Skip to main content

Advertisement

SpringerLink
Log in

The roles of tumor- and metastasis-promoting carcinoma-associated fibroblasts in human carcinomas

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Carcinoma-associated fibroblasts (CAFs) constitute a substantial proportion of the non-neoplastic mesenchymal cell compartment in various human tumors. These fibroblasts are phenotypically converted from their progenitors via interactions with nearby cancer cells during the course of tumor progression. The resulting CAFs, in turn, support the growth and progression of carcinoma cells. These fibroblasts have a major influence on the hallmarks of carcinoma and promote tumor malignancy through the secretion of tumor-promoting growth factors, cytokines and exosomes, as well as through the remodeling of the extracellular matrix. Coevolution of CAFs and carcinoma cells during tumorigenesis is therefore essential for progression into fully malignant tumors. Recent studies have revealed the molecular mechanisms underlying CAF functions, especially in tumor invasion, metastasis and drug resistance and have highlighted the significant heterogeneity among these cells. In this review, we summarize the impacts of recently identified roles of tumor-promoting CAFs and discuss the therapeutic implications of targeting the heterotypic interactions of these fibroblasts with carcinoma cells.

ᅟ

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H et al (2014) Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158:1110–1122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adegboyega PA, Mifflin RC, DiMari JF, Saada JI, Powell DW (2002) Immunohistochemical study of myofibroblasts in normal colonic mucosa, hyperplastic polyps, and adenomatous colorectal polyps. Arch Pathol Lab Med 126:829–836

    PubMed  Google Scholar 

  • Akhmetshina A, Palumbo K, Dees C, Bergmann C, Venalis P, Zerr P, Horn A, Kireva T, Beyer C, Zwerina J et al (2012) Activation of canonical Wnt signalling is required for TGF-beta-mediated fibrosis. Nat Commun 3:735

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Albrengues J, Bourget I, Pons C, Butet V, Hofman P, Tartare-Deckert S, Feral CC, Meneguzzi G, Gaggioli C (2014) LIF mediates proinvasive activation of stromal fibroblasts in cancer. Cell Rep 7:1664–1678

    Article  CAS  PubMed  Google Scholar 

  • Albrengues J, Bertero T, Grasset E, Bonan S, Maiel M, Bourget I, Philippe C, Herraiz Serrano C, Benamar S, Croce O et al (2015) Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts. Nat Commun 6:10204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alspach E, Flanagan KC, Luo X, Ruhland MK, Huang H, Pazolli E, Donlin MJ, Marsh T, Piwnica-Worms D, Monahan J et al (2014) p38MAPK plays a crucial role in stromal-mediated tumorigenesis. Cancer Discov 4:716–729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anderberg C, Pietras K (2009) On the origin of cancer-associated fibroblasts. Cell Cycle 8:1461–1462

    Article  CAS  PubMed  Google Scholar 

  • Augsten M (2014) Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front Oncol 4:62

    Article  PubMed  PubMed Central  Google Scholar 

  • Avgustinova A, Iravani M, Robertson D, Fearns A, Gao Q, Klingbeil P, Hanby AM, Speirs V, Sahai E, Calvo F et al (2016) Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness. Nat Commun 7:10305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bailey JM, Swanson BJ, Hamada T, Eggers JP, Singh PK, Caffery T, Ouellette MM, Hollingsworth MA (2008) Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin Cancer Res 14:5995–6004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bertolini G, D’Amico L, Moro M, Landoni E, Perego P, Miceli R, Gatti L, Andriani F, Wong D, Caserini R et al (2015) Microenvironment-modulated metastatic CD133+/CXCR4+/EpCAM- lung cancer-initiating cells sustain tumor dissemination and correlate with poor prognosis. Cancer Res 75:3636–3649

    Article  CAS  PubMed  Google Scholar 

  • Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, Washington MK, Neilson EG, Moses HL (2004) TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303:848–851

    Article  CAS  PubMed  Google Scholar 

  • Bianchi-Frias D, Basom R, Delrow JJ, Coleman IM, Dakhova O, Qu X, Fang M, Franco OE, Ericson NG, Bielas JH et al (2016) Cells comprising the prostate cancer microenvironment lack recurrent clonal somatic genomic aberrations. Mol Cancer Res 14(4):374–384

