Open Access

Cancer associated fibroblasts: An essential role in the tumor microenvironment (Review)

  • Authors:
    • Leilei Tao
    • Guichun Huang
    • Haizhu Song
    • Yitian Chen
    • Longbang Chen
  • View Affiliations

  • Published online on: June 30, 2017     https://doi.org/10.3892/ol.2017.6497
  • Pages: 2611-2620
  • Copyright: © Tao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Fibroblasts in the tumor stroma are well recognized as having an indispensable role in carcinogenesis, including in the initiation of epithelial tumor formation. The association between cancer cells and fibroblasts has been highlighted in several previous studies. Regulation factors released from cancer‑associated fibroblasts (CAFs) into the tumor microenvironment have essential roles, including the support of tumor growth, angiogenesis, metastasis and therapy resistance. A mutual interaction between tumor‑induced fibroblast activation, and fibroblast‑induced tumor proliferation and metastasis occurs, thus CAFs act as tumor supporters. Previous studies have reported that by developing fibroblast‑targeting drugs, it may be possible to interrupt the interaction between fibroblasts and the tumor, thus resulting in the suppression of tumor growth, and metastasis. The present review focused on the reciprocal feedback loop between fibroblasts and cancer cells, and evaluated the potential application of anti‑CAF agents in the treatment of cancer.

References

1 

Balkwill FR, Capasso M and Hagemann T: The tumor microenvironment at a glance. J Cell Sci. 125:5591–5596. 2012. View Article : Google Scholar : PubMed/NCBI

2 

Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000. View Article : Google Scholar : PubMed/NCBI

3 

Spano D and Zollo M: Tumor microenvironment: A main actor in the metastasis process. Clin Exp Metastasis. 29:381–395. 2012. View Article : Google Scholar : PubMed/NCBI

4 

Swartz MA, Iida N, Roberts EW, Sangaletti S, Wong MH, Yull FE, Coussens LM and DeClerck YA: Tumor microenvironment complexity: Emerging roles in cancer therapy. Cancer Res. 72:2473–2480. 2012. View Article : Google Scholar : PubMed/NCBI

5 

Quail DF and Joyce JA: Microenvironmental regulation of tumor progression and metastasis. Nat Med. 19:1423–1437. 2013. View Article : Google Scholar : PubMed/NCBI

6 

Cirri P and Chiarugi P: Cancer-associated-fibroblasts and tumour cells: A diabolic liaison driving cancer progression. Cancer Metast Rev. 31:195–208. 2012. View Article : Google Scholar

7 

Marsh T, Pietras K and McAllister SS: Fibroblasts as architects of cancer pathogenesis. Biochim Biophys Acta. 1832:1070–1078. 2013. View Article : Google Scholar : PubMed/NCBI

8 

Sun Y: Translational horizons in the tumor microenvironment: Harnessing breakthroughs and targeting cures. Med Res Rev. 35:408–436. 2015. View Article : Google Scholar : PubMed/NCBI

9 

Slany A, Bileck A, Muqaku B and Gerner C: Targeting breast cancer-associated fibroblasts to improve anti-cancer therapy. Breast. 24:532–538. 2015. View Article : Google Scholar : PubMed/NCBI

10 

Anderberg C and Pietras K: On the origin of cancer-associated fibroblasts. Cell Cycle. 8:1461–1462. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Liu Y, Hu T, Shen J, Li SF, Lin JW, Zheng XH, Gao QH and Zhou HM: Separation, cultivation and biological characteristics of oral carcinoma-associated fibroblasts. Oral Dis. 12:375–380. 2006. View Article : Google Scholar : PubMed/NCBI

12 

Sugimoto H, Mundel TM, Kieran MW and Kalluri R: Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol Ther. 5:1640–1646. 2006. View Article : Google Scholar : PubMed/NCBI

13 

Park JE, Lenter MC, Zimmermann RN, Garin-Chesa P, Old LJ and Rettig WJ: Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts. J Biol Chem. 274:36505–36512. 1999. View Article : Google Scholar : PubMed/NCBI

14 

Kim HM, Jung WH and Koo JS: Expression of cancer-associated fibroblast related proteins in metastatic breast cancer: An immunohistochemical analysis. J Transl Med. 13:2222015. View Article : Google Scholar : PubMed/NCBI

