Stromal biomarkers in breast cancer development and progression

Clinical and Experimental Metastasis

Volumn 29, Issue 7, 2012, Pages 663-672

  Rudnick, Jenny A ^a   Kuperwasser, Charlotte ^a,b  

^a TUFTS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b TUFTS MEDICAL CENTER   (United States)

Author keywords

Biomarkers; Breast; Cancer; Stroma

Indexed keywords

ALPHA SMOOTH MUSCLE ACTIN; BIOLOGICAL MARKER; CAVEOLIN 1; CD68 ANTIGEN; COLLAGEN TYPE 1; CYCLOOXYGENASE 2; CYCLOOXYGENASE 2 INHIBITOR; DNA VACCINE; EPIDERMAL GROWTH FACTOR RECEPTOR 2; ESTROGEN RECEPTOR ALPHA; INTERLEUKIN 6; MATRIX METALLOPROTEINASE; MICRORNA; MONOCYTE CHEMOTACTIC PROTEIN 1; NONSTEROID ANTIINFLAMMATORY AGENT; PROSTAGLANDIN E2; PROTEIN LYSINE 6 OXIDASE; SEPRASE; STROMAL CELL DERIVED FACTOR 1ALPHA; TENASCIN; TOLL LIKE RECEPTOR 4; VASCULOTROPIN;

ADAPTIVE IMMUNITY; ANGIOGENESIS; ANTINEOPLASTIC ACTIVITY; B LYMPHOCYTE; BLOOD VESSEL PERMEABILITY; BREAST CANCER; CANCER GROWTH; CANCER SURVIVAL; CARCINOGENESIS; CELL MIGRATION; CELL PROLIFERATION; CONFERENCE PAPER; DISEASE FREE SURVIVAL; DNA METHYLATION; DOWN REGULATION; DRUG TARGETING; EPIGENETICS; FIBRIN DEPOSITION; FIBROBLAST; GENE EXPRESSION; HUMAN; HYDROSTATIC PRESSURE; IMMUNOHISTOCHEMISTRY; INTRADUCTAL CARCINOMA; LUNG METASTASIS; NONHUMAN; PARTIAL MASTECTOMY; PROTEIN CLEAVAGE; PROTEIN CROSS LINKING; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; REGULATORY T LYMPHOCYTE; SERIAL ANALYSIS OF GENE EXPRESSION; SHEAR STRESS; SINGLE NUCLEOTIDE POLYMORPHISM; STROMA CELL; THROMBOCYTE ACTIVATION; TUMOR ASSOCIATED LEUKOCYTE; TUMOR MICROENVIRONMENT; UNSPECIFIED SIDE EFFECT; UPREGULATION; WOUND HEALING;

ACTINS; BREAST; BREAST NEOPLASMS; CELL LINE, TUMOR; DISEASE PROGRESSION; FEMALE; FIBROBLASTS; HUMANS; STROMAL CELLS; TUMOR MARKERS, BIOLOGICAL; TUMOR MICROENVIRONMENT;

EID: 84868202071     PISSN: 02620898     EISSN: 15737276     Source Type: Journal    
DOI: 10.1007/s10585-012-9499-8     Document Type: Conference Paper

References (139)

