The Role of Myofibroblasts in Communicating Tumor Ecosystems

  • Olivier De Wever
  • Astrid De Boeck
  • Pieter Demetter
  • Marc Mareel
  • Marc Bracke
Chapter
Part of the The Tumor Microenvironment book series (TTME, volume 4)

Abstract

Invasive growth of a tumor occurs within an ecosystem where a continuous communication exists between cancer cells and a wide network of tumor-associated host cells. Secretory factors from the cancer cells activate the recruitment of host cells, both near to and far from the primary tumor site, as well as promote the departure of cancer- and host cells to distant tissues. The present review focuses on the prominent role of myofibroblasts in local and distant ecosystems namely the primary tumor, the bone marrow, the circulation, the sites of lymph node and of distant metastases and the nervous system. We believe that there exist distinct types of myofibroblasts with distinct reaction patterns that affect invasive tumor growth in different ways. Mathematical models predict that the specific conditions in local ecosystems determine the invasive phenotype of a tumor. Experimental cell culture models incorporating cancer cells, primary tumor-derived myofibroblasts and matrix proteins in a three-dimensional context confirm the pro-invasive activity of myofibroblasts. New methodologies will facilitate the direct observation of invasive cells including their interaction with myofibroblasts in clinically relevant ecosystems. A better understanding of the local and distant tumor ecosystems may help us to design personalized strategies in the treatment of cancer.

Keywords

Collective Cell Migration Premetastatic Niche Invasive Tumor Growth Stromal Myofibroblasts Cancer Cell Spheroid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

This work was supported by Fund for Scientific Research-Flanders (Brussels, Belgium), O. De Wever is a post-doctoral researcher and A. De Boeck is a doctoral researcher supported by Fund for Scientific Research-Flanders.