15 

Rupp C, Scherzer M, Rudisch A, Unger C, Haslinger C, Schweifer N, Artaker M, Nivarthi H, Moriggl R, Hengstschläger M, et al: IGFBP7, a novel tumor stroma marker, with growth-promoting effects in colon cancer through a paracrine tumor-stroma interaction. Oncogene. 34:815–825. 2015. View Article : Google Scholar : PubMed/NCBI

16 

Navab R, Strumpf D, Bandarchi B, Zhu CQ, Pintilie M, Ramnarine VR, Ibrahimov E, Radulovich N, Leung L, Barczyk M, et al: Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer. Proc Natl Acad Sci USA. 108:pp. 7160–7165. 2011; View Article : Google Scholar : PubMed/NCBI

17 

Zhu CQ, Popova SN, Brown ER, Barsyte-Lovejoy D, Navab R, Shih W, Li M, Lu M, Jurisica I, Penn LZ, et al: Integrin alpha11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells. Proc Natl Acad Sci USA. 104:pp. 11754–11759. 2007; View Article : Google Scholar : PubMed/NCBI

18 

Nakagawa H, Liyanarachchi S, Davuluri RV, Auer H, Martin EW Jr, de la Chapelle A and Frankel WL: Role of cancer-associated stromal fibroblasts in metastatic colon cancer to the liver and their expression profiles. Oncogene. 23:7366–7377. 2004. View Article : Google Scholar : PubMed/NCBI

19 

Walter K, Omura N, Hong SM, Griffith M, Vincent A, Borges M and Goggins M: Overexpression of smoothened activates the sonic hedgehog signaling pathway in pancreatic cancer-associated fibroblasts. Clin Cancer Res. 16:1781–1789. 2010. View Article : Google Scholar : PubMed/NCBI

20 

Rozenchan PB, Carraro DM, Brentani H, de Carvalho Mota LD, Bastos EP, e Ferreira EN, Torres CH, Katayama ML, Roela RA, Lyra EC, et al: Reciprocal changes in gene expression profiles of cocultured breast epithelial cells and primary fibroblasts. Int J Cancer. 125:2767–2777. 2009. View Article : Google Scholar : PubMed/NCBI

21 

Kalluri R and Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer. 6:392–401. 2006. View Article : Google Scholar : PubMed/NCBI

22 

Räsänen K and Vaheri A: Activation of fibroblasts in cancer stroma. Exp Cell Res. 316:2713–2722. 2010. View Article : Google Scholar : PubMed/NCBI

23 

Clayton A, Evans RA, Pettit E, Hallett M, Williams JD and Steadman R: Cellular activation through the ligation of intercellular adhesion molecule-1. J Cell Sci. 111:443–453. 1998.PubMed/NCBI

24 

Zhang B, Pan X, Cobb GP and Anderson TA: microRNAs as oncogenes and tumor suppressors. Dev Biol. 302:1–12. 2007. View Article : Google Scholar : PubMed/NCBI

25 

Mitra AK, Zillhardt M, Hua Y, Tiwari P, Murmann AE, Peter ME and Lengyel E: MicroRNAs reprogram normal fibroblasts into cancer-associated fibroblasts in ovarian cancer. Cancer Discov. 2:1100–1108. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Zhao L, Sun Y, Hou Y, Peng Q, Wang L, Luo H, Tang X, Zeng Z and Liu M: MiRNA expression analysis of cancer-associated fibroblasts and normal fibroblasts in breast cancer. Int J Biochem Cell Biol. 44:2051–2059. 2012. View Article : Google Scholar : PubMed/NCBI

27 

Enkelmann A, Heinzelmann J, von Eggeling F, Walter M, Berndt A, Wunderlich H and Junker K: Specific protein and miRNA patterns characterise tumour-associated fibroblasts in bladder cancer. J Cancer Res Clin Oncol. 137:751–759. 2011. View Article : Google Scholar : PubMed/NCBI

28 

Yu Z, Willmarth NE, Zhou J, Katiyar S, Wang M, Liu Y, McCue PA, Quong AA, Lisanti MP and Pestell RG: microRNA 17/20 inhibits cellular invasion and tumor metastasis in breast cancer by heterotypic signaling. Proc Natl Acad Sci USA. 107:pp. 8231–8236. 2010; View Article : Google Scholar : PubMed/NCBI

29 

Aprelikova O, Yu X, Palla J, Wei BR, John S, Yi M, Stephens R, Simpson RM, Risinger JI, Jazaeri A and Niederhuber J: The role of miR-31 and its target gene SATB2 in cancer-associated fibroblasts. Cell Cycle. 9:4387–4398. 2014. View Article : Google Scholar

30 

Wang S, Wang Z, Xu K, Ruan Z and Chen L: miRNA expression analysis of cancer-associated fibroblasts and normal fibroblasts in colorectal cancer. J Mod Oncol. 09:1918–1922. 2013.

