inhibit tumor apoptosis by activating SDF1/CXCR4 signaling in hepatocellular carcinoma. Oncotarget, 6(14), 12061–12079.  https://doi.org/10.18632/oncotarget.3616.CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Dang, T. T., Prechtl, A. M., & Pearson, G. W. (2011). Breast cancer subtype-specific interactions with the microenvironment dictate mechanisms of invasion. Cancer Research, 71(21), 6857–6866.  https://doi.org/10.1158/0008-5472.can-11-1818.CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Hu, M., Yao, J., Carroll, D. K., Weremowicz, S., Chen, H., Carrasco, D., et al. (2008). Regulation of in situ to invasive breast carcinoma transition. Cancer Cell, 13(5), 394–406.  https://doi.org/10.1016/j.ccr.2008.03.007.CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Osuala, K. O., Sameni, M., Shah, S., Aggarwal, N., Simonait, M. L., Franco, O. E., et al. (2015). Il-6 signaling between ductal carcinoma in situ cells and carcinoma-associated fibroblasts mediates tumor cell growth and migration. BMC Cancer, 15, 584.  https://doi.org/10.1186/s12885-015-1576-3.CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Yu, Y., Xiao, C. H., Tan, L. D., Wang, Q. S., Li, X. Q., & Feng, Y. M. (2014). Cancer-associated fibroblasts induce epithelial-mesenchymal transition of breast cancer cells through paracrine TGF-beta signalling. British Journal of Cancer, 110(3), 724–732.  https://doi.org/10.1038/bjc.2013.768.CrossRefPubMedGoogle Scholar
  126. 126.
    Takai, K., Le, A., Weaver, V. M., & Werb, Z. (2016). Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer. Oncotarget, 7(50), 82889–82901.  https://doi.org/10.18632/oncotarget.12658.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Bellomo, C., Caja, L., & Moustakas, A. (2016). Transforming growth factor β as regulator of cancer stemness and metastasis. British Journal of Cancer, 115(7), 761–769.  https://doi.org/10.1038/bjc.2016.255.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Dvorak, K. M., Pettee, K. M., Rubinic-Minotti, K., Su, R., Nestor-Kalinoski, A., & Eisenmann, K. M. (2018). Carcinoma associated fibroblasts (CAFs) promote breast cancer motility by suppressing mammalian Diaphanous-related formin-2 (mDia2). PLoS One, 13(3), e0195278.  https://doi.org/10.1371/journal.pone.0195278.CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Ahirwar, D. K., Nasser, M. W., Ouseph, M. M., Elbaz, M., Cuitino, M. C., Kladney, R. D., et al. (2018). Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation. Oncogene.  https://doi.org/10.1038/s41388-018-0263-7.CrossRefGoogle Scholar
  130. 130.
    O'Connell, J. T., Sugimoto, H., Cooke, V. G., MacDonald, B. A., Mehta, A. I., LeBleu, V. S., et al. (2011). VEGF-A and tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization. Proceedings of the National Academy of Sciences of the United States of America, 108(38), 16002–16007.  https://doi.org/10.1073/pnas.1109493108.CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Studebaker, A. W., Storci, G., Werbeck, J. L., Sansone, P., Sasser, A. K., Tavolari, S., et al. (2008). Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner. Cancer Research, 68(21), 9087–9095.  https://doi.org/10.1158/0008-5472.can-08-0400.CrossRefPubMedGoogle Scholar
  132. 132.
    Xu, K., Tian, X., Oh, S. Y., Movassaghi, M., Naber, S. P., Kuperwasser, C., et al. (2016). The fibroblast Tiam1-osteopontin pathway modulates breast cancer invasion and metastasis. Breast Cancer Research, 18(1), 14.  https://doi.org/10.1186/s13058-016-0674-8.CrossRefPubMedGoogle Scholar
  133. 133.
    Lowry, M. C., Gallagher, W. M., & O'Driscoll, L. (2015). The role of exosomes in breast cancer. Clinical Chemistry, 61(12), 1457–1465.  https://doi.org/10.1373/clinchem.2015.240028.CrossRefPubMedGoogle Scholar
  134. 134.
    Chen, Y., Zeng, C., Zhan, Y., Wang, H., Jiang, X., & Li, W. (2017). Aberrant low expression of p85α in stromal fibroblasts promotes breast cancer cell metastasis through exosome-mediated paracrine Wnt10b. [original article]. Oncogene, 36, 4692.  https://doi.org/10.1038/onc.2017.100.CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Luga, V., Zhang, L., Viloria-Petit, A. M., Ogunjimi, A. A., Inanlou, M. R., Chiu, E., et al. (2012). Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell, 151(7), 1542–1556.  https://doi.org/10.1016/j.cell.2012.11.024.CrossRefPubMedGoogle Scholar
  136. 136.