    Article  CAS  PubMed  Google Scholar 

  • Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y, Yoon T, Azzam DJ, Twyman-Saint Victor C, Wiemann BZ, Ishwaran H et al (2014) Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 159:499–513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bruzzese F, Hagglof C, Leone A, Sjoberg E, Roca MS, Kiflemariam S, Sjoblom T, Hammarsten P, Egevad L, Bergh A et al (2014) Local and systemic protumorigenic effects of cancer-associated fibroblast-derived GDF15. Cancer Res 74:3408–3417

    Article  CAS  PubMed  Google Scholar 

  • Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Cespedes MV, Sevillano M, Nadal C, Jung P, Zhang XH et al (2012) Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell 22:571–584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Calon A, Lonardo E, Berenguer-Llergo A, Espinet E, Hernando-Momblona X, Iglesias M, Sevillano M, Palomo-Ponce S, Tauriello DV, Byrom D et al (2015) Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat Genet 47:320–329

    Article  CAS  PubMed  Google Scholar 

  • Calvo F, Ege N, Grande-Garcia A, Hooper S, Jenkins RP, Chaudhry SI, Harrington K, Williamson P, Moeendarbary E, Charras G et al (2013) Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol 15:637–646

    Article  CAS  PubMed  Google Scholar 

  • Campbell I, Polyak K, Haviv I (2009) Clonal mutations in the cancer-associated fibroblasts: the case against genetic coevolution. Cancer Res 69:6765–6768, discussion 6769

    Article  CAS  PubMed  Google Scholar 

  • Cardone A, Tolino A, Zarcone R, Borruto Caracciolo G, Tartaglia E (1997) Prognostic value of desmoplastic reaction and lymphocytic infiltration in the management of breast cancer. Panminerva Med 39:174–177

    CAS  PubMed  Google Scholar 

  • Carito V, Bonuccelli G, Martinez-Outschoorn UE, Whitaker-Menezes D, Caroleo MC, Cione E, Howell A, Pestell RG, Lisanti MP, Sotgia F (2012) Metabolic remodeling of the tumor microenvironment: migration stimulating factor (MSF) reprograms myofibroblasts toward lactate production, fueling anabolic tumor growth. Cell Cycle 11:3403–3414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castano Z, Marsh T, Tadipatri R, Kuznetsov HS, Al-Shahrour F, Paktinat M, Greene-Colozzi A, Nilsson B, Richardson AL, McAllister SS (2013) Stromal EGF and igf-I together modulate plasticity of disseminated triple-negative breast tumors. Cancer Discov 3:922–935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaffer CL, Brennan JP, Slavin JL, Blick T, Thompson EW, Williams ED (2006) Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res 66:11271–11278

    Article  CAS  PubMed  Google Scholar 

  • Chang HY, Chi JT, Dudoit S, Bondre C, van de Rijn M, Botstein D, Brown PO (2002) Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci U S A 99:12877–12882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K, Chi JT, van de Rijn M, Botstein D, Brown PO (2004) Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol 2:E7

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Chang PH, Hwang-Verslues WW, Chang YC, Chen CC, Hsiao M, Jeng YM, Chang KJ, Lee EY, Shew JY, Lee WH (2012) Activation of Robo1 signaling of breast cancer cells by Slit2 from stromal fibroblast restrains tumorigenesis via blocking PI3K/Akt/beta-catenin pathway. Cancer Res 72:4652–4661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaturvedi P, Gilkes DM, Wong CC, Kshitiz, Luo W, Zhang H, Wei H, Takano N, Schito L, Levchenko A et al (2013) Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis. J Clin Invest 123:189–205

    Article  CAS  PubMed  Google Scholar 

  • Chaudhri VK, Salzler GG, Dick SA, Buckman MS, Sordella R, Karoly ED, Mohney R, Stiles BM, Elemento O, Altorki NK et al (2013) Metabolic alterations in lung cancer-associated fibroblasts correlated with increased glycolytic metabolism of the tumor. Mol Cancer Res 11:579–592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen WJ, Ho CC, Chang YL, Chen HY, Lin CA, Ling TY, Yu SL, Yuan SS, Chen YJ, Lin CY, et al. (2014) Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling. Nat Commun 5:3472

