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Tumor Microenvironment Heterogeneity: Challenges and Opportunities

  • Molecular Biology of Prostate Cancer (M Kruithof-de Julio, Section Editor)
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Abstract

The tumor microenvironment (TME) has been recognized as an integral component of malignancies in breast and prostate tissues, contributing in confounding ways to tumor progression, metastasis, therapy resistance, and disease recurrence. Major components of the TME are immune cells, fibroblasts, pericytes, endothelial cells, mesenchymal stroma/stem cells (MSCs), and extracellular matrix (ECM) components. Herein, we discuss the molecular and cellular heterogeneity within the TME and how this presents unique challenges and opportunities for treating breast and prostate cancers.

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References

  1. 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;7:1120–34.

    Article  CAS  Google Scholar 

  2. 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;150:165–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Airoldi I, Cocco C, Sorrentino C, Angelucci D, Di Meo S, Manzoli L, et al. Interleukin-30 promotes breast cancer growth and progression. Cancer Res. 2016;76:6218–29.

    Article  PubMed  CAS  Google Scholar 

  4. Andrieu G, Tran AH, Strissel KJ, Denis GV. BRD4 regulates breast cancer dissemination through Jagged1/Notch1 signaling. Cancer Res. 2016;76:6555–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Baghel KS, Tewari BN, Shrivastava R, Malik SA, Lone MU, Jain NK, et al. Macrophages promote matrix protrusive and invasive function of breast cancer cells via MIP-1beta dependent upregulation of MYO3A gene in breast cancer cells. Oncoimmunology. 2016;5:e1196299.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Baker EL, Bonnecaze RT, Zaman MH. Extracellular matrix stiffness and architecture govern intracellular rheology in cancer. Biophys J. 2009;97:1013–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Barcus CE, O’Leary KA, Brockman JL, Rugowski DE, Liu Y, Garcia N, et al. Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells. Breast Cancer Res. 2017;19:9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Barron DA, Rowley DR. The reactive stroma microenvironment and prostate cancer progression. Endocr Relat Cancer. 2012;19:R187–204.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Beck JN, Singh A, Rothenberg AR, Elisseeff JH, Ewald AJ. The independent roles of mechanical, structural and adhesion characteristics of 3D hydrogels on the regulation of cancer invasion and dissemination. Biomaterials. 2013;34:9486–95.

    Article  PubMed  CAS  Google Scholar 

  10. Benyahia Z, Dussault N, Cayol M, Sigaud R, Berenguer-Daize C, Delfino C, et al. Stromal fibroblasts present in breast carcinomas promote tumor growth and angiogenesis through adrenomedullin secretion. Oncotarget. 2017;8:15744–62.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bertos NR, Park M. Breast cancer - one term, many entities? J Clin Invest. 2011;121:3789–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Bliss SA, Sinha G, Sandiford OA, Williams LM, Engelberth DJ, Guiro K, et al. Mesenchymal stem cell–derived exosomes stimulate cycling quiescence and early breast cancer dormancy in bone marrow. Cancer Res. 2016;76:5832–44.

    Article  PubMed  CAS  Google Scholar 

  13. Bobrie A, Krumeich S, Reyal F, Recchi C, Moita LF, Seabra MC, et al. Rab27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Cancer Re. 2012;72(19):4920–30.

  14. Bott A, Erdem N, Lerrer S, Hotz-Wagenblatt A, Breunig C, Abnaof K, et al. miRNA-1246 induces pro-inflammatory responses in mesenchymal stem/stromal cells by regulating PKA and PP2A. Oncotarget. 2017;8(27):43897–43914.

  15. Calvo F, Sahai E. Cell communication networks in cancer invasion. Curr Opin Cell Biol. 2011;23:621–9.

    Article  PubMed  CAS  Google Scholar 

  16. Calvo F, Ege N, Grande-Garcia A, Hooper S, Jenkins RP, Chaudhry SI, et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol. 2013;15:637–46.