    Shimoda, M., Principe, S., Jackson, H. W., Luga, V., Fang, H., Molyneux, S. D., et al. (2014). Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. Nature Cell Biology, 16(9), 889–901.  https://doi.org/10.1038/ncb3021.CrossRefPubMedGoogle Scholar
  137. 137.
    Nabet, B. Y., Qiu, Y., Shabason, J. E., Wu, T. J., Yoon, T., Kim, B. C., et al. (2017). Exosome RNA unshielding couples stromal activation to pattern recognition receptor signaling in cancer. Cell, 170(2), 352–366.e313.  https://doi.org/10.1016/j.cell.2017.06.031.CrossRefPubMedGoogle Scholar
  138. 138.
    Choi, Y. P., Lee, J. H., Gao, M. Q., Kim, B. G., Kang, S., Kim, S. H., et al. (2014). Cancer-associated fibroblast promote transmigration through endothelial brain cells in three-dimensional in vitro models. International Journal of Cancer, 135(9), 2024–2033.  https://doi.org/10.1002/ijc.28848.CrossRefPubMedGoogle Scholar
  139. 139.
    Gaggioli, C., Hooper, S., Hidalgo-Carcedo, C., Grosse, R., Marshall, J. F., Harrington, K., et al. (2007). Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nature Cell Biology, 9(12), 1392–1400.  https://doi.org/10.1038/ncb1658.CrossRefPubMedGoogle Scholar
  140. 140.
    Yang, N., Mosher, R., Seo, S., Beebe, D., & Friedl, A. (2011). Syndecan-1 in breast cancer stroma fibroblasts regulates extracellular matrix fiber organization and carcinoma cell motility. The American Journal of Pathology, 178(1), 325–335.  https://doi.org/10.1016/j.ajpath.2010.11.039.CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Chute, C., Yang, X., Meyer, K., Yang, N., O'Neil, K., Kasza, I., et al. (2018). Syndecan-1 induction in lung microenvironment supports the establishment of breast tumor metastases. Breast Cancer Research, 20(1), 66.  https://doi.org/10.1186/s13058-018-0995-x.CrossRefPubMedGoogle Scholar
  142. 142.
    Corsa, C. A., Brenot, A., Grither, W. R., Van Hove, S., Loza, A. J., Zhang, K., et al. (2016). The action of Discoidin domain receptor 2 in basal tumor cells and stromal cancer-associated fibroblasts is critical for breast cancer metastasis. Cell Reports, 15(11), 2510–2523.  https://doi.org/10.1016/j.celrep.2016.05.033.CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Farmaki, E., Chatzistamou, I., Kaza, V., & Kiaris, H. (2016). A CCL8 gradient drives breast cancer cell dissemination. Oncogene, 35(49), 6309–6318.  https://doi.org/10.1038/onc.2016.161.CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Wang, K., Wu, F., Seo, B. R., Fischbach, C., Chen, W., Hsu, L., et al. (2017). Breast cancer cells alter the dynamics of stromal fibronectin-collagen interactions. Matrix Biology, 60-61, 86–95.  https://doi.org/10.1016/j.matbio.2016.08.001.CrossRefPubMedGoogle Scholar
  145. 145.
    Dvorak, H. F. (1986). Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. The New England Journal of Medicine, 315(26), 1650–1659.  https://doi.org/10.1056/nejm198612253152606.CrossRefPubMedGoogle Scholar
  146. 146.
    Hanahan, D., & Coussens, L. M. (2012). Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell, 21(3), 309–322.  https://doi.org/10.1016/j.ccr.2012.02.022.CrossRefPubMedGoogle Scholar
  147. 147.
    Neuzillet, C., Tijeras-Raballand, A., Cohen, R., Cros, J., Faivre, S., Raymond, E., et al. (2015). Targeting the TGFbeta pathway for cancer therapy. Pharmacology & Therapeutics, 147, 22–31.  https://doi.org/10.1016/j.pharmthera.2014.11.001.CrossRefGoogle Scholar
  148. 148.