1. Mintz B, Illmensee K (1975) Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Nat Acad Sci USA 72(9):3585-3589
2. Stoker AW, Hatier C, Bissell MJ (1990) The embryonic environment strongly attenuates v-src oncogenesis in mesenchymal and epithelial tissues, but not in endothelia. J Cell Biol 111(1):217-228
3. Bissell MJ, Radisky D (2001) Putting tumours in context. Nat Rev Cancer 1(1):46-54
4. Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6(5):392-401
5. Bissell MJ, Radisky DC, Rizki A et al (2002) The organizing principle: Microenvironmental influences in the normal and malignant breast. Differentiation 70(9-10):537-546
6. Dvorak HF (1986) Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315(26):1650-1659
7. Tlsty TD, Coussens LM (2006) Tumor stroma and regulation of cancer development. Annu Rev Pathol 1:119-150
8. Mori L, Bellini A, Stacey MA et al (2005) Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow. Exp Cell Res 304(1):81-90
9. Wixler V, Hirner S, Muller JM et al (2007) Deficiency in the LIM-only protein Fhl2 impairs skin wound healing. J Cell Biol 177(1):163-172
10. Allinen M, Beroukhim R, Cai L et al (2004) Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6(1):17-32
11. Casey T, Bond J, Tighe S et al (2009) Molecular signatures suggest a major role for stromal cells in development of invasive breast cancer. Breast Cancer Res Treat 114(1):47-62
12. Finak G, Bertos N, Pepin F et al (2008) Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 14(5):518-527
13. Ma XJ, Dahiya S, Richardson E et al (2009) Gene expression profiling of the tumor microenvironment during breast cancer progression. Breast Cancer Res 11(1):R7
14. Orimo A, Gupta PB, Sgroi DC 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
15. Erez N, Truitt M, Olson P et al (2010) Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell 17(2):135-147
16. Hwang RF, Moore T, Arumugam T et al (2008) Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res 68(3):918-926
17. O'Connell JT, Sugimoto H, Cooke VG et al (2011) VEGF-A and Tenascin-C produced by S100A4? stromal cells are important for metastatic colonization. Proc Nat Acad Sci USA 108(38):16002-16007
18. Olumi AF, Grossfeld GD, Hayward SW et al (1999) Carcinomaassociated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 59(19):5002-5011
19. Kojima Y, Acar A, Eaton EN et al (2010) Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Nat Acad Sci USA 107(46):20009-20014
20. Studebaker AW, Storci G, Werbeck JL 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 Res 68(21):9087-9095
21. Rudnick JA, Arendt LM, Klebba I et al (2011) Functional heterogeneity of breast fibroblasts is defined by a prostaglandin secretory phenotype that promotes expansion of cancer-stem like cells. PLoS ONE 6(9):e24605
22. Ronnov-Jessen L, Petersen OW, Koteliansky VE et al (1995) The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest 95(2):859-873
23. Liu R, Li H, Liu L et al (2012) Fibroblast activation protein: A potential therapeutic target in cancer. Cancer Biol Ther 13(3): 123-129
24. Wolf BB, Quan C, Tran T et al (2008) On the edge of validation: Cancer protease fibroblast activation protein. Mini Rev Med Chem 8(7):719-727
25. Lee J, Fassnacht M, Nair S et al (2005) Tumor immunotherapy targeting fibroblast activation protein, a product expressed in tumor-associated fibroblasts. Cancer Res 65(23):11156-11163
26. Scanlan MJ, Raj BK, Calvo B et al (1994) Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc Nat Acad Sci USA 91(12):5657-5661
27. Park JE, Lenter MC, Zimmermann RN et al (1999) Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts. J Biol Chem 274(51): 36505-36512
28. Huang Y, Simms AE, Mazur A et al (2011) Fibroblast activation protein-alpha promotes tumor growth and invasion of breast cancer cells through non-enzymatic functions. Clin Exp Metastasis 28(6):567-579
29. LeBeau AM, Brennen WN, Aggarwal S et al (2009) Targeting the cancer stroma with a fibroblast activation protein-activated promelittin protoxin. Mol Cancer Ther 8(5):1378-1386
30. Loeffler M, Kruger JA, Niethammer AG et al (2006) Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest 116(7):1955-1962