References

  1. Abe R, Donnelly SC, Peng T, Bucala R, Metz CN (2001) Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol 166:7556–7562PubMedGoogle Scholar
  2. Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, Porter D, Hu M, Chin L, Richardson A, Schnitt S, Sellers WR, Polyak K (2004) Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6:17–32PubMedCrossRefGoogle Scholar
  3. Anderson AR, Quaranta V (2008) Integrative mathematical oncology. Nat Rev Cancer 8:227–234PubMedCrossRefGoogle Scholar
  4. Anderson AR, Weaver AM, Cummings PT, Quaranta V (2006) Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment. Cell 127:905–915PubMedCrossRefGoogle Scholar
  5. Bacac M, Provero P, Mayran N, Stehle JC, Fusco C, Stamenkovic I (2006) A mouse stromal response to tumor invasion predicts prostate and breast cancer patient survival. PLoS One 1:e32PubMedCrossRefGoogle Scholar
  6. Barth PJ, Ebrahimsade S, Ramaswamy A, Moll R (2002) CD34+ fibrocytes in invasive ductal carcinoma, ductal carcinoma in situ, and benign breast lesions. Virchows Arch 440:298–303PubMedCrossRefGoogle Scholar
  7. Bearer EL, Lowengrub JS, Frieboes HB, Chuang YL, Jin F, Wise SM, Ferrari M, Agus DB, Cristini V (2009) Multiparameter computational modeling of tumor invasion. Cancer Res 69:4493–4501PubMedCrossRefGoogle Scholar
  8. Beck AH, Espinosa I, Gilks CB, van de Rijn M, West RB (2008) The fibromatosis signature defines a robust stromal response in breast carcinoma. Lab Invest 88:591–601PubMedCrossRefGoogle Scholar
  9. Bellini A, Mattoli S (2007) The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibroses. Lab Invest 87:858–870PubMedCrossRefGoogle Scholar
  10. Borchers AH, Steinbauer H, Schafer BS, Kramer M, Bowden GT, Fusenig NE (1997) Fibroblast-directed expression and localization of 92-kDa type IV collagenase along the tumor-stroma interface in an in vitro three-dimensional model of human squamous cell carcinoma. Mol Carcinog 19:258–266PubMedCrossRefGoogle Scholar
  11. Carragher NO (2009) Profiling distinct mechanisms of tumour invasion for drug discovery: imaging adhesion, signalling and matrix turnover. Clin Exp Metastasis 26:381–397PubMedCrossRefGoogle Scholar
  12. 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 99:12877–12882CrossRefGoogle Scholar
  13. 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:E7PubMedCrossRefGoogle Scholar
  14. Chang HY, Nuyten DS, Sneddon JB, Hastie T, Tibshirani R, Sorlie T, Dai H, He YD, van’t Veer LJ, Bartelink H, van de Rijn M, Brown PO, van de Vijver MJ (2005) Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc Natl Acad Sci U S A 102:3738–3743PubMedCrossRefGoogle Scholar
  15. 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 44:646–651PubMedCrossRefGoogle Scholar
  16. de Jonge MJ, Dumez H, Verweij J, Yarkoni S, Snyder D, Lacombe D, Marreaud S, Yamaguchi T, Punt CJ, van Oosterom A (2006) Phase I and pharmacokinetic study of halofuginone, an oral quinazolinone derivative in patients with advanced solid tumours. Eur J Cancer 42:1768–1774PubMedCrossRefGoogle Scholar
  17. Denys H, Derycke L, Hendrix A, Westbroek W, Gheldof A, Narine K, Pauwels P, Gespach C, Bracke M, De Wever O (2008) Differential impact of TGF-beta and EGF on fibroblast differentiation and invasion reciprocally promotes colon cancer cell invasion. Cancer Lett 266:263–274PubMedCrossRefGoogle Scholar
  18. De Wever O, Mareel M (2003) Role of tissue stroma in cancer cell invasion. J Pathol 200:429–447PubMedCrossRefGoogle Scholar
  19. 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 18:1016–1018PubMedGoogle Scholar
  20. De Wever O, Demetter P, Mareel M, Bracke M (2008) Stromal myofibroblasts are drivers of invasive cancer growth. Int J Cancer 123:2229–2238PubMedCrossRefGoogle Scholar
  21. De Wever O, Hendrix A, De Boeck A, Westbroek W, Braems G, Emami S, Sabbah M, Gespach C, Bracke M (2010) Modeling and quantification of cancer cell invasion through collagen type I matrices. Int J Dev Biol 54(5):887–896Google Scholar