    Ziani, L., Chouaib, S., & Thiery, J. (2018). Alteration of the antitumor immune response by cancer-associated fibroblasts. Frontiers in Immunology, 9, 414.  https://doi.org/10.3389/fimmu.2018.00414.CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Kinoshita, T., Ishii, G., Hiraoka, N., Hirayama, S., Yamauchi, C., Aokage, K., et al. (2013). Forkhead box P3 regulatory T cells coexisting with cancer associated fibroblasts are correlated with a poor outcome in lung adenocarcinoma. Cancer Science, 104(4), 409–415.  https://doi.org/10.1111/cas.12099.CrossRefPubMedGoogle Scholar
  150. 150.
    Li, T., Yi, S., Liu, W., Jia, C., Wang, G., Hua, X., et al. (2013). Colorectal carcinoma-derived fibroblasts modulate natural killer cell phenotype and antitumor cytotoxicity. Medical Oncology, 30(3), 663.  https://doi.org/10.1007/s12032-013-0663-z.CrossRefPubMedGoogle Scholar
  151. 151.
    Shen, C. C., Kang, Y. H., Zhao, M., He, Y., Cui, D. D., Fu, Y. Y., et al. (2014). WNT16B from ovarian fibroblasts induces differentiation of regulatory T cells through beta-catenin signal in dendritic cells. International Journal of Molecular Sciences, 15(7), 12928–12939.  https://doi.org/10.3390/ijms150712928.CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Takahashi, H., Sakakura, K., Kudo, T., Toyoda, M., Kaira, K., Oyama, T., et al. (2017). Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages. Oncotarget, 8(5), 8633–8647.  https://doi.org/10.18632/oncotarget.14374.CrossRefGoogle Scholar
  153. 153.
    Fu, Z., Zuo, Y., Li, D., Xu, W., Li, D., Chen, H., et al. (2013). The crosstalk: tumor-infiltrating lymphocytes rich in regulatory T cells suppressed cancer-associated fibroblasts. Acta Oncologica, 52(8), 1760–1770.  https://doi.org/10.3109/0284186X.2012.760847.CrossRefPubMedGoogle Scholar
  154. 154.
    Allaoui, R., Bergenfelz, C., Mohlin, S., Hagerling, C., Salari, K., Werb, Z., et al. (2016). Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. Nature Communications, 7, 13050.  https://doi.org/10.1038/ncomms13050.CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Silzle, T., Kreutz, M., Dobler, M. A., Brockhoff, G., Knuechel, R., & Kunz-Schughart, L. A. (2003). Tumor-associated fibroblasts recruit blood monocytes into tumor tissue. European Journal of Immunology, 33(5), 1311–1320.  https://doi.org/10.1002/eji.200323057.CrossRefPubMedGoogle Scholar
  156. 156.
    Qian, B. Z., Li, J., Zhang, H., Kitamura, T., Zhang, J., Campion, L. R., et al. (2011). CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature, 475(7355), 222–225.  https://doi.org/10.1038/nature10138.CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Liao, D., Luo, Y., Markowitz, D., Xiang, R., & Reisfeld, R. A. (2009). Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS One, 4(11), e7965.  https://doi.org/10.1371/journal.pone.0007965.CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Li, A., Chen, P., Leng, Y., & Kang, J. (2018). Histone deacetylase 6 regulates the immunosuppressive properties of cancer-associated fibroblasts in breast cancer through the STAT3-COX2-dependent pathway. Oncogene.  https://doi.org/10.1038/s41388-018-0379-9.CrossRefGoogle Scholar
  159. 159.
    Cohen, N., Shani, O., Raz, Y., Sharon, Y., Hoffman, D., Abramovitz, L., et al. (2017). Fibroblasts drive an immunosuppressive and growth-promoting microenvironment in breast cancer via secretion of Chitinase 3-like 1. Oncogene, 36(31), 4457–4468.  https://doi.org/10.1038/onc.2017.65.CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Costa, A., Kieffer, Y., Scholer-Dahirel, A., Pelon, F., Bourachot, B., Cardon, M., et al. (2018). Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell, 33(3), 463–479.e410.  https://doi.org/10.1016/j.ccell.2018.01.011.CrossRefPubMedGoogle Scholar
  161. 161.
    Panagopoulos, V., Leach, D. A., Zinonos, I., Ponomarev, V., Licari, G., Liapis, V., et al. (2017). Inflammatory peroxidases promote breast cancer progression in mice via regulation of the tumour microenvironment. International Journal of Oncology, 50(4), 1191–1200.  https://doi.org/10.3892/ijo.2017.3883.CrossRefPubMedGoogle Scholar
  162. 162.