31. Tahtis K, Lee FT, Wheatley JM et al (2003) Expression and targeting of human fibroblast activation protein in a human skin/ severe combined immunodeficient mouse breast cancer xenograft model. Mol Cancer Ther 2(8):729-737
32. Sotgia F, Martinez-Outschoorn UE, Howell A et al (2012) Caveolin-1 and Cancer metabolism in the tumor microenvironment: Markers, models, and mechanisms. Annu Rev Pathol 7:423-467
33. Koo JS, Park S, Kim SI et al (2011) The impact of caveolin protein expression in tumor stroma on prognosis of breast cancer. Tumour Biol 32(4):787-799
34. Witkiewicz AK, Dasgupta A, Sammons S et al (2010) Loss of stromal caveolin-1 expression predicts poor clinical outcome in triple negative and basal-like breast cancers. Cancer Biol Ther 10(2):135-143
35. Witkiewicz AK, Dasgupta A, Sotgia F et al (2009) An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers. Am J Pathol 174(6):2023-2034
36. Witkiewicz AK, Kline J, Queenan M et al (2011) Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers. Cell Cycle 10(11):1794-1809
37. Goetz JG, Minguet S, Navarro-Lerida I et al (2011) Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 146(1):148-163
38. Guttery DS, Shaw JA, Lloyd K et al (2010) Expression of tenascin-C and its isoforms in the breast. Cancer Metastasis Rev 29(4):595-606
39. Howeedy AA, Virtanen I, Laitinen L et al (1990) Differential distribution of tenascin in the normal, hyperplastic, and neoplastic breast. Lab Investig 63(6):798-806
40. Lightner VA, Marks JR, McCachren SS (1994) Epithelial cells are an important source of tenascin in normal and malignant human breast tissue. Exp Cell Res 210(2):177-184
41. Kawakatsu H, Shiurba R, Obara M et al (1992) Human carcinoma cells synthesize and secrete tenascin in vitro. Jpn J Cancer Res 83(10):1073-1080
42. Hancox RA, Allen MD, Holliday DL et al (2009) Tumourassociated tenascin-C isoforms promote breast cancer cell invasion and growth by matrix metalloproteinase-dependent and independent mechanisms. Breast Cancer Res 11(2):R24
43. Dandachi N, Hauser-Kronberger C, More E et al (2001) Coexpression of tenascin-C and vimentin in human breast cancer cells indicates phenotypic transdifferentiation during tumour progression: Correlation with histopathological parameters, hormone receptors, and oncoproteins. J Pathol 193(2):181-189
44. Jahkola T, Toivonen T, Nordling S et al (1998) Expression of tenascin-C in intraductal carcinoma of human breast: Relationship to invasion. Eur J Cancer 34(11):1687-1692
45. Jahkola T, Toivonen T, Virtanen I et al (1998) Tenascin-C expression in invasion border of early breast cancer: A predictor of local and distant recurrence. Br J Cancer 78(11):1507-1513
46. Suwiwat S, Ricciardelli C, Tammi R et al (2004) Expression of extracellular matrix components versican, chondroitin sulfate, tenascin, and hyaluronan, and their association with disease outcome in node-negative breast cancer. Clin Cancer Res 10(7):2491-2498
47. Jahkola T, Toivonen T, von Smitten K et al (1996) Expression of tenascin in invasion border of early breast cancer correlates with higher risk of distant metastasis. Int J Cancer 69(6): 445-447
48. Oskarsson T, Acharyya S, Zhang XH et al (2011) Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med 17(7):867-874
49. Minn AJ, Gupta GP, Padua D et al (2007) Lung metastasis genes couple breast tumor size and metastatic spread. Proc Nat Acad Sci USA 104(16):6740-6745
50. Minn AJ, Gupta GP, Siegel PM et al (2005) Genes that mediate breast cancer metastasis to lung. Nature 436(7050):518-524
51. Nakahara H, Gabazza EC, Fujimoto H et al (2006) Deficiency of tenascin C attenuates allergen-induced bronchial asthma in the mouse. Eur J Immunol 36(12):3334-3345
52. Midwood K, Sacre S, Piccinini AM et al (2009) Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat Med 15(7):774-780
53. Houghton J, Wang TC (2005) Helicobacter pylori and gastric cancer: A new paradigm for inflammation-associated epithelial cancers. Gastroenterology 128(6):1567-1578
54. Grivennikov S, Karin E, Terzic J et al (2009) IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15(2):103-113