  22. 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 64:8492–8495PubMedCrossRefGoogle Scholar
  23. Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650–1659PubMedCrossRefGoogle Scholar
  24. Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ (2009) Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15:35–44PubMedCrossRefGoogle Scholar
  25. Eyden B (2005) The myofibroblast: a study of normal, reactive and neoplastic tissues, with an emphasis on ultrastructure. Part I—normal and reactive cells. J Submicroscop Cytol Pathol 37:109–204Google Scholar
  26. Farmer P, Bonnefoi H, Anderle P, Cameron D, Wirapati P, Becette V, Andre S, Piccart M, Campone M, Brain E, Macgrogan G, Petit T, Jassem J, Bibeau F, Blot E, Bogaerts J, Aguet M, Bergh J, Iggo R, Delorenzi M (2009) A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med 15:68–74PubMedCrossRefGoogle Scholar
  27. Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A, Hallett M, Park M (2008) Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 14:518–527PubMedCrossRefGoogle Scholar
  28. Frieboes HB, Zheng X, Sun CH, Tromberg B, Gatenby R, Cristini V (2006) An integrated computational/experimental model of tumor invasion. Cancer Res 66:1597–1604PubMedCrossRefGoogle Scholar
  29. Garabedian EM, Humphrey PA, Gordon JI (1998) A transgenic mouse model of metastatic prostate cancer originating from neuroendocrine cells. Proc Natl Acad Sci U S A 95:15382–15387PubMedCrossRefGoogle Scholar
  30. Genin O, Rechavi G, Nagler A, Ben-Itzhak O, Nazemi KJ, Pines M (2008) Myofibroblasts in pulmonary and brain metastases of alveolar soft-part sarcoma: a novel target for treatment? Neoplasia 10:940–948PubMedGoogle Scholar
  31. Hasebe T, Tsuda H, Hirohashi S, Shimosato Y, Tsubono Y, Yamamoto H, Mukai K (1998) Fibrotic focus in infiltrating ductal carcinoma of the breast: a significant histopathological prognostic parameter for predicting the long-term survival of the patients. Breast Cancer Res Treat 49:195–208PubMedCrossRefGoogle Scholar
  32. Ishii G, Sangai T, Oda T, Aoyagi Y, Hasebe T, Kanomata N, Endoh Y, Okumura C, Okuhara Y, Magae J, Emura M, Ochiya T, Ochiai A (2003) Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem Biophys Res Commun 309:232–240PubMedCrossRefGoogle Scholar
  33. Iyer VR, Eisen MB, Ross DT, Schuler G, Moore T, Lee JC, Trent JM, Staudt LM, Hudson J Jr, Boguski MS, Lashkari D, Shalon D, Botstein D, Brown PO (1999) The transcriptional program in the response of human fibroblasts to serum. Science 283:83–87PubMedCrossRefGoogle Scholar
  34. Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239–252PubMedCrossRefGoogle Scholar
  35. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827PubMedCrossRefGoogle Scholar
  36. Kunz-Schughart LA, Heyder P, Schroeder J, Knuechel R (2001) A heterologous 3-D coculture model of breast tumor cells and fibroblasts to study tumor-associated fibroblast differentiation. Exp Cell Res 266:74–86PubMedCrossRefGoogle Scholar
  37. Lang P, Yeow K, Nichols A, Scheer A (2006) Cellular imaging in drug discovery. Nat Rev Drug Discov 5:343–356PubMedCrossRefGoogle Scholar
  38. Lehn CN, Rapoport A (1994) The desmoplastic lymph node reaction as a prognostic factor of cancer of the tongue and floor of the mouth. Sao Paulo Med J 112:591–596PubMedGoogle Scholar
  39. Lu J, Marnell LL, Marjon KD, Mold C, Du Clos TW, Sun PD (2008) Structural recognition and functional activation of FcgammaR by innate pentraxins. Nature 456:989–992PubMedCrossRefGoogle Scholar
  40. Mantyh PW, Clohisy DR, Koltzenburg M, Hunt SP (2002) Molecular mechanisms of cancer pain. Nat Rev Cancer 2:201–209PubMedCrossRefGoogle Scholar
  41. Mareel M, Oliveira MJ, Madani I (2009) Cancer invasion and metastasis: interacting ecosystems. Virchows Arch 454:599–622PubMedCrossRefGoogle Scholar