    PubMed  Google Scholar 

  • Crawford Y, Kasman I, Yu L, Zhong C, Wu X, Modrusan Z, Kaminker J, Ferrara N (2009) PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell 15:21–34

    Article  CAS  PubMed  Google Scholar 

  • Daly AJ, McIlreavey L, Irwin CR (2008) Regulation of HGF and SDF-1 expression by oral fibroblasts--implications for invasion of oral cancer. Oral Oncol 44:646–651

    Article  CAS  PubMed  Google Scholar 

  • De Monte L, Reni M, Tassi E, Clavenna D, Papa I, Recalde H, Braga M, Di Carlo V, Doglioni C, Protti MP (2011) Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J Exp Med 208:469–478

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • De Wever O, Nguyen QD, Van Hoorde L, Bracke M, Bruyneel E, Gespach C, Mareel M (2004) Tenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. FASEB J 18:1016–1018

    PubMed  Google Scholar 

  • Del Pozo Martin Y, Park D, Ramachandran A, Ombrato L, Calvo F, Chakravarty P, Spencer-Dene B, Derzsi S, Hill CS, Sahai E et al (2015) Mesenchymal cancer cell-stroma crosstalk promotes niche activation, epithelial reversion, and metastatic colonization. Cell Rep 13:2456–2469

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Desmouliere A, Guyot C, Gabbiani G (2004) The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. Int J Dev Biol 48:509–517

    Article  CAS  PubMed  Google Scholar 

  • Direkze NC, Hodivala-Dilke K, Jeffery R, Hunt T, Poulsom R, Oukrif D, Alison MR, Wright NA (2004) Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res 64:8492–8495

    Article  CAS  PubMed  Google Scholar 

  • Driskell RR, Lichtenberger BM, Hoste E, Kretzschmar K, Simons BD, Charalambous M, Ferron SR, Herault Y, Pavlovic G, Ferguson-Smith AC et al (2013) Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 504:277–281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dulauroy S, Di Carlo SE, Langa F, Eberl G, Peduto L (2012) Lineage tracing and genetic ablation of ADAM12(+) perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat Med 18:1262–1270

    Article  CAS  PubMed  Google Scholar 

  • Dumont N, Liu B, Defilippis RA, Chang H, Rabban JT, Karnezis AN, Tjoe JA, Marx J, Parvin B, Tlsty TD (2013) Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics. Neoplasia 15:249–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650–1659

    Article  CAS  PubMed  Google Scholar 

  • Elkabets M, Gifford AM, Scheel C, Nilsson B, Reinhardt F, Bray MA, Carpenter AE, Jirstrom K, Magnusson K, Ebert BL et al (2011) Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice. J Clin Invest 121:784–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Erez N, Truitt M, Olson P, Arron ST, Hanahan D (2010) Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell 17:135–147

    Article  CAS  PubMed  Google Scholar 

  • Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL et al (2013) Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A 110:20212–20217

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A et al (2008) Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 14:518–527

    Article  CAS  PubMed  Google Scholar 

  • Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, Choi H, El Rayes T, Ryu S, Troeger J et al (2015) Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527:472–476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Friedl P, Locker J, Sahai E, Segall JE (2012) Classifying collective cancer cell invasion. Nat Cell Biol 14:777–783

    Article  PubMed  CAS  Google Scholar 

  • Frings O, Augsten M, Tobin NP, Carlson J, Paulsson J, Pena C, Olsson E, Veerla S, Bergh J, Ostman A et al (2013) Prognostic significance in breast cancer of a gene signature capturing stromal PDGF signaling. Am J Pathol 182:2037–2047

    Article  CAS  PubMed  Google Scholar 

  • Fukumura D, Xavier R, Sugiura T, Chen Y, Park EC, Lu N, Selig M, Nielsen G, Taksir T, Jain RK et al (1998) Tumor induction of VEGF promoter activity in stromal cells. Cell 94:715–725

    Article  CAS  PubMed  Google Scholar 

  • Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K, Sahai E (2007) Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol 9:1392–1400

    Article  CAS  PubMed  Google Scholar 

  • Gascard P, Tlsty TD (2016) Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev 30:1002–1019

    Article  PubMed  Google Scholar 

  • Giannoni E, Bianchini F, Masieri L, Serni S, Torre E, Calorini L, Chiarugi P (2010) Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res 70:6945–6956