55. Park EJ, Lee JH, Yu GY et al (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140(2):197-208
56. de Visser KE, Korets LV, Coussens LM (2005) De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7(5):411-423
57. Greten FR, Eckmann L, Greten TF et al (2004) IKKbeta links inflammation and tumorigenesis in a mouse model of colitisassociated cancer. Cell 118(3):285-296
58. Okayasu I, Ohkusa T, Kajiura K et al (1996) Promotion of colorectal neoplasia in experimental murine ulcerative colitis. Gut 39(1):87-92
59. DeNardo DG, Barreto JB, Andreu P et al (2009) CD4(?) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16(2):91-102
60. Tan W, Zhang W, Strasner A et al (2011) Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470(7335):548-553
61. Yang L, Huang J, Ren X et al (2008) Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1? CD11b? myeloid cells that promote metastasis. Cancer Cell 13(1):23-35
62. Doedens AL, Stockmann C, Rubinstein MP et al (2010) Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res 70(19):7465-7475
63. Mahmoud SM, Lee AH, Paish EC et al (2012) Tumour-infiltrating macrophages and clinical outcome in breast cancer. J Clin Pathol 65(2):159-163
64. Mahmoud SM, Lee AH, Paish EC et al (2012) The prognostic significance of B lymphocytes in invasive carcinoma of the breast. Breast Cancer Res Treat 132(2):545-553
65. Mahmoud SM, Paish EC, Powe DG et al (2011) Tumor-infiltrating CD8? lymphocytes predict clinical outcome in breast cancer. J Clin Oncol 29(15):1949-1955
66. Ruffell B, Au A, Rugo HS et al (2011) Leukocyte composition of human breast cancer. Proc Natl Acad Sci USA 109(8):2796-2801
67. Denardo DG, Brennan DJ, Rexhepaj E et al (2011) Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1:54-67
68. Menard S, Tomasic G, Casalini P et al (1997) Lymphoid infiltration as a prognostic variable for early-onset breast carcinomas. Clin Cancer Res 3(5):817-819
69. Calabro A, Beissbarth T, Kuner R et al (2009) Effects of infiltrating lymphocytes and estrogen receptor on gene expression and prognosis in breast cancer. Breast Cancer Res Treat 116(1):69-77
70. Mukhtar RA, Nseyo O, Campbell MJ et al (2011) Tumorassociated macrophages in breast cancer as potential biomarkers for new treatments and diagnostics. Expert Rev Mol Diagn 11(1):91-100
71. Lee AH, Happerfield LC, Bobrow LG et al (1997) Angiogenesis and inflammation in invasive carcinoma of the breast. J Clin Pathol 50(8):669-673
72. Campbell MJ, Tonlaar NY, Garwood ER et al (2011) Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. Breast Cancer Res Treat 128(3):703-711
73. Leek RD, Lewis CE, Whitehouse R et al (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56(20):4625-4629
74. Lin EY, Li JF, Gnatovskiy L et al (2006) Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66(23):11238-11246
75. Fujimoto H, Sangai T, Ishii G et al (2009) Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer 125(6):1276-1284
76. Tsutsui S, Yasuda K, Suzuki K et al (2005) Macrophage infiltration and its prognostic implications in breast cancer: The relationship with VEGF expression and microvessel density. Oncol Rep 14(2):425-431
77. Bolat F, Kayaselcuk F, Nursal TZ et al (2006) Microvessel density, VEGF expression, and tumor-associated macrophages in breast tumors: Correlations with prognostic parameters. J Exp Clin Cancer Res 25(3):365-372
78. Gottfried E, Kunz-Schughart LA, Weber A et al (2008) Expression of CD68 in non-myeloid cell types. Scand J Immunol 67(5):453-463
79. Meric JB, Rottey S, Olaussen K et al (2006) Cyclooxygenase-2 as a target for anticancer drug development. Crit Rev Oncol Hematol 59(1):51-64
80. Ricciotti E, Fitzgerald GA (2010) Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol 31(5):986-1000
81. Denkert C, Winzer KJ, Muller BM et al (2003) Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma. Cancer 97(12):2978-2987
82. Boland GP, Butt IS, Prasad R et al (2004) COX-2 expression is associated with an aggressive phenotype in ductal carcinoma in situ. Br J Cancer 90(2):423-429
83. Wulfing P, Diallo R, Muller C et al (2003) Analysis of cyclooxygenase-2 expression in human breast cancer: High throughput tissue microarray analysis. J Cancer Res Clin Oncol 129(7):375-382