    Article  PubMed  CAS  Google Scholar 

  17. Castaño Z, Fillmore CM, Kim CF, McAllister SS. The bed and the bugs: interactions between the tumor microenvironment and cancer stem cells. Semin Cancer Biol. 2012;22:462–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Castano Z, Marsh T, Tadipatri R, Kuznetsov HS, Al-Shahrour F, Paktinat M, et al. Stromal EGF and igf-I together modulate plasticity of disseminated triple-negative breast tumors. Cancer Discov. 2013;3:922–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Chaffer CL, Marjanovic ND, Lee T, Bell G, Kleer CG, Reinhardt F, et al. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances Tumorigenicity. Cell. 2013;154:61–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Chang Y, Zuka M, Perez-Pinera P, Astudillo A, Mortimer J, Berenson JR, et al. Secretion of pleiotrophin stimulates breast cancer progression through remodeling of the tumor microenvironment. Proc Natl Acad Sci. 2007;104:10888–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Cheung KJ, Gabrielson E, Werb Z, Ewald AJ. Collective invasion in breast cancer requires a conserved basal epithelial program. Cell. 2013;155:1639–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Cheung KJ, Padmanaban V, Silvestri V, Schipper K, Cohen JD, Fairchild AN, et al. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. Proc Natl Acad Sci U S A. 2016;113:E854–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Cho JA, Park H, Lim EH, Lee KW. Exosomes from breast cancer cells can convert adipose tissue-derived mesenchymal stem cells into myofibroblast-like cells. Int J Oncol. 2012;40:130–8.

    Article  PubMed  CAS  Google Scholar 

  24. Chung LW, Baseman A, Assikis V, Zhau HE. Molecular insights into prostate cancer progression: the missing link of tumor microenvironment. J Urol. 2005;173:10–20.

    Article  PubMed  Google Scholar 

  25. Coleman RE, Gregory W, Marshall H, Wilson C, Holen I. The metastatic microenvironment of breast cancer: clinical implications. Breast. 2013;22(Suppl 2):S50–6.

    Article  PubMed  Google Scholar 

  26. Descot A, Oskarsson T. The molecular composition of the metastatic niche. Exp Cell Res. 2013;319:1679–86.

    Article  PubMed  CAS  Google Scholar 

  27. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7.

    Article  PubMed  CAS  Google Scholar 

  28. Donnarumma E, Fiore D, Nappa M, Roscigno G, Adamo A, Iaboni M, et al. Cancer-associated fibroblasts release exosomal microRNAs that dictate an aggressive phenotype in breast cancer. Oncotarget. 2017;8:19592–608.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Dumont N, Liu B, Defilippis RA, Chang H, Rabban JT, Karnezis AN, et al. Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics. Neoplasia. 2013;15:249–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Elkabets M, Gifford AM, Scheel C, Nilsson B, Reinhardt F, Bray MA, et al. Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice. J Clin Invest. 2011;121:784–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Erez N, Truitt M, Olson P, Arron ST, Hanahan D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell. 2010;17:135–47.

    Article  PubMed  CAS  Google Scholar 

  32. Fong MY, Zhou W, Liu L, Alontaga AY, Chandra M, Ashby J, et al. Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol. 2015;17:183–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Friedl P, Alexander S. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell. 2011;147:992–1009.

    Article  PubMed  CAS  Google Scholar 

  34. Ganguly SS, Li X, Miranti CK. The host microenvironment influences prostate cancer invasion, systemic spread, bone colonization, and osteoblastic metastasis. Front Oncol. 2014;4:364.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Ghesquiere B, Wong BW, Kuchnio A, Carmeliet P. Metabolism of stromal and immune cells in health and disease. Nature. 2014;511:167–76.

    Article  PubMed  CAS  Google Scholar 

  36. Gonzalez ME, Martin EE, Anwar T, Arellano-Garcia C, Medhora N, Lama A, et al. Mesenchymal stem cell-induced DDR2 mediates stromal-breast cancer interactions and metastasis growth. Cell Rep. 2017;18:1215–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Gritsenko PG, Ilina O, Friedl P. Interstitial guidance of cancer invasion. J Pathol. 2012;226:185–99.

    Article  PubMed  CAS  Google Scholar 

  38. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309–22.

    Article  PubMed  CAS  Google Scholar 

  39. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  PubMed  CAS  Google Scholar 

  40. Harney AS, Arwert EN, Entenberg D, Wang Y, Guo P, Qian BZ, et al. Real-time imaging reveals local, transient vascular permeability, and tumor cell Intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov. 2015;5:932–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. He N, Feng G, Li Y, Xu Y, Xie X, Wang H, et al. Embryonic stem cell preconditioned microenvironment suppresses tumorigenic properties in breast cancer. Stem Cell Res Ther. 2016;7:95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Iijima J, Konno K, Itano N. Inflammatory alterations of the extracellular matrix in the tumor microenvironment. Cancers. 2011;3:3189–205.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Insua-Rodríguez J, Oskarsson T. The extracellular matrix in breast cancer. Adv Drug Deliv Rev. 2016;97:41–55.