    Article  CAS  PubMed  Google Scholar 

  • Glenisson W, Castronovo V, Waltregny D (2007) Histone deacetylase 4 is required for TGFbeta1-induced myofibroblastic differentiation. Biochim Biophys Acta 1773:1572–1582

    Article  CAS  PubMed  Google Scholar 

  • Goetz JG, Minguet S, Navarro-Lerida I, Lazcano JJ, Samaniego R, Calvo E, Tello M, Osteso-Ibanez T, Pellinen T, Echarri A et al (2011) Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 146:148–163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goruppi S, Dotto GP (2013) Mesenchymal stroma: primary determinant and therapeutic target for epithelial cancer. Trends Cell Biol 23:593–602

    Article  CAS  PubMed  Google Scholar 

  • Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grugan KD, Miller CG, Yao Y, Michaylira CZ, Ohashi S, Klein-Szanto AJ, Diehl JA, Herlyn M, Han M, Nakagawa H et al (2010) Fibroblast-secreted hepatocyte growth factor plays a functional role in esophageal squamous cell carcinoma invasion. Proc Natl Acad Sci U S A 107:11026–11031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gu J, Qian H, Shen L, Zhang X, Zhu W, Huang L, Yan Y, Mao F, Zhao C, Shi Y et al (2012) Gastric cancer exosomes trigger differentiation of umbilical cord derived mesenchymal stem cells to carcinoma-associated fibroblasts through TGF-beta/Smad pathway. PLoS ONE 7:e52465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guido C, Whitaker-Menezes D, Capparelli C, Balliet R, Lin Z, Pestell RG, Howell A, Aquila S, Ando S, Martinez-Outschoorn U, 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 11:3019–3035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo X, Oshima H, Kitmura T, Taketo MM, Oshima M (2008) Stromal fibroblasts activated by tumor cells promote angiogenesis in mouse gastric cancer. J Biol Chem 283:19864–19871

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21:309–322

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  • Herrera M, Islam AB, Herrera A, Martin P, Garcia V, Silva J, Garcia JM, Salas C, Casal I, de Herreros AG et al (2013) Functional heterogeneity of cancer-associated fibroblasts from human colon tumors shows specific prognostic gene expression signature. Clin Cancer Res 19:5914–5926

    Article  CAS  PubMed  Google Scholar 

  • Herter-Sprie GS, Kung AL, Wong KK (2013) New cast for a new era: preclinical cancer drug development revisited. J Clin Invest 123:3639–3645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirata E, Girotti MR, Viros A, Hooper S, Spencer-Dene B, Matsuda M, Larkin J, Marais R, Sahai E (2015) Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin beta1/FAK signaling. Cancer Cell 27:574–588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hosein AN, Wu M, Arcand SL, Lavallee S, Hebert J, Tonin PN, Basik M (2010) Breast carcinoma-associated fibroblasts rarely contain p53 mutations or chromosomal aberrations. Cancer Res 70:5770–5777

    Article  CAS  PubMed  Google Scholar 

  • Hu M, Yao J, Cai L, Bachman KE, van den Brule F, Velculescu V, Polyak K (2005) Distinct epigenetic changes in the stromal cells of breast cancers. Nat Genet 37:899–905

    Article  CAS  PubMed  Google Scholar 

  • Hu B, Castillo E, Harewood L, Ostano P, Reymond A, Dummer R, Raffoul W, Hoetzenecker W, Hofbauer GF, Dotto GP (2012) Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling. Cell 149:1207–1220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, Rivera A, Ji B, Evans DB, Logsdon CD (2008) Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res 68:918–926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Isella C, Terrasi A, Bellomo SE, Petti C, Galatola G, Muratore A, Mellano A, Senetta R, Cassenti A, Sonetto C et al (2015) Stromal contribution to the colorectal cancer transcriptome. Nat Genet 47:312–319

    Article  CAS  PubMed  Google Scholar 

  • Ishii G, Sangai T, Oda T, Aoyagi Y, Hasebe T, Kanomata N, Endoh Y, Okumura C, Okuhara Y, Magae J, et al. (2003) Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem Biophys Res Commun 309:232–240