    Lu, P., Weaver, V. M., & Werb, Z. (2012). The extracellular matrix: a dynamic niche in cancer progression. The Journal of Cell Biology, 196(4), 395–406.  https://doi.org/10.1083/jcb.201102147.CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Bae, Y. K., Kim, A., Kim, M. K., Choi, J. E., Kang, S. H., & Lee, S. J. (2013). Fibronectin expression in carcinoma cells correlates with tumor aggressiveness and poor clinical outcome in patients with invasive breast cancer. Human Pathology, 44(10), 2028–2037.  https://doi.org/10.1016/j.humpath.2013.03.006.CrossRefPubMedGoogle Scholar
  164. 164.
    Fernandez-Garcia, B., Eiro, N., Marin, L., Gonzalez-Reyes, S., Gonzalez, L. O., Lamelas, M. L., et al. (2014). Expression and prognostic significance of fibronectin and matrix metalloproteases in breast cancer metastasis. Histopathology, 64(4), 512–522.  https://doi.org/10.1111/his.12300.CrossRefPubMedGoogle Scholar
  165. 165.
    Acerbi, I., Cassereau, L., Dean, I., Shi, Q., Au, A., Park, C., et al. (2015). Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integrative Biology: Quantitative Biosciences from Nano to Macro, 7(10), 1120–1134.  https://doi.org/10.1039/c5ib00040h.CrossRefGoogle Scholar
  166. 166.
    Jachetti, E., Caputo, S., Mazzoleni, S., Brambillasca, C. S., Parigi, S. M., Grioni, M., et al. (2015). Tenascin-C protects cancer stem-like cells from immune surveillance by arresting T-cell activation. Cancer Research, 75(10), 2095–2108.  https://doi.org/10.1158/0008-5472.can-14-2346.CrossRefPubMedGoogle Scholar
  167. 167.
    Huang, J. Y., Cheng, Y. J., Lin, Y. P., Lin, H. C., Su, C. C., Juliano, R., et al. (2010). Extracellular matrix of glioblastoma inhibits polarization and transmigration of T cells: the role of tenascin-C in immune suppression. Journal of Immunology, 185(3), 1450–1459.  https://doi.org/10.4049/jimmunol.0901352.CrossRefGoogle Scholar
  168. 168.
    Tsunoda, T., Inada, H., Kalembeyi, I., Imanaka-Yoshida, K., Sakakibara, M., Okada, R., et al. (2003). Involvement of large tenascin-C splice variants in breast cancer progression. The American Journal of Pathology, 162(6), 1857–1867.  https://doi.org/10.1016/s0002-9440(10)64320-9.CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Kelsh, R., You, R., Horzempa, C., Zheng, M., & McKeown-Longo, P. J. (2014). Regulation of the innate immune response by fibronectin: synergism between the III-1 and EDA domains. PLoS One, 9(7), e102974.  https://doi.org/10.1371/journal.pone.0102974.CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    Rossnagl, S., Altrock, E., Sens, C., Kraft, S., Rau, K., Milsom, M. D., et al. (2016). EDA-fibronectin originating from osteoblasts inhibits the immune response against cancer. PLoS Biology, 14(9), e1002562.  https://doi.org/10.1371/journal.pbio.1002562.CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Farmer, P., Bonnefoi, H., Anderle, P., Cameron, D., Wirapati, P., Becette, V., et al. (2009). A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nature Medicine, 15(1), 68–74.  https://doi.org/10.1038/nm.1908.CrossRefPubMedGoogle Scholar
  172. 172.
    Jia, D., Liu, Z., Deng, N., Tan, T. Z., Huang, R. Y., Taylor-Harding, B., et al. (2016). A COL11A1-correlated pan-cancer gene signature of activated fibroblasts for the prioritization of therapeutic targets. Cancer Letters, 382(2), 203–214.  https://doi.org/10.1016/j.canlet.2016.09.001.CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Cukierman, E., & Bassi, D. E. (2012). The mesenchymal tumor microenvironment. Cell Adhesion & Migration, 6(3), 285–296.  https://doi.org/10.4161/cam.20210.CrossRefGoogle Scholar
  174. 174.
    Shain, K. H., & Dalton, W. S. (2001). Cell adhesion is a key determinant in de novo multidrug resistance (MDR): new targets for the prevention of acquired MDR. Molecular Cancer Therapeutics, 1(1), 69–78.PubMedGoogle Scholar
  175. 175.