31 

Bhowmick NA, Neilson E G and Moses HL: Stromal fibroblasts in cancer initiation and progression. Nature. 432:332–337. 2004. View Article : Google Scholar : PubMed/NCBI

32 

Gonda TA, Varro A, Wang TC and Tycko B: Molecular biology of cancer-associated fibroblasts: Can these cells be targeted in anti-cancer therapy? Seminars Cell Dev Biol. 21:pp. 2–10. 2009; View Article : Google Scholar

33 

Ostman A and Augsten M: Cancer-associated fibroblasts and tumor growth-bystanders turning into key players. Curr Opin Genet Dev. 19:67–73. 2009. View Article : Google Scholar : PubMed/NCBI

34 

Servais C and Erez N: From sentinel cells to inflammatory culprits: Cancer-associated fibroblasts in tumour-related inflammation. J Pathol. 229:198–207. 2013. View Article : Google Scholar : PubMed/NCBI

35 

Luker KE, Lewin SA, Mihalko LA, Schmidt BT, Winkler JS, Coggins NL, Thomas DG and Luker GD: Scavenging of CXCL12 by CXCR7 promotes tumor growth and metastasis of CXCR4-positive breast cancer cells. Oncogene. 31:4750–4758. 2012. View Article : Google Scholar : PubMed/NCBI

36 

Augsten M, Sjöberg E, Frings O, Vorrink SU, Frijhoff J, Olsson E, Borg Å and Östman A: Cancer-associated fibroblasts expressing CXCL14 rely upon NOS1-derived nitric oxide signaling for their tumor-supporting properties. Cancer Res. 74:2999–3010. 2014. View Article : Google Scholar : PubMed/NCBI

37 

Mi Z, Bhattacharya SD, Kim VM, Guo H, Talbot LJ and Kuo PC: Osteopontin promotes CCL5-mesenchymal stromal cell-mediated breast cancer metastasis. Carcinogenesis. 32:477–487. 2011. View Article : Google Scholar : PubMed/NCBI

38 

Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, Baik GH, Shibata W, Diprete B, Betz KS, et al: Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell. 19:257–272. 2011. View Article : Google Scholar : PubMed/NCBI

39 

Li X, Xu Q, Wu Y, Li J, Tang D, Han L and Fan Q: A CCL2/ROS autoregulation loop is critical for cancer-associated fibroblasts-enhanced tumor growth of oral squamous cell carcinoma. Carcinogenesis. 35:1362–1370. 2014. View Article : Google Scholar : PubMed/NCBI

40 

Shibuya M and Claesson-Welsh L: Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res. 312:549–560. 2006. View Article : Google Scholar : PubMed/NCBI

41 

Gomes FG, Nedel F, Alves AM, Nör JE and Tarquinio SB: Tumor angiogenesis and lymphangiogenesis: Tumor/endothelial crosstalk and cellular/microenvironmental signaling mechanisms. Life Sci. 92:101–107. 2013. View Article : Google Scholar : PubMed/NCBI

42 

Ferrara N: Pathways mediating VEGF-independent tumor angiogenesis. Cytokine Growth Factor Rev. 21:21–26. 2010. View Article : Google Scholar : PubMed/NCBI

43 

Zhang J and Liu J: Tumor stroma as targets for cancer therapy. Pharmacol Ther. 137:200–215. 2013. View Article : Google Scholar : PubMed/NCBI

44 

Nagasaki T, Hara M, Nakanishi H, Takahashi H, Sato M and Takeyama H: Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: Anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction. Br J Cancer. 110:469–478. 2014. View Article : Google Scholar : PubMed/NCBI

45 

Karagiannis GS, Poutahidis T, Erdman SE, Kirsch R, Riddell RH and Diamandis EP: Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Mol Cancer Res. 10:1403–1418. 2012. View Article : Google Scholar : PubMed/NCBI

46 

Vpavlides S, Vera I, Gandara R, Sneddon S, Pestell RG, Mercier I, Martinez-Outschoorn UE, Whitaker-Menezes D, Howell A, Sotgia F and Lisanti MP: Warburg meets autophagy: Cancer-associated fibroblasts accelerate tumor growth and metastasis via oxidative stress, mitophagy, and aerobic glycolysis. Antioxid Redox Signal. 16:1264–1284. 2012. View Article : Google Scholar : PubMed/NCBI