    Article  CAS  PubMed  Google Scholar 

  • Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, Feig C, Nakagawa T, Caldwell ME, Zecchini HI et al (2013) Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62:112–120

    Article  CAS  PubMed  Google Scholar 

  • Jaster R (2004) Molecular regulation of pancreatic stellate cell function. Mol Cancer 3:26

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jeon ES, Moon HJ, Lee MJ, Song HY, Kim YM, Cho M, Suh DS, Yoon MS, Chang CL, Jung JS, et al. (2008) Cancer-derived lysophosphatidic acid stimulates differentiation of human mesenchymal stem cells to myofibroblast-like cells. Stem Cells 26:789–797

    Article  CAS  PubMed  Google Scholar 

  • Jiang L, Gonda TA, Gamble MV, Salas M, Seshan V, Tu S, Twaddell WS, Hegyi P, Lazar G, Steele I et al (2008) Global hypomethylation of genomic DNA in cancer-associated myofibroblasts. Cancer Res 68:9900–9908

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401

    Article  CAS  PubMed  Google Scholar 

  • Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449:557–563

    Article  CAS  PubMed  Google Scholar 

  • Kojima Y, Acar A, Eaton EN, Mellody KT, Scheel C, Ben-Porath I, Onder TT, Wang ZC, Richardson AL, Weinberg RA 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 Natl Acad Sci U S A 107:20009–20014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koliaraki V, Pasparakis M, Kollias G (2015) IKKbeta in intestinal mesenchymal cells promotes initiation of colitis-associated cancer. J Exp Med 212:2235–2251

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Korpal M, Ell BJ, Buffa FM, Ibrahim T, Blanco MA, Celia-Terrassa T, Mercatali L, Khan Z, Goodarzi H, Hua Y et al (2011) Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med 17:1101–1108

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Koukourakis MI, Giatromanolaki A, Harris AL, Sivridis E (2006) Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res 66:632–637

    Article  CAS  PubMed  Google Scholar 

  • Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT (2010) Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 330:827–830

    Article  CAS  PubMed  Google Scholar 

  • Lee JJ, Perera RM, Wang H, Wu DC, Liu XS, Han S, Fitamant J, Jones PD, Ghanta KS, Kawano S et al (2014) Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc Natl Acad Sci U S A 111:E3091–E3100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, Buchanan M, Hosein AN, Basik M, Wrana JL (2012) Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 151:1542–1556

    Article  CAS  PubMed  Google Scholar 

  • Madar S, Goldstein I, Rotter V (2013) ‘Cancer associated fibroblasts’--more than meets the eye. Trends Mol Med 19:447–453

    Article  CAS  PubMed  Google Scholar 

  • Maeshima AM, Niki T, Maeshima A, Yamada T, Kondo H, Matsuno Y (2002) Modified scar grade: a prognostic indicator in small peripheral lung adenocarcinoma. Cancer 95:2546–2554

    Article  PubMed  Google Scholar 

  • Malanchi I, Santamaria-Martinez A, Susanto E, Peng H, Lehr HA, Delaloye JF, Huelsken J (2012) Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481:85–89

    Article  CAS  Google Scholar 

  • Mayor R, Etienne-Manneville S (2016) The front and rear of collective cell migration. Nat Rev Mol Cell Biol 17:97–109

    Article  CAS  PubMed  Google Scholar 

  • McAllister SS, Gifford AM, Greiner AL, Kelleher SP, Saelzler MP, Ince TA, Reinhardt F, Harris LN, Hylander BL, Repasky EA et al (2008) Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell 133:994–1005

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mikula M, Proell V, Fischer AN, Mikulits W (2006) Activated hepatic stellate cells induce tumor progression of neoplastic hepatocytes in a TGF-beta dependent fashion. J Cell Physiol 209:560–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mishra PJ, Mishra PJ, Humeniuk R, Medina DJ, Alexe G, Mesirov JP, Ganesan S, Glod JW, Banerjee D (2008) Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res 68:4331–4339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mitra AK, Zillhardt M, Hua Y, Tiwari P, Murmann AE, Peter ME, Lengyel E (2012) MicroRNAs reprogram normal fibroblasts into cancer-associated fibroblasts in ovarian cancer. Cancer Discov 2:1100–1108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Navab R, Strumpf D, Bandarchi B, Zhu CQ, Pintilie M, Ramnarine VR, Ibrahimov E, Radulovich N, Leung L, Barczyk M et al (2011) Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer. Proc Natl Acad Sci U S A 108:7160–7165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nielsen SR, Quaranta V, Linford A, Emeagi P, Rainer C, Santos A, Ireland L, Sakai T, Sakai K, Kim YS et al (2016) Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat Cell Biol 18:549–560