    Giussani, M., Merlino, G., Cappelletti, V., Tagliabue, E., & Daidone, M. G. (2015). Tumor-extracellular matrix interactions: identification of tools associated with breast cancer progression. Seminars in Cancer Biology, 35, 3–10.  https://doi.org/10.1016/j.semcancer.2015.09.012.CrossRefPubMedGoogle Scholar
  176. 176.
    Soon, P. S., Kim, E., Pon, C. K., Gill, A. J., Moore, K., Spillane, A. J., et al. (2013). Breast cancer-associated fibroblasts induce epithelial-to-mesenchymal transition in breast cancer cells. Endocrine-Related Cancer, 20(1), 1–12.  https://doi.org/10.1530/erc-12-0227.CrossRefPubMedGoogle Scholar
  177. 177.
    Gao, M. Q., Kim, B. G., Kang, S., Choi, Y. P., Park, H., Kang, K. S., et al. (2010). Stromal fibroblasts from the interface zone of human breast carcinomas induce an epithelial-mesenchymal transition-like state in breast cancer cells in vitro. Journal of Cell Science, 123(Pt 20), 3507–3514.  https://doi.org/10.1242/jcs.072900.CrossRefPubMedGoogle Scholar
  178. 178.
    Yuan, J., Liu, M., Yang, L., Tu, G., Zhu, Q., Chen, M., et al. (2015). Acquisition of epithelial-mesenchymal transition phenotype in the tamoxifen-resistant breast cancer cell: a new role for G protein-coupled estrogen receptor in mediating tamoxifen resistance through cancer-associated fibroblast-derived fibronectin and beta1-integrin signaling pathway in tumor cells. Breast Cancer Research, 17, 69.  https://doi.org/10.1186/s13058-015-0579-y.CrossRefPubMedGoogle Scholar
  179. 179.
    Amornsupak, K., Insawang, T., Thuwajit, P., O-Charoenrat, P., Eccles, S. A., & Thuwajit, C. (2014). Cancer-associated fibroblasts induce high mobility group box 1 and contribute to resistance to doxorubicin in breast cancer cells. BMC Cancer, 14, 955.  https://doi.org/10.1186/1471-2407-14-955.CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Huang, J., Ni, J., Liu, K., Yu, Y., Xie, M., Kang, R., et al. (2012). HMGB1 promotes drug resistance in osteosarcoma. Cancer Research, 72(1), 230–238.  https://doi.org/10.1158/0008-5472.can-11-2001.CrossRefPubMedGoogle Scholar
  181. 181.
    Boelens, M. C., Wu, T. J., Nabet, B. Y., Xu, B., Qiu, Y., Yoon, T., et al. (2014). Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell, 159(3), 499–513.  https://doi.org/10.1016/j.cell.2014.09.051.CrossRefPubMedPubMedCentralGoogle Scholar
  182. 182.
    Cui, Q., Wang, B., Li, K., Sun, H., Hai, T., Zhang, Y., et al. (2018). Upregulating MMP-1 in carcinoma-associated fibroblasts reduces the efficacy of Taxotere on breast cancer synergized by Collagen IV. Oncology Letters, 16(3), 3537–3544.  https://doi.org/10.3892/ol.2018.9092.CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Landry, B. D., Leete, T., Richards, R., Cruz-Gordillo, P., Schwartz, H. R., Honeywell, M. E., et al. (2018). Tumor-stroma interactions differentially alter drug sensitivity based on the origin of stromal cells. Molecular Systems Biology, 14(8), e8322–10.15252/msb.20188322.CrossRefGoogle Scholar
  184. 184.
    Marusyk, A., Tabassum, D. P., Janiszewska, M., Place, A. E., Trinh, A., Rozhok, A. I., et al. (2016). Spatial proximity to fibroblasts impacts molecular features and therapeutic sensitivity of breast cancer cells influencing clinical outcomes. Cancer Research, 76(22), 6495–6506.  https://doi.org/10.1158/0008-5472.can-16-1457.CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Senthebane, D. A., Rowe, A., Thomford, N. E., Shipanga, H., Munro, D., Al Mazeedi, M. A. M., et al. (2017). The role of tumor microenvironment in chemoresistance: to survive, keep your enemies closer. International Journal of Molecular Sciences, 18(7), 1586.  https://doi.org/10.3390/ijms18071586.CrossRefPubMedCentralGoogle Scholar
  186. 186.
    Lin, C. H., Pelissier, F. A., Zhang, H., Lakins, J., Weaver, V. M., Park, C., et al. (2015). Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors. Molecular Biology of the Cell, 26(22), 3946–3953.  https://doi.org/10.1091/mbc.E15-07-0456.CrossRefPubMedPubMedCentralGoogle Scholar
  187. 187.