  42. McAllister SS, Gifford AM, Greiner AL, Kelleher SP, Saelzler MP, Ince TA, Reinhardt F, Harris LN, Hylander BL, Repasky EA, Weinberg RA (2008) Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell 133:994–1005PubMedCrossRefGoogle Scholar
  43. McGaha TL, Kodera T, Spiera H, Stan AC, Pines M, Bona CA (2002) Halofuginone inhibition of COL1A2 promoter activity via a c-Jun-dependent mechanism. Arthritis Rheum 46:2748–2761PubMedCrossRefGoogle Scholar
  44. Mori L, Bellini A, Stacey MA, Schmidt M, Mattoli S (2005) Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow. Exp Cell Res 304:81–90PubMedCrossRefGoogle Scholar
  45. Muehlberg FL, Song YH, Krohn A, Pinilla SP, Droll LH, Leng X, Seidensticker M, Ricke J, Altman AM, Devarajan E, Liu W, Arlinghaus RB, Alt EU (2009) Tissue-resident stem cells promote breast cancer growth and metastasis. Carcinogenesis 30:589–597PubMedCrossRefGoogle Scholar
  46. Mueller MM, Fusenig NE (2004) Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4:839–849PubMedCrossRefGoogle Scholar
  47. Newman LA, Pernick NL, Adsay V, Carolin KA, Philip PA, Sipierski S, Bouwman DL, Kosir MA, White M, Visscher DW (2003) Histopathologic evidence of tumor regression in the axillary lymph nodes of patients treated with preoperative chemotherapy correlates with breast cancer outcome. Ann Surg Oncol 10:734–739PubMedCrossRefGoogle Scholar
  48. Nystrom ML, Thomas GJ, Stone M, Mackenzie IC, Hart IR, Marshall JF (2005) Development of a quantitative method to analyse tumour cell invasion in organotypic culture. J Pathol 205:468–475PubMedCrossRefGoogle Scholar
  49. Okamoto T, Tsuburaya A, Kameda Y, Yoshikawa T, Cho H, Tsuchida K, Hasegawa S, Noguchi Y (2008) Prognostic value of extracapsular invasion and fibrotic focus in single lymph node metastasis of gastric cancer. Gastric Cancer 11:160–167PubMedCrossRefGoogle Scholar
  50. Olaso E, Santisteban A, Bidaurrazaga J, Gressner AM, Rosenbaum J, Vidal-Vanaclocha F (1997) Tumor-dependent activation of rodent hepatic stellate cells during experimental melanoma metastasis. Hepatology 26:634–642PubMedCrossRefGoogle Scholar
  51. Pepys MB, Herbert J, Hutchinson WL, Tennent GA, Lachmann HJ, Gallimore JR, Lovat LB, Bartfai T, Alanine A, Hertel C, Hoffmann T, Jakob-Roetne R, Norcross RD, Kemp JA, Yamamura K, Suzuki M, Taylor GW, Murray S, Thompson D, Purvis A, Kolstoe S, Wood SP, Hawkins PN (2002) Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 417:254–259PubMedCrossRefGoogle Scholar
  52. Pilling D, Buckley CD, Salmon M, Gomer RH (2003) Inhibition of fibrocyte differentiation by serum amyloid P. J Immunol 171:5537–5546PubMedGoogle Scholar
  53. Pilling D, Tucker NM, Gomer RH (2006) Aggregated IgG inhibits the differentiation of human fibrocytes. J Leukoc Biol 79:1242–1251PubMedCrossRefGoogle Scholar
  54. Pilling D, Buckley CD, Salmon M, Gomer RH (2007) Serum amyloid P and fibrosis in systemic sclerosis: comment on the article by Tennent et al. Arthritis Rheum 56:4229; author reply 4229–4230PubMedCrossRefGoogle Scholar
  55. Possemiers S, Grootaert C, Vermeiren J, Gross G, Marzorati M, Verstraete W, van de Wiele T (2009) The intestinal environment in health and disease—recent insights on the potential of intestinal bacteria to influence human health. Curr Pharm Des 15:2051–2065PubMedCrossRefGoogle Scholar
  56. Postlethwaite AE, Shigemitsu H, Kanangat S (2004) Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosis. Curr Opin Rheumatol 16:733–738PubMedCrossRefGoogle Scholar
  57. Provenzano PP, Eliceiri KW, Campbell JM, Inman DR, White JG, Keely PJ (2006) Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med 4:38PubMedCrossRefGoogle Scholar
  58. Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, White JG, Keely PJ (2008) Collagen density promotes mammary tumor initiation and progression. BMC Med 6:11PubMedCrossRefGoogle Scholar
  59. Reilly JT, Nash JR (1988) Vitronectin (serum spreading factor): its localisation in normal and fibrotic tissue. J Clin Pathol 41:1269–1272PubMedCrossRefGoogle Scholar