84. Denkert C, Winzer KJ, Hauptmann S (2004) Prognostic impact of cyclooxygenase-2 in breast cancer. Clin Breast Cancer 4(6):428-433
85. Hu M, Peluffo G, Chen H et al (2009) Role of COX-2 in epithelial-stromal cell interactions and progression of ductal carcinoma in situ of the breast. Proc Nat Acad Sci USA 106(9): 3372-3377
86. Howe LR, Chang SH, Tolle KC et al (2005) HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-2 knockout mice. Cancer Res 65(21):10113-10119
87. Perrone G, Santini D, Vincenzi B et al (2005) COX-2 expression in DCIS: Correlation with VEGF, HER-2/neu, prognostic molecular markers and clinicopathological features. Histopathology 46(5):561-568
88. Kerlikowske K, Molinaro AM, Gauthier ML et al (2010) Biomarker expression and risk of subsequent tumors after initial ductal carcinoma in situ diagnosis. J Nat Cancer Inst 102(9): 627-637
89. Radisky DC, Santisteban M, Berman HK et al (2011) p16(INK4a) expression and breast cancer risk in women with atypical hyperplasia. Cancer Prev Res (Phila) 4(12):1953-1960
90. Yang WT, Lewis MT, Hess K et al (2010) Decreased TGFbeta signaling and increased COX2 expression in high risk women with increased mammographic breast density. Breast Cancer Res Treat 119(2):305-314
91. Hu M, Yao J, Carroll DK et al (2008) Regulation of in situ to invasive breast carcinoma transition. Cancer Cell 13(5):394-406
92. Baglole CJ, Ray DM, Bernstein SH et al (2006) More than structural cells, fibroblasts create and orchestrate the tumor microenvironment. Immunol Invest 35(3-4):297-325
93. Ulrich CM, Bigler J, Potter JD (2006) Non-steroidal antiinflammatory drugs for cancer prevention: Promise, perils and pharmacogenetics. Nat Rev Cancer 6(2):130-140
94. Butcher DT, Alliston T, Weaver VM (2009) A tense situation: Forcing tumour progression. Nat Rev Cancer 9(2):108-122
95. DuFort CC, Paszek MJ, Weaver VM (2011) Balancing forces: Architectural control of mechanotransduction. Nat Rev Mol Cell Biol 12(5):308-319
96. Weaver VM, Petersen OW, Wang F et al (1997) Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J Cell Biol 137(1):231-245
97. Paszek MJ, Zahir N, Johnson KR et al (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8(3):241-254
98. Huang S, Ingber DE (2005) Cell tension, matrix mechanics, and cancer development. Cancer Cell 8(3):175-176
99. Provenzano PP, Inman DR, Eliceiri KW et al (2008) Collagen density promotes mammary tumor initiation and progression. BMC Med 6:11
100. Erler JT, Bennewith KL, Nicolau M et al (2006) Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440(7088):1222-1226
101. Kirschmann DA, Seftor EA, Nieva DR et al (1999) Differentially expressed genes associated with the metastatic phenotype in breast cancer. Breast Cancer Res Treat 55(2):127-136
102. Peyrol S, Raccurt M, Gerard F et al (1997) Lysyl oxidase gene expression in the stromal reaction to in situ and invasive ductal breast carcinoma. Am J Pathol 150(2):497-507
103. Kuperwasser C, Chavarria T, Wu M et al (2004) Reconstruction of functionally normal and malignant human breast tissues in mice. Proc Natl Acad Sci USA 101(14):4966-4971
104. Levental KR, Yu H, Kass L et al (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139(5):891-906
105. Decitre M, Gleyzal C, Raccurt M et al (1998) Lysyl oxidase-like protein localizes to sites of de novo fibrinogenesis in fibrosis and in the early stromal reaction of ductal breast carcinomas. Lab Invest 78(2):143-151
106. Barry-Hamilton V, Spangler R, Marshall D et al (2010) Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 16(9):1009-1017
107. Hu M, Yao J, Cai L et al (2005) Distinct epigenetic changes in the stromal cells of breast cancers. Nat Genet 37(8):899-905
108. Campbell I, Polyak K, Haviv I (2009) Clonal mutations in the cancer-associated fibroblasts: The case against genetic coevolution. Cancer Res 69(17):6765-6768 discussion 9
109. Enkelmann A, Heinzelmann J, von Eggeling F et al (2011) Specific protein and miRNA patterns characterise tumourassociated fibroblasts in bladder cancer. J Cancer Res Clin Oncol 137(5):751-759