    Ozdemir, B. C., Pentcheva-Hoang, T., Carstens, J. L., Zheng, X., Wu, C. C., Simpson, T. R., et al. (2015). Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell, 28(6), 831–833.  https://doi.org/10.1016/j.ccell.2015.11.002.CrossRefPubMedGoogle Scholar
  188. 188.
    Duyverman, A. M. M. J., Steller, E. J. A., Fukumura, D., Jain, R. K., & Duda, D. G. (2012). Studying primary tumor-associated fibroblast involvement in cancer metastasis in mice. Nature Protocols, 7(4), 756–762.  https://doi.org/10.1038/nprot.2012.031.CrossRefPubMedPubMedCentralGoogle Scholar
  189. 189.
    Rhim, A. D., Oberstein, P. E., Thomas, D. H., Mirek, E. T., Palermo, C. F., Sastra, S. A., et al. (2014). Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell, 25(6), 735–747.  https://doi.org/10.1016/j.ccr.2014.04.021.CrossRefPubMedPubMedCentralGoogle Scholar
  190. 190.
    Yauch, R. L., Gould, S. E., Scales, S. J., Tang, T., Tian, H., Ahn, C. P., et al. (2008). A paracrine requirement for hedgehog signalling in cancer. Nature, 455(7211), 406–410.  https://doi.org/10.1038/nature07275.CrossRefPubMedGoogle Scholar
  191. 191.
    Olive, K. P., Jacobetz, M. A., Davidson, C. J., Gopinathan, A., McIntyre, D., Honess, D., et al. (2009). Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science, 324(5933), 1457–1461.  https://doi.org/10.1126/science.1171362.CrossRefPubMedPubMedCentralGoogle Scholar
  192. 192.
    Ko, A. H., LoConte, N., Tempero, M. A., Walker, E. J., Kate Kelley, R., Lewis, S., et al. (2016). A phase I study of FOLFIRINOX plus IPI-926, a hedgehog pathway inhibitor, for advanced pancreatic adenocarcinoma. Pancreas, 45(3), 370–375.  https://doi.org/10.1097/mpa.0000000000000458.CrossRefPubMedPubMedCentralGoogle Scholar
  193. 193.
    Fearon, D. T. (2014). The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunology Research, 2(3), 187–193.  https://doi.org/10.1158/2326-6066.cir-14-0002.CrossRefPubMedGoogle Scholar
  194. 194.
    Kraman, M., Bambrough, P. J., Arnold, J. N., Roberts, E. W., Magiera, L., Jones, J. O., et al. (2010). Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science, 330(6005), 827–830.  https://doi.org/10.1126/science.1195300.CrossRefPubMedGoogle Scholar
  195. 195.
    Duperret, E. K., Trautz, A., Ammons, D., Perales-Puchalt, A., Wise, M. C., Yan, J., et al. (2018). Alteration of the tumor stroma using a consensus DNA vaccine targeting fibroblast activation protein (FAP) synergizes with antitumor vaccine therapy in mice. Clinical Cancer Research, 24(5), 1190–1201.  https://doi.org/10.1158/1078-0432.ccr-17-2033.CrossRefPubMedGoogle Scholar
  196. 196.
    Gottschalk, S., Yu, F., Ji, M., Kakarla, S., & Song, X. T. (2013). A vaccine that co-targets tumor cells and cancer associated fibroblasts results in enhanced antitumor activity by inducing antigen spreading. PLoS One, 8(12), e82658.  https://doi.org/10.1371/journal.pone.0082658.CrossRefPubMedPubMedCentralGoogle Scholar
  197. 197.
    Loeffler, M., Kruger, J. A., Niethammer, A. G., & Reisfeld, R. A. (2006). Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. The Journal of Clinical Investigation, 116(7), 1955–1962.  https://doi.org/10.1172/jci26532.CrossRefPubMedPubMedCentralGoogle Scholar
  198. 198.
    Meng, M., Wang, W., Yan, J., Tan, J., Liao, L., Shi, J., et al. (2016). Immunization of stromal cell targeting fibroblast activation protein providing immunotherapy to breast cancer mouse model. Tumour Biology, 37(8), 10317–10327.  https://doi.org/10.1007/s13277-016-4825-4.CrossRefPubMedGoogle Scholar
  199. 199.