    Article  CAS  PubMed  Google Scholar 

  • O’Connell JT, Sugimoto H, Cooke VG, MacDonald BA, Mehta AI, LeBleu VS, Dewar R, Rocha RM, Brentani RR, Resnick MB et al (2011) VEGF-A and Tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization. Proc Natl Acad Sci U S A 108:16002–16007

    Article  PubMed  PubMed Central  Google Scholar 

  • Ohlund D, Elyada E, Tuveson D (2014) Fibroblast heterogeneity in the cancer wound. J Exp Med 211:1503–1523

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D et al (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324:1457–1461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Ocana OH, Corcoles R, Fabra A, Moreno-Bueno G, Acloque H, Vega S, Barrallo-Gimeno A, Cano A, Nieto MA (2012) Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer cell 22:709-724

  • Orimo A, Weinberg RA (2007) Heterogeneity of stromal fibroblasts in tumors. Cancer Biol Ther 6:618–619

    Article  CAS  PubMed  Google Scholar 

  • Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348

    Article  CAS  PubMed  Google Scholar 

  • Oskarsson T, Acharyya S, Zhang XH, Vanharanta S, Tavazoie SF, Morris PG, Downey RJ, Manova-Todorova K, Brogi E, Massague J (2011) Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med 17:867–874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oskarsson T, Batlle E, Massague J (2014) Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell 14:306–321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV et al (2014) Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25:719–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paggetti J, Haderk F, Seiffert M, Janji B, Distler U, Ammerlaan W, Kim YJ, Adam J, Lichter P, Solary E et al (2015) Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts. Blood 126:1106–1117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pallangyo CK, Ziegler PK, Greten FR (2015) IKKbeta acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis. J Exp Med 212:2253–2266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palucka AK, Coussens LM (2016) The basis of oncoimmunology. Cell 164:1233–1247

    Article  CAS  PubMed  Google Scholar 

  • Pang W, Su J, Wang Y, Feng H, Dai X, Yuan Y, Chen X, Yao W (2015) Pancreatic cancer-secreted miR-155 implicates in the conversion from normal fibroblasts to cancer-associated fibroblasts. Cancer Sci 106:1362–1369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patocs A, Zhang L, Xu Y, Weber F, Caldes T, Mutter GL, Platzer P, Eng C (2007) Breast-cancer stromal cells with TP53 mutations and nodal metastases. N Engl J Med 357:2543–2551

    Article  CAS  PubMed  Google Scholar 

  • Paulsson J, Micke P (2014) Prognostic relevance of cancer-associated fibroblasts in human cancer. Semin Cancer Biol 25:61–68

    Article  CAS  PubMed  Google Scholar 

  • Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, et al. (2014) The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8:3984–4001

    Article  Google Scholar 

  • Perugorria MJ, Wilson CL, Zeybel M, Walsh M, Amin S, Robinson S, White SA, Burt AD, Oakley F, Tsukamoto H et al (2012) Histone methyltransferase ASH1 orchestrates fibrogenic gene transcription during myofibroblast transdifferentiation. Hepatology 56:1129–1139

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pietras K, Ostman A (2010) Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res 316:1324–1331

    Article  CAS  PubMed  Google Scholar 

  • Pietras K, Pahler J, Bergers G, Hanahan D (2008) Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med 5:e19

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Polanska UM, Orimo A (2013) Carcinoma-associated fibroblasts: non-neoplastic tumour-promoting mesenchymal cells. J Cell Physiol 228:1651–1657

    Article  CAS  PubMed  Google Scholar 

  • Polyak K, Haviv I, Campbell IG (2009) Co-evolution of tumor cells and their microenvironment. Trends Genet 25:30–38