    Article  PubMed  CAS  Google Scholar 

  44. Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. Journal of molecular medicine (Berlin, Germany). 2013;91:431–7.

    Article  CAS  Google Scholar 

  45. Kai F, Laklai H, Weaver VM. Force matters: biomechanical regulation of cell invasion and migration in disease. Trends Cell Biol. 2016;26:486–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16:582–98.

    Article  PubMed  CAS  Google Scholar 

  47. Khamis ZI, Sahab ZJ, Sang QX. Active roles of tumor stroma in breast cancer metastasis. Int J Breast Cancer. 2012;2012:574025.

    Article  PubMed  PubMed Central  Google Scholar 

  48. King HW, Michael MZ, Gleadle JM. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer. 2012;12:421.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Ko P, Kim D, You E, Jung J, Oh S, Kim J, et al. Extracellular matrix rigidity-dependent sphingosine-1-phosphate secretion regulates metastatic cancer cell invasion and adhesion. Sci Rep. 2016;6:21564.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Kong W, Philipps AF, Dvorak B, Anderson GG, Lake M, Koldovsky O. Presence of insulin-like growth factor I but absence of the binding proteins in the bile of rats. Am J Phys. 1995;268:R266–71.

    CAS  Google Scholar 

  51. Kreger BT, Johansen ER, Cerione RA, Antonyak MA. The enrichment of survivin in exosomes from breast cancer cells treated with paclitaxel promotes cell survival and chemoresistance. Cancers (Basel). 2016;8(12). https://doi.org/10.3390/cancers812011.

  52. Kuznetsov HS, Marsh T, Markens BA, Castano Z, Greene-Colozzi A, Hay SA, et al. Identification of luminal breast cancers that establish a tumor-supportive macroenvironment defined by proangiogenic platelets and bone marrow-derived cells. Cancer Discov. 2012;2:1150–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Li S, Lu J, Chen Y, Xiong N, Li L, Zhang J, et al. MCP-1-induced ERK/GSK-3beta/Snail signaling facilitates the epithelial-mesenchymal transition and promotes the migration of MCF-7 human breast carcinoma cells. Cell Mol Immunol. 2016;

  54. Lin JR, Fallahi-Sichani M, Sorger PK. Highly multiplexed imaging of single cells using a high-throughput cyclic immunofluorescence method. Nat Commun. 2015;6:8390.

    Article  PubMed  CAS  Google Scholar 

  55. Lin JR, Fallahi-Sichani M, Chen JY, Sorger PK. Cyclic immunofluorescence (CycIF), a highly multiplexed method for single-cell imaging. Curr Protoc Chem Biol. 2016;8:251–64.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Lin J-R, Izar B, Mei S, Wang S, Shah P, Sorger P. A simple open-source method for highly multiplexed imaging of single cells in tissues and tumours. bioRxiv. 2017. https://doi.org/10.1101/151738.

  57. Loskutov YV, Kozyulina PY, Kozyreva VK, Ice RJ, Jones BC, Roston TJ, et al. NEDD9/Arf6-dependent endocytic trafficking of matrix metalloproteinase 14: a novel mechanism for blocking mesenchymal cell invasion and metastasis of breast cancer. Oncogene. 2015;34:3662–75.

    Article  PubMed  CAS  Google Scholar 

  58. Lu H, Clauser KR, Tam WL, Frose J, Ye X, Eaton EN, et al. A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol. 2014a;16:1105–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Lu H, Clauser KR, Tam WL, Fröse J, Ye X, Eaton EN, et al. A breast cancer stem cell niche supported by Juxtacrine signaling from monocytes and macrophages. Nat Cell Biol. 2014b;16:1105–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell. 2012;151:1542–56.

    Article  PubMed  CAS  Google Scholar 

  61. Luo YP, Zhou H, Krueger J, Kaplan C, Liao D, Markowitz D, et al. The role of proto-oncogene Fra-1 in remodeling the tumor microenvironment in support of breast tumor cell invasion and progression. Oncogene. 2009;29:662–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Luo M, Hou L, Li J, Shao S, Huang S, Meng D, et al. VEGF/NRP-1axis promotes progression of breast cancer via enhancement of epithelial-mesenchymal transition and activation of NF-kappaB and beta-catenin. Cancer Lett. 2016;373:1–11.