47 

De Wever O, Van Bockstal M, Mareel M, Hendrix A and Bracke M: Carcinoma-associated fibroblasts provide operational flexibility in metastasis. Semin Cancer Biol. 25:33–46. 2014. View Article : Google Scholar : PubMed/NCBI

48 

Dumont N, Liu B, DeFilippis RA, Chang H, Rabban JT, Karnezis AN, Tjoe JA, Marx J, Parvin B and Tlsty TD: Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics. Neoplasia. 15:249–262. 2013. View Article : Google Scholar : PubMed/NCBI

49 

Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD and Cunha GR: Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59:5002–5011. 1999.PubMed/NCBI

50 

Calvo F, Ege N, Grande-Garcia A, Hooper S, Jenkins RP, Chaudhry SI, Harrington K, Williamson P, Moeendarbary E, Charras G and Sahai E: Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol. 15:637–646. 2013. View Article : Google Scholar : PubMed/NCBI

51 

Erez N, Truitt M, Olson P, Arron ST and Hanahan D: Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer cell. 17:135–147. 2010. View Article : Google Scholar : PubMed/NCBI

52 

Zhang XH, Jin X, Malladi S, Zou Y, Wen YH, Brogi E, Smid M, Foekens JA and Massagué J: Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell. 154:1060–1073. 2013. View Article : Google Scholar : PubMed/NCBI

53 

Aprelikova O, Palla J, Hibler B, Yu X, Greer YE, Yi M, Stephens R, Maxwell GL, Jazaeri A, Risinger JI, et al: Silencing of miR-148a in cancer-associated fibroblasts results in WNT10B-mediated stimulation of tumor cell motility. Oncogene. 32:3246–3253. 2013. View Article : Google Scholar : PubMed/NCBI

54 

Verghese ET, Drury R, Green CA, Holliday DL, Lu X, Nash C, Speirs V, Thorne JL, Thygesen HH, Zougman A, et al: MiR-26b is down-regulated in carcinoma-associated fibroblasts from ER-positive breast cancers leading to enhanced cell migration and invasion. J Pathol. 231:388–399. 2013. View Article : Google Scholar : PubMed/NCBI

55 

Bronisz A, Godlewski J, Wallace JA, Merchant AS, Nowicki MO, Mathsyaraja H, Srinivasan R, Trimboli AJ, Martin CK, Li F, et al: Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320. Nat Cell Biol. 14:159–167. 2012. View Article : Google Scholar

56 

Mongiat M, Marastoni S, Ligresti G, Lorenzon E, Schiappacassi M, Perris R, Frustaci S and Colombatti A: The extracellular matrix glycoprotein elastin microfibril interface located protein 2: A dual role in the tumor microenvironment. Neoplasia. 12:294–304. 2010. View Article : Google Scholar : PubMed/NCBI

57 

Correia AL and Bissell MJ: The tumor microenvironment is a dominant force in multidrug resistance. Drug Resist Updat. 15:39–49. 2012. View Article : Google Scholar : PubMed/NCBI

58 

Kerbel RS: A cancer therapy resistant to resistance. Nature. 390:335–336. 1997. View Article : Google Scholar : PubMed/NCBI

59 

Swartz MA and Lund AW: Lymphatic and interstitial flow in the tumour microenvironment: Linking mechanobiology with immunity. Nat Rev Cancer. 12:210–219. 2012. View Article : Google Scholar : PubMed/NCBI

60 

Khawar IA, Kim JH and Kuh HJ: Improving drug delivery to solid tumors: Priming the tumor microenvironment. J Control Release. 201:78–89. 2015. View Article : Google Scholar : PubMed/NCBI

61 

Pietras K, Östman A, Sjöquist M, Buchdunger E, Reed RK, Heldin CH and Rubin K: Inhibition of Platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res. 61:2929–2934. 2001.PubMed/NCBI

62 

Pietras K, Rubin K, Sjöblom T, Buchdunger E, Sjöquist M, Heldin CH and Ostman A: Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy. Cancer Res. 62:5476–5484. 2002.PubMed/NCBI

63 

Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, Peng J, Lin E, Wang Y, Sosman J, et al: Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature. 487:505–509. 2012. View Article : Google Scholar : PubMed/NCBI