    Article  CAS  PubMed  Google Scholar 

  • Procopio MG, Laszlo C, Al Labban D, Kim DE, Bordignon P, Jo SH, Goruppi S, Menietti E, Ostano P, Ala U et al (2015) Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation. Nat Cell Biol 17:1193–1204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR (2012) Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21:418–429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19:1423–1437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, Dekleva EN, Saunders T, Becerra CP, Tattersall IW et al (2014) Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25:735–747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rinkevich Y, Walmsley GG, Hu MS, Maan ZN, Newman AM, Drukker M, et al (2015) Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science. 348(6232)

  • Ronnov-Jessen L, Petersen OW (1993) Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab Invest 68:696–707

    CAS  PubMed  Google Scholar 

  • Sanz-Moreno V, Gaggioli C, Yeo M, Albrengues J, Wallberg F, Viros A, Hooper S, Mitter R, Feral CC, Cook M et al (2011) ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer Cell 20:229–245

    Article  CAS  PubMed  Google Scholar 

  • Schafer M, Werner S (2008) Cancer as an overhealing wound: an old hypothesis revisited. Nat Rev Mol Cell Biol 9:628–638

    Article  CAS  PubMed  Google Scholar 

  • Scherz-Shouval R, Santagata S, Mendillo ML, Sholl LM, Ben-Aharon I, Beck AH, Dias-Santagata D, Koeva M, Stemmer SM, Whitesell L et al (2014) The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy. Cell 158:564–578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Serini G, Gabbiani G (1999) Mechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res 250:273–283

    Article  CAS  PubMed  Google Scholar 

  • Shakya R, Gonda T, Quante M, Salas M, Kim S, Brooks J, Hirsch S, Davies J, Cullo A, Olive K et al (2013) Hypomethylating therapy in an aggressive stroma-rich model of pancreatic carcinoma. Cancer Res 73:885–896

    Article  CAS  PubMed  Google Scholar 

  • Shimoda M, Mellody KT, Orimo A (2010) Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression. Semin Cell Dev Biol 21:19–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shin K, Lim A, Zhao C, Sahoo D, Pan Y, Spiekerkoetter E, Liao JC, Beachy PA (2014) Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors. Cancer Cell 26:521–533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spaeth EL, Dembinski JL, Sasser AK, Watson K, Klopp A, Hall B, Andreeff M, Marini F (2009) Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS ONE 4:e4992

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stankic M, Pavlovic S, Chin Y, Brogi E, Padua D, Norton L, Massague J, Benezra R (2013) TGF-beta-Id1 signaling opposes Twist1 and promotes metastatic colonization via a mesenchymal-to-epithelial transition. Cell reports 5:1228–1242

  • Stuelten CH, Busch JI, Tang B, Flanders KC, Oshima A, Sutton E, Karpova TS, Roberts AB, Wakefield LM, Niederhuber JE (2010) Transient tumor-fibroblast interactions increase tumor cell malignancy by a TGF-Beta mediated mechanism in a mouse xenograft model of breast cancer. PLoS ONE 5:e9832

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Sugimoto H, Mundel TM, Kieran MW, Kalluri R (2006) Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol Ther 5:1640–1646

    Article  CAS  PubMed  Google Scholar 

  • Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I, True L, Nelson PS (2012) Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med 18:1359–1368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun Y, Zhu D, Chen F, Qian M, Wei H, Chen W, Xu J (2016) SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment. Oncogene (in press)

  • Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, Karin M (2011) Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470:548–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890

    Article  CAS  PubMed  Google Scholar 

  • Togo S, Polanska UM, Horimoto Y, Orimo A (2013) Carcinoma-associated fibroblasts are a promising therapeutic target. Cancers (Basel) 5:149–169

    Article  CAS  Google Scholar 

  • Toste PA, Nguyen AH, Kadera BE, Duong M, Wu N, Gawlas I, Tran LM, Bikhchandani M, Li L, Patel SG et al (2016) Chemotherapy-induced inflammatory gene signature and pro-tumorigenic phenotype in pancreatic CAFs via stress-associated MAPK. Mol Cancer Res 14(5):437–447

    Article  CAS  PubMed  Google Scholar 

  • Trimboli AJ, Cantemir-Stone CZ, Li F, Wallace JA, Merchant A, Creasap N, Thompson JC, Caserta E, Wang H, Chong JL et al (2009) Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature 461:1084–1091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J (2012) Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22:725–736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Turley SJ, Cremasco V, Astarita JL (2015) Immunological hallmarks of stromal cells in the tumour microenvironment. Nat Rev Immunol 15:669–682