    Article  PubMed  CAS  Google Scholar 

  63. Mao Y, Keller ET, Garfield DH, Shen K, Wang J. Stroma cells in tumor microenvironment and breast cancer. Cancer Metastasis Rev. 2013;32:303–15.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Mao L, Li J, Chen WX, Cai YQ, Yu DD, Zhong SL, et al. Exosomes decrease sensitivity of breast cancer cells to adriamycin by delivering microRNAs. Tumour Biol. 2016;37:5247–56.

    Article  PubMed  CAS  Google Scholar 

  65. Marsh T, Pietras K, McAllister SS. Fibroblasts as architects of cancer pathogenesis. Biochim Biophys Acta (BBA) - Mol Basis Dis. 2013;1832:1070–8.

    Article  CAS  Google Scholar 

  66. McAllister SS, Weinberg RA. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol. 2014;16:717–27.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  67. McAndrews KM, McGrail DJ, Ravikumar N, Dawson MR. Mesenchymal stem cells induce directional migration of invasive breast cancer cells through TGF-beta. Sci Rep. 2015;5:16941.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Melo SA, Sugimoto H, O'Connell JT, Kato N, Villanueva A, Vidal A, et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell. 2014;26:707–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Melzer C, von der Ohe J, Lehnert H, Ungefroren H, Hass R. Cancer stem cell niche models and contribution by mesenchymal stroma/stem cells. Mol Cancer. 2017;16:28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Nguyen-Ngoc KV, Cheung KJ, Brenot A, Shamir ER, Gray RS, Hines WC, et al. ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium. Proc Natl Acad Sci U S A. 2012;109:E2595–604.

    Article  PubMed  PubMed Central  Google Scholar 

  71. O'Connell JT, Sugimoto H, Cooke VG, MacDonald BA, Mehta AI, LeBleu VS, et al. VEGF-A and Tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization. Proc Natl Acad Sci U S A. 2011;108:16002–7.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Ono M, Kosaka N, Tominaga N, Yoshioka Y, Takeshita F, Takahashi R-U, et al. Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci Signal. 2014;7:ra63.

    Article  PubMed  CAS  Google Scholar 

  73. Patel BB, Ackerstaff E, Serganova IS, Kerrigan JE, Blasberg RG, Koutcher JA, et al. Tumor stroma interaction is mediated by monocarboxylate metabolism. Exp Cell Res. 2017;352:20–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Pickup MW, Mouw JK, Weaver VM. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 2014;15:1243–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.

    Article  PubMed  CAS  Google Scholar 

  76. Place AE, Jin Huh S, Polyak K. The microenvironment in breast cancer progression: biology and implications for treatment. Breast Cancer Research : BCR. 2011;13:227.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Rahman M, Mohammed S. Breast cancer metastasis and the lymphatic system. Oncol Lett. 2015;10:1233–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Santoni M, Piva F, Scarpelli M, Cheng L, Lopez-Beltran A, Massari F, et al. The origin of prostate metastases: emerging insights. Cancer Metastasis Rev. 2015;34:765–73.

    Article  PubMed  CAS  Google Scholar 

  80. Santos JC, Ribeiro ML, Sarian LO, Ortega MM, Derchain SF. Exosomes-mediate microRNAs transfer in breast cancer chemoresistance regulation. Am J Cancer Res. 2016;6:2129–39.

    PubMed  PubMed Central  CAS  Google Scholar 

  81. Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ, et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell. 2011;145:926–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Sevenich L, Bowman RL, Mason SD, Quail DF, Rapaport F, Elie BT, et al. Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat Cell Biol. 2014;16:876–88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Sharon Y, Alon L, Glanz S, Servais C, Erez N. Isolation of normal and cancer-associated fibroblasts from fresh tissues by fluorescence activated cell sorting (FACS). J Vis Exp. 2013;14(71);e4425.

  84. Shiao SL, Chu GC, Chung LW. Regulation of prostate cancer progression by the tumor microenvironment. Cancer Lett. 2016;380:340–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Shree T, Olson OC, Elie BT, Kester JC, Garfall AL, Simpson K, et al. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev. 2011;25:2465–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.

    Article  PubMed  Google Scholar 

  87. Sieh S, Taubenberger AV, Rizzi SC, Sadowski M, Lehman ML, Rockstroh A, et al. Phenotypic characterization of prostate cancer LNCaP cells cultured within a bioengineered microenvironment. PLoS One. 2012;7:e40217.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Smirnova T, Bonapace L, MacDonald G, Kondo S, Wyckoff J, Ebersbach H, et al. Serpin E2 promotes breast cancer metastasis by remodeling the tumor matrix and polarizing tumor associated macrophages. Oncotarget. 2016;7:82289–304.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Soysal SD, Tzankov A, Muenst SE. Role of the tumor microenvironment in breast cancer. Pathobiology. 2015;82:142–52.