64 

Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, et al: Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 487:500–504. 2012. View Article : Google Scholar : PubMed/NCBI

65 

Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science. 304:1497–1500. 2004. View Article : Google Scholar : PubMed/NCBI

66 

Yano S, Wang W, Li Q, Yamada T, Takeuchi S, Matsumoto K, Nishioka Y and Sone S: HGF-MET in resistance to EGFR tyrosine kinase inhibitors in lung cancer. Curr Signal Trans Ther. 6:228–233. 2011. View Article : Google Scholar

67 

Liska D, Chen CT, Bachleitner-Hofmann T, Christensen JG and Weiser MR: HGF rescues colorectal cancer cells from EGFR inhibition via MET activation. Clin Cancer Res. 17:472–482. 2011. View Article : Google Scholar : PubMed/NCBI

68 

Yamatodani T, Ekblad L, Kjellén E, Johnsson A, Mineta H and Wennerberg J: Epidermal growth factor receptor status and persistent activation of Akt and p44/42 MAPK pathways correlate with the effect of cetuximab in head and neck and colon cancer cell lines. J Cancer Res Clin Oncol. 135:3954022009. View Article : Google Scholar

69 

Liska D, Chen CT, Bachleitner-Hofmann T, Christensen JG and Weiser MR: HGF rescues colorectal cancer cells from EGFR inhibition via MET activation. Clin Cancer Res. 17:472–482. 2011. View Article : Google Scholar : PubMed/NCBI

70 

Luraghi P, Reato G, Cipriano E, Sassi F, Orzan F, Bigatto V, De Bacco F, Menietti E, Han M, Rideout WM III, et al: MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors. Cancer Res. 74:1857–1869. 2014. View Article : Google Scholar : PubMed/NCBI

71 

Qian DZ, Rademacher BL, Pittsenbarger J, Huang CY, Myrthue A, Higano CS, Garzotto M, Nelson PS and Beer TM: CCL2 is induced by chemotherapy and protects prostate cancer cells from docetaxel-induced cytotoxicity. Prostate. 70:433–442. 2010.PubMed/NCBI

72 

Moisan F, Francisco EB, Brozovic A, Duran GE, Wang YC, Chaturvedi S, Seetharam S, Snyder LA, Doshi P and Sikic BI: Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers. Mol Oncol. 8:1231–1239. 2014. View Article : Google Scholar : PubMed/NCBI

73 

Tsuyada A, Chow A, Wu J, Somlo G, Chu P, Loera S, Luu T, Li AX, Wu X, Ye W, et al: CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer Res. 72:2768–2779. 2012. View Article : Google Scholar : PubMed/NCBI

74 

Weekes CD, Song D, Arcaroli J, Wilson LA, Rubio-Viqueira B, Cusatis G, Garrett-Mayer E, Messersmith WA, Winn RA and Hidalgo M: Stromal cell-derived factor 1α mediates resistance to mTOR-directed therapy in pancreatic cancer. Neoplasia. 14:690–701. 2012. View Article : Google Scholar : PubMed/NCBI

75 

Singh S, Srivastava SK, Bhardwaj A, Owen LB and Singh AP: CXCL12-CXCR4 signalling axis confers gemcitabine resistance to pancreatic cancer cells: A novel target for therapy. Br J Cancer. 103:1671–1679. 2010. View Article : Google Scholar : PubMed/NCBI

76 

Domanska UM, Timmer-Bosscha H, Nagengast WB, Munnink TH Oude, Kruizinga RC, Ananias HJ, Kliphuis NM, Huls G, De Vries EG, de Jong IJ and Walenkamp AM: CXCR4 inhibition with AMD3100 sensitizes prostate cancer to docetaxel chemotherapy. Neoplasia. 14:709–718. 2012. View Article : Google Scholar : PubMed/NCBI

77 

Heckmann D, Maier P, Laufs S, Wenz F, Zeller WJ, Fruehauf S and Allgayer H: CXCR4 expression and treatment with SDF-1α or plerixafor modulate proliferation and chemosensitivity of colon cancer cells. Transl Oncol. 6:124–132. 2013. View Article : Google Scholar : PubMed/NCBI

78 

Burger JA, Stewart DJ, Wald O and Peled A: Potential of CXCR4 antagonists for the treatment of metastatic lung cancer. Expert Rev Anticancer Ther. 11:621–630. 2011. View Article : Google Scholar : PubMed/NCBI