110. Fiegl H, Millinger S, Goebel G et al (2006) Breast cancer DNA methylation profiles in cancer cells and tumor stroma: Association with HER-2/neu status in primary breast cancer. Cancer Res 66(1):29-33
111. Orimo A, Weinberg RA (2006) Stromal fibroblasts in cancer: A novel tumor-promoting cell type. Cell Cycle 5(15):1597-1601
112. Jiang L, Gonda TA, Gamble MV et al (2008) Global hypomethylation of genomic DNA in cancer-associated myofibroblasts. Cancer Res 68(23):9900-9908
113. Ronnov-Jessen L, Petersen OW (1993) Induction of alphasmooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab Invest 68(6): 696-707
114. Desmouliere A, Chaponnier C, Gabbiani G (2005) Tissue repair, contraction, and the myofibroblast. Wound Repair Regen 13(1): 7-12
115. Krenning G, Zeisberg EM, Kalluri R (2010) The origin of fibroblasts and mechanism of cardiac fibrosis. J Cell Physiol 225(3):631-637
116. Bechtel W, McGoohan S, Zeisberg EM et al (2010) Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med 16(5):544-550
117. Cheng N, Chytil A, Shyr Y et al (2007) Enhanced hepatocyte growth factor signaling by type II transforming growth factorbeta receptor knockout fibroblasts promotes mammary tumorigenesis. Cancer Res 67(10):4869-4877
118. Bhowmick NA, Chytil A, Plieth D et al (2004) TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303(5659):848-851
119. Trimboli AJ, Cantemir-Stone CZ, Li F et al (2009) Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature 461(7267):1084-1091
120. Fazi F, Nervi C (2008) MicroRNA: Basic mechanisms and transcriptional regulatory networks for cell fate determination. Cardiovasc Res 79(4):553-561
121. Gangaraju VK, Lin H (2009) MicroRNAs: Key regulators of stem cells. Nat Rev Mol Cell Biol 10(2):116-125
122. Leung AK, Sharp PA (2006) Function and localization of microRNAs in mammalian cells. Cold Spring Harb Symp Quant Biol 71:29-38
123. Tiscornia G, Izpisua Belmonte JC (2010) MicroRNAs in embryonic stem cell function and fate. Genes Dev 24(24): 2732-2741
124. Davis BN, Hata A (2010) microRNA in cancer: The involvement of aberrant microRNA biogenesis regulatory pathways. Genes Cancer 1(11):1100-1114
125. Farazi TA, Horlings HM, Ten Hoeve JJ et al (2011) MicroRNA sequence and expression analysis in breast tumors by deep sequencing. Cancer Res 71(13):4443-4453
126. Iliopoulos D, Hirsch HA, Struhl K (2009) An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139(4):693-706
127. Iliopoulos D, Jaeger SA, Hirsch HA et al (2010) STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell 39(4):493-506
128. Iorio MV, Ferracin M, Liu CG et al (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65(16):7065-7070
129. Jazbutyte V, Thum T (2010) MicroRNA-21: From cancer to cardiovascular disease. Curr Drug Targets 11(8):926-935
130. Davis BN, Hilyard AC, Lagna G et al (2008) SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454(7200):56-61
131. Liu G, Friggeri A, Yang Y et al (2010) miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J Exp Med 207(8):1589-1597
132. Thum T, Gross C, Fiedler J et al (2008) MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456(7224):980-984
133. Yao Q, Cao S, Li C et al (2011) Micro-RNA-21 regulates TGFbeta-induced myofibroblast differentiation by targeting PDCD4 in tumor-stroma interaction. Int J Cancer 128(8):1783-1792
134. Lu Z, Liu M, Stribinskis V et al (2008) MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene 27(31):4373-4379
135. Song B, Wang C, Liu J et al (2010) MicroRNA-21 regulates breast cancer invasion partly by targeting tissue inhibitor of metalloproteinase 3 expression. J Exp Clin Cancer Res 29:29
136. Zhu S, Wu H,Wu F et al (2008) MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res 18(3):350-359
137. Qian B, Katsaros D, Lu L et al (2008) High miR-21 expression in breast cancer associated with poor disease-free survival in early stage disease and high TGF-beta1. Breast Cancer Res Treat 117(1):131-140
138. Farmer P, Bonnefoi H, Anderle P et al (2009) A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med 15(1):68-74
139. Ostermann E, Garin-Chesa P, Heider KH et al (2008) Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clin Cancer Res 14(14):4584-4592