    Article  CAS  PubMed  Google Scholar 

  • Valencia T, Kim JY, Abu-Baker S, Moscat-Pardos J, Ahn CS, Reina-Campos M, Duran A, Castilla EA, Metallo CM, Diaz-Meco MT et al (2014) Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis. Cancer Cell 26:121–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vicent S, Sayles LC, Vaka D, Khatri P, Gevaert O, Chen R, Zheng Y, Gillespie AK, Clarke N, Xu Y et al (2012) Cross-species functional analysis of cancer-associated fibroblasts identifies a critical role for CLCF1 and IL-6 in non-small cell lung cancer in vivo. Cancer Res 72:5744–5756

    Article  CAS  PubMed  Google Scholar 

  • Wagner EF (2016) Cancer: fibroblasts for all seasons. Nature 530:42–43

    Article  CAS  PubMed  Google Scholar 

  • Walter K, Omura N, Hong SM, Griffith M, Goggins M (2008) Pancreatic cancer associated fibroblasts display normal allelotypes. Cancer Biol Ther 7:882–888

    Article  PubMed Central  PubMed  Google Scholar 

  • Wang W, Li Q, Yamada T, Matsumoto K, Matsumoto I, Oda M, Watanabe G, Kayano Y, Nishioka Y, Sone S et al (2009) Crosstalk to stromal fibroblasts induces resistance of lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors. Clin Cancer Res 15:6630–6638

    Article  CAS  PubMed  Google Scholar 

  • Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, Peng J, Lin E, Wang Y, Sosman J et al (2012) Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487:505–509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamashita M, Ogawa T, Zhang X, Hanamura N, Kashikura Y, Takamura M, Yoneda M, Shiraishi T (2012) Role of stromal myofibroblasts in invasive breast cancer: stromal expression of alpha-smooth muscle actin correlates with worse clinical outcome. Breast Cancer 19:170–176

    Article  PubMed  Google Scholar 

  • Yang F, Tuxhorn JA, Ressler SJ, McAlhany SJ, Dang TD, Rowley DR (2005) Stromal expression of connective tissue growth factor promotes angiogenesis and prostate cancer tumorigenesis. Cancer Res 65:8887–8895

    Article  CAS  PubMed  Google Scholar 

  • Yang G, Rosen DG, Zhang Z, Bast RC Jr, Mills GB, Colacino JA, Mercado-Uribe I, Liu J (2006) The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc Natl Acad Sci U S A 103:16472–16477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu J, Walter K, Omura N, Hong SM, Young A, Li A, Vincent A, Goggins M (2012) Unlike pancreatic cancer cells pancreatic cancer associated fibroblasts display minimal gene induction after 5-aza-2’-deoxycytidine. PLoS ONE 7:e43456

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang XH, Jin X, Malladi S, Zou Y, Wen YH, Brogi E, Smid M, Foekens JA, Massague J (2013) Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell 154:1060–1073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, Wu CC, LeBleu VS, Kalluri R (2015) Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527:525–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhuang J, Lu Q, Shen B, Huang X, Shen L, Zheng X, Huang R, Yan J, Guo H (2015) TGFbeta1 secreted by cancer-associated fibroblasts induces epithelial-mesenchymal transition of bladder cancer cells through lncRNA-ZEB2NAT. Sci Rep 5:11924

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors apologize to researchers whose work is not cited due to space limitations. We gratefully acknowledge Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (Research Project Number: 24300332, 25640069 and 15K14385 to A.O.) and a Grant-in-Aid (S1311011) from the Foundation of Strategic Research Projects in Private Universities from the MEXT, Japan (A.O.) for funding.

Author information

Authors and Affiliations

  1. Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, 113-8412, Japan

    Yoshihiro Mezawa & Akira Orimo

Authors
  1. Yoshihiro Mezawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akira Orimo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akira Orimo.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mezawa, Y., Orimo, A. The roles of tumor- and metastasis-promoting carcinoma-associated fibroblasts in human carcinomas. Cell Tissue Res 365, 675–689 (2016). https://doi.org/10.1007/s00441-016-2471-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-016-2471-1

Keywords

Search

Navigation