79 

Lotti F, Jarrar AM, Pai RK, Hitomi M, Lathia J, Mace A, Gantt GA Jr, Sukhdeo K, DeVecchio J, Vasanji A, et al: Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J Exp Med. 210:2851–2872. 2013. View Article : Google Scholar : PubMed/NCBI

80 

Cochaud S, Giustiniani J, Thomas C, Laprevotte E, Garbar C, Savoye AM, Curé H, Mascaux C, Alberici G, Bonnefoy N, et al: IL-17A is produced by breast cancer TILs and promotes chemoresistance and proliferation through ERK1/2. Sci Rep. 3:34562013. View Article : Google Scholar : PubMed/NCBI

81 

Studebaker AW, Storci G, Werbeck JL, Sansone P, Sasser AK, Tavolari S, Huang T, Chan MW, Marini FC, Rosol TJ, et al: Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner. Cancer Res. 68:9087–9095. 2008. View Article : Google Scholar : PubMed/NCBI

82 

Gao SP, Mark KG, Leslie K, Pao W, Motoi N, Gerald WL, Travis WD, Bornmann W, Veach D, Clarkson B and Bromberg JF: Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest. 117:3846–3856. 2007. View Article : Google Scholar : PubMed/NCBI

83 

Yao Z, Fenoglio S, Gao DC, Camiolo M, Stiles B, Lindsted T, Schlederer M, Johns C, Altorki N, Mittal V, et al: TGF-beta IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proc Natl Acad Sci USA. 107:pp. 15535–15540. 2010; View Article : Google Scholar : PubMed/NCBI

84 

Sun X, Mao Y, Wang J, Zu L, Hao M, Cheng G, Qu Q, Cui D, Keller ET, Chen X, et al: IL-6 secreted by cancer-associated fibroblasts induces tamoxifen resistance in luminal breast cancer. Oncogene. doi: 10.1038/onc.2014.158.

85 

Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I, True L and Nelson PS: Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med. 18:1359–1368. 2012. View Article : Google Scholar : PubMed/NCBI

86 

Amornsupuk K, Insawang T, Thuwajit P, O-Charoenrat P, Eccles SA and Thuwajit C: Cancer-associated fibroblasts induce high mobility group box 1 and contribute to resistance to doxorubicin in breast cancer cells. BMC Cancer. 14:9552014. View Article : Google Scholar : PubMed/NCBI

87 

Cullen KJ, Smith HS, Hill S, Rosen N and Lippman ME: Growth factor messenger RNA expression by human breast fibroblasts from benign and malignant lesions. Cancer Res. 51:4978–4985. 1991.PubMed/NCBI

88 

Shay G, Lynch CC and Fingleton B: Moving targets: Emerging roles for MMPs in cancer progression and metastasis. Matrix Biol 44–46. 1–206. 2015.

89 

Jia CC, Wang TT, Liu W, Fu BS, Hua X, Wang GY, Li TJ, Li X, Wu XY, Tai Y, et al: Cancer-associated fibroblasts from hepatocellular carcinoma promote malignant cell proliferation by HGF secretion. PLoS One. 8:e632432013. View Article : Google Scholar : PubMed/NCBI

90 

Lin J, Liu C, Ge L, Gao Q, He X, Liu Y, Li S, Zhou M, Chen Q and Zhou H: Carcinoma-associated fibroblasts promotes the proliferation of a lingual carcinoma cell line by secreting keratinocyte growth factor. Tumor Biol. 32:597–602. 2011. View Article : Google Scholar

91 

Weroha SJ and Haluska P: The insulin-like growth factor system in cancer. Endocrinol Metab Clin North Am. 41:335–350.vi. 2012. View Article : Google Scholar : PubMed/NCBI

92 

Hawinkels LJ, Paauwe M, Verspaget HW, Wiercinska E, van der Zon JM, van der Ploeg K, Koelink PJ, Lindeman JH, Mesker W, ten Dijke P and Sier CF: Interaction with colon cancer cells hyperactivates TGF-β signaling in cancer-associated fibroblasts. Oncogene. 33:97–107. 2014. View Article : Google Scholar : PubMed/NCBI

93 

Mueller MM and Fusenig NE: Friends or foes-bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 4:839–849. 2004. View Article : Google Scholar : PubMed/NCBI

94 

Liu R, Li H, Liu L, Yu J and Ren X: Fibroblast activation protein: A potential therapeutic target in cancer. Cancer Biol Ther. 13:123–129. 2012. View Article : Google Scholar : PubMed/NCBI