    Ostermann, E., Garin-Chesa, P., Heider, K. H., Kalat, M., Lamche, H., Puri, C., et al. (2008). Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clinical Cancer Research, 14(14), 4584–4592.  https://doi.org/10.1158/1078-0432.ccr-07-5211.CrossRefPubMedGoogle Scholar
  200. 200.
    Femel, J., Huijbers, E. J., Saupe, F., Cedervall, J., Zhang, L., Roswall, P., et al. (2014). Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer. Oncotarget, 5(23), 12418–12427.  https://doi.org/10.18632/oncotarget.2628.CrossRefPubMedPubMedCentralGoogle Scholar
  201. 201.
    Park, C. Y., Min, K. N., Son, J. Y., Park, S. Y., Nam, J. S., Kim, D. K., et al. (2014). An novel inhibitor of TGF-beta type I receptor, IN-1130, blocks breast cancer lung metastasis through inhibition of epithelial-mesenchymal transition. Cancer Letters, 351(1), 72–80.  https://doi.org/10.1016/j.canlet.2014.05.006.CrossRefPubMedGoogle Scholar
  202. 202.
    Fang, Y., Chen, Y., Yu, L., Zheng, C., Qi, Y., Li, Z., et al. (2013). Inhibition of breast cancer metastases by a novel inhibitor of TGFbeta receptor 1. Journal of the National Cancer Institute, 105(1), 47–58.  https://doi.org/10.1093/jnci/djs485.CrossRefPubMedGoogle Scholar
  203. 203.
    Ehata, S., Hanyu, A., Fujime, M., Katsuno, Y., Fukunaga, E., Goto, K., et al. (2007). Ki26894, a novel transforming growth factor-beta type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Cancer Science, 98(1), 127–133.  https://doi.org/10.1111/j.1349-7006.2006.00357.x.CrossRefPubMedGoogle Scholar
  204. 204.
    Bandyopadhyay, A., Agyin, J. K., Wang, L., Tang, Y., Lei, X., Story, B. M., et al. (2006). Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-β type I receptor kinase inhibitor. Cancer Research, 66(13), 6714–6721.  https://doi.org/10.1158/0008-5472.can-05-3565.CrossRefPubMedGoogle Scholar
  205. 205.
    Formenti, S. C., Lee, P., Adams, S., Goldberg, J. D., Li, X., Xie, M. W., et al. (2018). Focal irradiation and systemic TGFbeta blockade in metastatic breast cancer. Clinical Cancer Research, 24(11), 2493–2504.  https://doi.org/10.1158/1078-0432.ccr-17-3322.CrossRefPubMedGoogle Scholar
  206. 206.
    Giaccone, G., Bazhenova, L. A., Nemunaitis, J., Tan, M., Juhasz, E., Ramlau, R., et al. (2015). A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. European Journal of Cancer, 51(16), 2321–2329.  https://doi.org/10.1016/j.ejca.2015.07.035.CrossRefPubMedGoogle Scholar
  207. 207.
    Xiang, J., Hurchla, M. A., Fontana, F., Su, X., Amend, S. R., Esser, A. K., et al. (2015). CXCR4 protein epitope mimetic antagonist POL5551 disrupts metastasis and enhances chemotherapy effect in triple-negative breast cancer. Molecular Cancer Therapeutics, 14(11), 2473–2485.  https://doi.org/10.1158/1535-7163.mct-15-0252.CrossRefPubMedPubMedCentralGoogle Scholar
  208. 208.
    Peng, S. B., Zhang, X., Paul, D., Kays, L. M., Gough, W., Stewart, J., et al. (2015). Identification of LY2510924, a novel cyclic peptide CXCR4 antagonist that exhibits antitumor activities in solid tumor and breast cancer metastatic models. Molecular Cancer Therapeutics, 14(2), 480–490.  https://doi.org/10.1158/1535-7163.mct-14-0850.CrossRefPubMedGoogle Scholar
  209. 209.
    Ling, X., Spaeth, E., Chen, Y., Shi, Y., Zhang, W., Schober, W., et al. (2013). The CXCR4 antagonist AMD3465 regulates oncogenic signaling and invasiveness in vitro and prevents breast cancer growth and metastasis in vivo. PLoS One, 8(3), e58426.  https://doi.org/10.1371/journal.pone.0058426.CrossRefPubMedPubMedCentralGoogle Scholar
  210. 210.
    Galsky, M. D., Vogelzang, N. J., Conkling, P., Raddad, E., Polzer, J., Roberson, S., et al. (2014). A phase I trial of LY2510924, a CXCR4 peptide antagonist, in patients with advanced cancer. Clinical Cancer Research, 20(13), 3581–3588.  https://doi.org/10.1158/1078-0432.ccr-13-2686.CrossRefPubMedGoogle Scholar
  211. 211.