  60. Rønnov-Jessen L, Petersen OW, Koteliansky VE, Bissell MJ (1995) The origin of the myofibroblasts in breast-cancer—recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth. J Clin Investig 95:859–873PubMedCrossRefGoogle Scholar
  61. Sabeh F, Shimizu-Hirota R, Weiss SJ (2009) Protease-dependent versus -independent cancer cell invasion programs: three-dimensional amoeboid movement revisited. J Cell Biol 185:11–19PubMedCrossRefGoogle Scholar
  62. Schurch W, Seemayer TA, Lagace R (1981) Stromal myofibroblasts in primary invasive and metastatic carcinomas. A combined immunological, light and electron microscopic study. Virchows Arch A Pathol Anat Histol 391:125–139PubMedCrossRefGoogle Scholar
  63. Shao DD, Suresh R, Vakil V, Gomer RH, Pilling D (2008) Pivotal advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation. J Leukoc Biol 83:1323–1333PubMedCrossRefGoogle Scholar
  64. Sheffer Y, Leon O, Pinthus JH, Nagler A, Mor Y, Genin O, Iluz M, Kawada N, Yoshizato K, Pines M (2007) Inhibition of fibroblast to myofibroblast transition by halofuginone contributes to the chemotherapy-mediated antitumoral effect. Mol Cancer Ther 6:570–577PubMedCrossRefGoogle Scholar
  65. Tanaka Y, Hirokawa M, Wakatsuki S, Sano T (2002) Metastatic adenocarcinoma of the lymph node: peculiar desmoplasia mimicking intravenous metastasis. Histopathology 41:566–567PubMedCrossRefGoogle Scholar
  66. Tennent GA, Dziadzio M, Triantafillidou E, Davies P, Gallimore JR, Denton CP, Pepys MB (2007) Normal circulating serum amyloid P component concentration in systemic sclerosis. Arthritis Rheum 56:2013–2017PubMedCrossRefGoogle Scholar
  67. Thariat J, Ahamad A, El-Naggar AK, Williams MD, Holsinger FC, Glisson BS, Allen PK, Morrison WH, Weber RS, Ang KK, Garden AS (2008) Outcomes after radiotherapy for basaloid squamous cell carcinoma of the head and neck: a case-control study. Cancer 112:2698–2709PubMedCrossRefGoogle Scholar
  68. Tsujino T, Seshimo I, Yamamoto H, Ngan CY, Ezumi K, Takemasa I, Ikeda M, Sekimoto M, Matsuura N, Monden M (2007) Stromal myofibroblasts predict disease recurrence for colorectal cancer. Clin Cancer Res 13:2082–2090PubMedCrossRefGoogle Scholar
  69. Tuxhorn JA, Ayala GE, Smith MJ, Smith VC, Dang TD, Rowley DR (2002) Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling. Clin Cancer Res 8:2912–2923PubMedGoogle Scholar
  70. Vidal-Vanaclocha F (2008) The prometastatic microenvironment of the liver. Cancer Microenviron 1:113–129PubMedCrossRefGoogle Scholar
  71. Wels J, Kaplan RN, Rafii S, Lyden D (2008a) Migratory neighbors and distant invaders: tumor-associated niche cells. Genes Dev 22:559–574CrossRefGoogle Scholar
  72. Wels J, Kaplan RN, Rafii S, Lyden D (2008b) Migratory neighbors and distant invaders: tumor-associated niche cells. Genes Dev 22:559–574CrossRefGoogle Scholar
  73. Wolf K, Mazo I, Leung H, Engelke K, von Andrian UH, Deryugina EI, Strongin AY, Brocker EB, Friedl P (2003) Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J Cell Biol 160:267–277PubMedCrossRefGoogle Scholar
  74. Wolf K, Wu YI, Liu Y, Geiger J, Tam E, Overall C, Stack MS, Friedl P (2007) Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nat Cell Biol 9:893–904PubMedCrossRefGoogle Scholar
  75. Yee KO, Connolly CM, Pines M, Lawler J (2006) Halofuginone inhibits tumor growth in the polyoma middle T antigen mouse via a thrombospondin-1 independent mechanism. Cancer Biol Ther 5:218–224PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Olivier De Wever
    • 1
  • Astrid De Boeck
    • 1
  • Pieter Demetter
    • 2
  • Marc Mareel
    • 1
  • Marc Bracke
    • 1
  1. 1.Laboratory of Experimental Cancer Research, Department of Radiotherapy and Experimental Cancer ResearchGhent University HospitalGhentBelgium
  2. 2.Department of PathologyErasme University Hospital, Université Libre de Bruxelles (ULB)BrusselsBelgium

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