95 

LeBeau AM, Brennen WN, Aggarwal S and Denmeade SR: Targeting the cancer stroma with a fibroblast activation protein-activated promelittin protoxin. Mol Cancer Ther. 8:1378–1386. 2009. View Article : Google Scholar : PubMed/NCBI

96 

Ostermann E, Garin-Chesa P, Heider KH, Kalat M, Lamche H, Puri C, Kerjaschki D, Rettig WJ and Adolf GR: Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clin Cancer Res. 14:4584–4592. 2008. View Article : Google Scholar : PubMed/NCBI

97 

Adams S, Miller GT, Jesson MI, Watanabe T, Jones B and Wallner BP: PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res. 64:5471–5480. 2004. View Article : Google Scholar : PubMed/NCBI

98 

Santos AM, Jung J, Aziz N, Kissil JL and Puré E: Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J Clin Invest. 119:3613–3625. 2009. View Article : Google Scholar : PubMed/NCBI

99 

Heldin CH: Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Signal. 11:972013. View Article : Google Scholar : PubMed/NCBI

100 

Steeghs N, Nortier JW and Gelderblom H: Small molecule tyrosine kinase inhibitors in the treatment of solid tumors: An update of recent developments. Ann Surg Oncol. 14:942–953. 2007. View Article : Google Scholar : PubMed/NCBI

101 

Pietras K, Pahler J, Bergers G and Hanahan D: Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLos Med. 5:e192008. View Article : Google Scholar : PubMed/NCBI

102 

Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, et al: BIBF 1120: Triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 68:4774–4782. 2008. View Article : Google Scholar : PubMed/NCBI

103 

Cecchi F, Rabe DC and Bottaro DP: Targeting the HGF/Met signaling pathway in cancer therapy. Expert Opin Ther Targets. 16:553–572. 2012. View Article : Google Scholar : PubMed/NCBI

104 

Gherardi E, Birchmeier W, Birchmeier C and Woude G Vande: Targeting MET in cancer: Rationale and progress. Nat Rev Cancer. 12:89–103. 2012. View Article : Google Scholar : PubMed/NCBI

105 

Sadiq AA and Salgia R: MET as a possible target for non-small-cell lung cancer. J Clin Oncol. 31:1089–1096. 2013. View Article : Google Scholar : PubMed/NCBI

106 

Oliner KS, Tang R, Anderson A, et al: Evaluation of MET pathway biomarkers in a phase II study of rilotumumab (R, AMG 102) or placebo (P) in combination with epirubicin, cisplatin and capecitabine (ECX) in patients (pts) with locally advanced or metastatic gastric (G) or esophagogastric junction (EGJ) cancerJ Clin Oncol Amer Soc Clin Oncol. 2318 Mill Road, Ste 800, Alexandria, Va 22314 USA: 2012

107 

Tan E, Park K, Lim WT, et al: Phase 1b study of ficlatuzumab (AV-299), an anti-hepatocyte growth factor monoclonal antibody, in combination with gefitinib in Asian patients with NSCLC. J Clin Oncol. 29 Suppl:493S2011. View Article : Google Scholar

108 

Katayama R, Aoyama A, Yamori T, Qi J, Oh-hara T, Song Y, Engelman JA and Fujita N: Cytotoxic activity of tivantinib (ARQ 197) is not due solely to c-MET inhibition. Cancer Res. 73:3087–3096. 2013. View Article : Google Scholar : PubMed/NCBI

109 

Wakelee H, Gettinger S, Engelman J, et al: A phase Ib/II study of XL184 (BMS 907351) with and without erlotinib (E) in patients (pts) with non-small cell lung cancer (NSCLC). ASCO Annual Meeting Proceedings. pp. 30172010;

110 

Tanizaki J, Okamoto I, Okamoto K, Takezawa K, Kuwata K, Yamaguchi H and Nakagawa K: MET tyrosine kinase inhibitor crizotinib (PF-02341066) shows differential antitumor effects in non-small cell lung cancer according to MET alterations. J Thorac Oncol. 6:1624–1631. 2011. View Article : Google Scholar : PubMed/NCBI

111 

Feng Y, Thiagarajan PS and Ma PC: MET signaling: Novel targeted inhibition and its clinical development in lung cancer. J Thorac Oncol. 7:459–467. 2012. View Article : Google Scholar : PubMed/NCBI