    Hainsworth, J. D., Reeves, J. A., Mace, J. R., Crane, E. J., Hamid, O., Stille, J. R., et al. (2016). A randomized, open-label phase 2 study of the CXCR4 inhibitor LY2510924 in combination with sunitinib versus sunitinib alone in patients with metastatic renal cell carcinoma (RCC). Targeted Oncology, 11(5), 643–653.  https://doi.org/10.1007/s11523-016-0434-9.CrossRefPubMedGoogle Scholar
  212. 212.
    Salgia, R., Stille, J. R., Weaver, R. W., McCleod, M., Hamid, O., Polzer, J., et al. (2017). A randomized phase II study of LY2510924 and carboplatin/etoposide versus carboplatin/etoposide in extensive-disease small cell lung cancer. Lung Cancer, 105, 7–13.  https://doi.org/10.1016/j.lungcan.2016.12.020.CrossRefPubMedGoogle Scholar
  213. 213.
    Loktev, A., Lindner, T., Mier, W., Debus, J., Altmann, A., Jager, D., et al. (2018). A tumor-imaging method targeting cancer-associated fibroblasts. Journal of Nuclear Medicine, 59(9), 1423–1429.  https://doi.org/10.2967/jnumed.118.210435.CrossRefPubMedGoogle Scholar
  214. 214.
    Zhou, Z., Qutaish, M., Han, Z., Schur, R. M., Liu, Y., Wilson, D. L., et al. (2015). MRI detection of breast cancer micrometastases with a fibronectin-targeting contrast agent. Nature Communications, 6, 7984.  https://doi.org/10.1038/ncomms8984.CrossRefPubMedPubMedCentralGoogle Scholar
  215. 215.
    Butsch, V., Borgel, F., Galla, F., Schwegmann, K., Hermann, S., Schafers, M., et al. (2018). Design, (radio)synthesis, and in vitro and in vivo evaluation of highly selective and potent matrix metalloproteinase 12 (MMP-12) inhibitors as radiotracers for positron emission tomography. Journal of Medicinal Chemistry, 61(9), 4115–4134.  https://doi.org/10.1021/acs.jmedchem.8b00200.CrossRefPubMedGoogle Scholar
  216. 216.
    Matusiak, N., Castelli, R., Tuin, A. W., Overkleeft, H. S., Wisastra, R., Dekker, F. J., et al. (2015). A dual inhibitor of matrix metalloproteinases and a disintegrin and metalloproteinases, [(1)(8)F]FB-ML5, as a molecular probe for non-invasive MMP/ADAM-targeted imaging. Bioorganic & Medicinal Chemistry, 23(1), 192–202.  https://doi.org/10.1016/j.bmc.2014.11.013.CrossRefGoogle Scholar
  217. 217.
    Matusiak, N., van Waarde, A., Bischoff, R., Oltenfreiter, R., van de Wiele, C., Dierckx, R. A., et al. (2013). Probes for non-invasive matrix metalloproteinase-targeted imaging with PET and SPECT. Current Pharmaceutical Design, 19(25), 4647–4672.CrossRefGoogle Scholar
  218. 218.
    Wagner, S., Breyholz, H. J., Faust, A., Holtke, C., Levkau, B., Schober, O., et al. (2006). Molecular imaging of matrix metalloproteinases in vivo using small molecule inhibitors for SPECT and PET. Current Medicinal Chemistry, 13(23), 2819–2838.CrossRefGoogle Scholar
  219. 219.
    Xu, K., Rajagopal, S., Klebba, I., Dong, S., Ji, Y., Liu, J., et al. (2010). The role of fibroblast Tiam1 in tumor cell invasion and metastasis. Oncogene, 29(50), 6533–6542.  https://doi.org/10.1038/onc.2010.385.CrossRefPubMedPubMedCentralGoogle Scholar
  220. 220.
    Chang, P. H., Hwang-Verslues, W. W., Chang, Y. C., Chen, C. C., Hsiao, M., Jeng, Y. M., et al. (2012). Activation of Robo1 signaling of breast cancer cells by Slit2 from stromal fibroblast restrains tumorigenesis via blocking PI3K/Akt/beta-catenin pathway. Cancer Research, 72(18), 4652–4661.  https://doi.org/10.1158/0008-5472.can-12-0877.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Molecular PathologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands

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