    Article  PubMed  CAS  Google Scholar 

  90. Spill F, Reynolds DS, Kamm RD, Zaman MH. Impact of the physical microenvironment on tumor progression and metastasis. Curr Opin Biotechnol. 2016;40:41–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Taddei ML, Giannoni E, Comito G, Chiarugi P. Microenvironment and tumor cell plasticity: an easy way out. Cancer Lett. 2013;341:80–96.

    Article  PubMed  CAS  Google Scholar 

  92. Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, et al. Fibroblast-recruited, tumor-infiltrating CD4(+) T cells stimulate mammary cancer metastasis through RANKL-RANK signaling. Nature. 2011;470:548–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Tripathi M, Billet S, Bhowmick NA. Understanding the role of stromal fibroblasts in cancer progression. Cell Adhes Migr. 2012;6:231–5.

    Article  Google Scholar 

  94. Uhlen M, Bjorling E, Agaton C, Szigyarto CA, Amini B, Andersen E, et al. A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol Cell Proteomics. 2005;4:1920–32.

    Article  PubMed  CAS  Google Scholar 

  95. Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M, et al. Towards a knowledge-based human protein atlas. Nat Biotechnol. 2010;28:1248–50.

    Article  PubMed  CAS  Google Scholar 

  96. Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347:1260419.

    Article  PubMed  CAS  Google Scholar 

  97. Wei SC, Fattet L, Tsai JH, Guo Y, Pai VH, Majeski HE, et al. Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway. Nat Cell Biol. 2015;17:678–88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Wen SW, Sceneay J, Lima LG, Wong CS, Becker M, Krumeich S, et al. The biodistribution and immune suppressive effects of breast cancer-derived exosomes. Cancer Res. 2016;76:6816–27.

    Article  PubMed  CAS  Google Scholar 

  99. Wolf K, Friedl P. Extracellular matrix determinants of proteolytic and non-proteolytic cell migration. Trends Cell Biol. 2011;21:736–44.

    Article  PubMed  CAS  Google Scholar 

  100. Wolfe AR, Trenton NJ, Debeb BG, Larson R, Ruffell B, Chu K, et al. Mesenchymal stem cells and macrophages interact through IL-6 to promote inflammatory breast cancer in pre-clinical models. Oncotarget. 2016;7:82482–92.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Xiong G-F, Xu R. Function of cancer cell-derived extracellular matrix in tumor progression. Journal of Cancer Metastasis and Treatment. 2016;2:357–64.

    Article  CAS  Google Scholar 

  102. Yang M, Chen J, Su F, Yu B, Su F, Lin L, et al. Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol Cancer. 2011;10:117.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Yang M, Ma B, Shao H, Clark AM, Wells A. Macrophage phenotypic subtypes diametrically regulate epithelial-mesenchymal plasticity in breast cancer cells. BMC Cancer. 2016;16:419.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Yu W, Chai H, Li Y, Zhao H, Xie X, Zheng H, et al. Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer. Toxicol Appl Pharmacol. 2012;264:73–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Yu S, Cao H, Shen B, Feng J. Tumor-derived exosomes in cancer progression and treatment failure. Oncotarget. 2015;6:37151–68.

    PubMed  PubMed Central  Google Scholar 

  106. Zaman MH, Trapani LM, Sieminski AL, Mackellar D, Gong H, Kamm RD, et al. Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis. Proc Natl Acad Sci U S A. 2006;103:10889–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Zhang W, Grivennikov SI. Top notch cancer stem cells by paracrine NF-kappaB signaling in breast cancer. Breast Cancer Res. 2013;15:316.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Biology, California State University, Northridge, CA, USA

    F. Runa, S. Hamalian, K. Meade, P. Shisgal & J. A. Kelber

  2. The Salk Institute for Biological Studies, La Jolla, CA, USA

    P. C. Gray

  3. ScienceMedia Inc., 6256 Greenwich Dr #515, San Diego, CA, 92122, USA

    P. C. Gray

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  1. F. Runa
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F. Runa, S. Hamalian, K. Meade, P. Shisgal, P.C. Gray, and J.A. Kelber declare that they have no conflict of interest.

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Runa, F., Hamalian, S., Meade, K. et al. Tumor Microenvironment Heterogeneity: Challenges and Opportunities. Curr Mol Bio Rep 3, 218–229 (2017). https://doi.org/10.1007/s40610-017-0073-7

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