112 

Blumenschein GR Jr, Mills GB and Gonzalez-Angulo AM: Targeting the hepatocyte growth factor-cMET axis in cancer therapy. J Clin Oncol. 30:3287–3296. 2012. View Article : Google Scholar : PubMed/NCBI

113 

Egeblad M and Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2:161–174. 2002. View Article : Google Scholar : PubMed/NCBI

114 

Rundhaug JE: Matrix metalloproteinases and angiogenesis. J Cell Mol Med. 9:267–285. 2005. View Article : Google Scholar : PubMed/NCBI

115 

Pavlaki M and Zucker S: Matrix metalloproteinase inhibitors (MMPIs): The beginning of phase I or the termination of phase III clinical trials. Cancer Metastasis Rev. 22:177–203. 2003. View Article : Google Scholar : PubMed/NCBI

116 

Shepherd FA, Giaccone G, Seymour L, Debruyne C, Bezjak A, Hirsh V, Smylie M, Rubin S, Martins H, Lamont A, et al: Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: A trial of the national cancer institute of Canada-clinical trials group and the European organization for research and treatment of cancer. J Clin Oncol. 20:4434–4439. 2002. View Article : Google Scholar : PubMed/NCBI

117 

Konstantinopoulos PA, Karamouzis MV, Papatsoris AG and Papavassiliou AG: Matrix metalloproteinase inhibitors as anticancer agents. Int J Biochem Cell Biol. 40:1156–1168. 2008. View Article : Google Scholar : PubMed/NCBI

118 

Bierie B and Moses HL: TGF-β and cancer. Cytokine Growth Factor Rev. 17:29–40. 2006. View Article : Google Scholar : PubMed/NCBI

119 

Lonning S, Mannick J and McPherson J: Antibody targeting of TGF-β in cancer patients. Curr Pharm Biotechnol. 12:2176–2189. 2011. View Article : Google Scholar : PubMed/NCBI

120 

Hawinkels LJ and Ten Dijke P: Exploring anti-TGF-β therapies in cancer and fibrosis. Growth Factors. 29:140–152. 2011. View Article : Google Scholar : PubMed/NCBI

121 

Rodon J, Carducci MA, Sepulveda-Sánchez JM, Azaro A, Calvo E, Seoane J, Braña I, Sicart E, Gueorguieva I, Cleverly AL, et al: First-in-human dose study of the novel transforming growth factor-β receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma. Clin Cancer Res. 21:553–560. 2015. View Article : Google Scholar : PubMed/NCBI

122 

Rani B, Dituri F, Cao Y, Engström U, Lupo L, Dooley S, Moustakas A and Giannelli G: P0320: Targeting TGF-beta I with the transforming growth factor receptor type I kinase inhibitor, LY2157299, modulates stemness-related biomarkers in hepatocellular carcinoma. J Hepatol. 62:S4292015. View Article : Google Scholar

123 

Whatcott CJ, Dumas SN, Watanabe A, LoBello J, Von Hoff DD and Han H: Abstract 2135: TGFβRI inhibition results in reduced collagen expression in pancreatic ductal adenocarcinoma. Cancer Res. DOI: 10.1158/1538-7445.

124 

Johnstone CN, Chand A, Putoczki TL and Ernst M: Emerging roles for IL-11 signaling in cancer development and progression: Focus on breast cancer. Cytokine Growth Factor Rev. 26:489–498. 2015. View Article : Google Scholar : PubMed/NCBI

125 

Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Céspedes MV, Sevillano M, Nadal C, Jung P, Zhang XH, et al: Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell. 22:571–584. 2012. View Article : Google Scholar : PubMed/NCBI

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September 2017
Volume 14 Issue 3

Print ISSN: 1792-1074
Online ISSN:1792-1082

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APA
Tao, L., Huang, G., Song, H., Chen, Y., & Chen, L. (2017). Cancer associated fibroblasts: An essential role in the tumor microenvironment (Review). Oncology Letters, 14, 2611-2620. https://doi.org/10.3892/ol.2017.6497
MLA
Tao, L., Huang, G., Song, H., Chen, Y., Chen, L."Cancer associated fibroblasts: An essential role in the tumor microenvironment (Review)". Oncology Letters 14.3 (2017): 2611-2620.
Chicago
Tao, L., Huang, G., Song, H., Chen, Y., Chen, L."Cancer associated fibroblasts: An essential role in the tumor microenvironment (Review)". Oncology Letters 14, no. 3 (2017): 2611-2620. https://doi.org/10.3892/ol.2017.6497