Skip to main content
SpringerLink
Log in

Tumor-Stromal Interactions in Invasion and Metastases

  • Reference work entry
Pancreatic Cancer

Abstract:

Pancreatic ductal adenocarcinoma is characterized by “tumor desmoplasia,” a remarkable increase in connective tissue that penetrates and envelopes the neoplasm. Although excessive desmoplasia also occurs in breast and prostate cancers, it is rarely observed in other tumors of the pancreas. Desmoplastic reaction consists of abundant fibrous tissue composed of extracellular matrix proteins, new blood vessels, inflammatory and stellate cells. After their isolation a decade ago, it is now clear that pancreatic stellate cells produce this highly fibrotic microenvironment of pancreatic cancer. Through secretion of growth factors and cytokines, cancer cells can activate the stellate cells within their immediate vicinity. Moreover, the interactions between the inflammatory cells, stellate cells and cancer cells sustain the activity of the stromal reaction. Once activated, pancreatic stellate cells can also perpetuate their own activity by forming autonomous feedback loops. Experimental data is emerging that there is a symbiotic relationship between pancreatic adenocarcinoma cells and pancreatic stellate cells that results in an overall increase in the growth rate of the tumor. Similarly, recent evidence supports an active protumorigenic role of inflammatory cells in the development and progression of pancreatic cancer. Nevertheless, despite abundant experimental evidence, the exact role of the stromal component of the tumor mass in human cancer progression in vivo is not yet fully clarified. Recently however, the ratio of the tumor desmoplasia to the amount of activated stellate cells was identified as an independent prognostic marker with an impact on patient survival equivalent to that of the lymph node status of the pancreatic cancer. Likewise, the number of tumor infiltrating macrophages and mast cells correlate with the microvessel density and aggressiveness of the pancreatic ductal adenocarcinoma. Although the mechanisms behind these important observations have to be elucidated individually, one possible fundamental biologic explanation could be made through a selection process leading to the evolution of cancer cells. Carcinogenesis requires tumor populations to surmount distinct microenvironmental proliferation barriers that arise in the adaptive landscapes of normal and premalignant populations growing from epithelial surfaces. Therefore, somatic evolution of invasive cancer could be viewed as a sequence of phenotypical adaptations to these barriers, highlighting the importance of tumor microenvironment on cancer behavior.

For the clarity of understanding, while analyzing the tumor-stromal interaction and its impact on invasion and metastases, the authors will focus only on pancreatic ductal adenocarcinoma (PDAC) and not on other neoplasms of the pancreas.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 649.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Koong AC, Mehta VK, Le QT, Fisher GA, Terris DJ, Brown JM, Bastidas AJ, Vierra M: Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys 2000;48(4):919–922.

    Article  CAS  PubMed  Google Scholar 

  2. Reiser-Erkan C, Erkan M, Pan Z, Bekasi S, Giese NA, Streit S, Michalski CW, Friess H, Kleeff J: Hypoxia-inducible proto-oncogene Pim-1 is a prognostic marker in pancreatic ductal adenocarcinoma. Cancer Biol Ther 2008;7(9):1352–1359.

    Google Scholar 

  3. Masamune A, Kikuta K, Watanabe T, Satoh K, Hirota M, Shimosegawa T: Hypoxia stimulates pancreatic stellate cells to induce fibrosis and angiogenesis in pancreatic cancer. Am J Physiol Gastrointest Liver Physiol 2008;295(4):G709–G717.

    Google Scholar 

  4. Erkan M, Kleeff J, Gorbachevski A, Reiser C, Mitkus T, Esposito I, Giese T, Buchler MW, Giese NA, Friess H: Periostin creates a tumor-supportive microenvironment in the pancreas by sustaining fibrogenic stellate cell activity. Gastroenterology 2007;132(4):1447–1464.

    Article  CAS  PubMed  Google Scholar 

  5. Armstrong T, Packham G, Murphy LB, Bateman AC, Conti JA, Fine DR, Johnson CD, Benyon RC, Iredale JP: Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Clin Cancer Res 2004;10(21):7427–7437.

    Article  CAS  PubMed  Google Scholar 

  6. Coussens LM, Werb Z: Inflammation and cancer. Nature 2002;420(6917):860–867.

    Article  CAS  PubMed  Google Scholar 

  7. Michalski CW, Gorbachevski A, Erkan M, Reiser C, Deucker S, Bergmann F, Giese T, Weigand M, Giese NA, Friess H, Kleeff J: Mononuclear cells modulate the activity of pancreatic stellate cells which in turn promote fibrosis and inflammation in chronic pancreatitis. J Transl Med 2007;5:63.

    Article  PubMed  Google Scholar 

  8. Pollard JW: Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004;4(1):71–78.

    Article  CAS  PubMed  Google Scholar 

  9. Esposito I, Menicagli M, Funel N, Bergmann F, Boggi U, Mosca F, Bevilacqua G, Campani D: Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol 2004;57(6):630–636.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang W, Erkan M, Abiatari I, Giese NA, Felix K, Kayed H, Buchler MW, Friess H, Kleeff J: Expression of extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) in pancreatic neoplasm and pancreatic stellate cells. Cancer Biol Ther 2007;6(2):218–227.

    Article  CAS  PubMed  Google Scholar 

  11. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000;100(1):57–70.

    Article  CAS  PubMed  Google Scholar 

  12. Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J: Vascular-specific growth factors and blood vessel formation. Nature 2000;407(6801):242–248.

    Article  CAS  PubMed  Google Scholar 

  13. Folkman J: angiogenesis. Annu Rev Med 2006;57:1–18.

    Article  CAS  PubMed  Google Scholar 

  14. Hori A, Sasada R, Matsutani E, Naito K, Sakura Y, Fujita T, Kozai Y: Suppression of solid tumor growth by immunoneutralizing monoclonal antibody against human basic fibroblast growth factor. Cancer Res 1991;51(22):6180–6184.

    CAS  PubMed  Google Scholar 

  15. Bissell MJ, Radisky D: Putting tumours in context. Nat Rev Cancer 2001;1(1):46–54.

    Article  CAS  PubMed  Google Scholar 

  16. Brown LF, Dvorak AM, Dvorak HF: Leaky vessels, fibrin deposition, and fibrosis: a sequence of events common to solid tumors and to many other types of disease. Am Rev Respir Dis 1989;140(4):1104–1107.

    CAS  PubMed  Google Scholar 

  17. Kalluri R, Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer 2006;6(5):392–401.

    Article  CAS  PubMed  Google Scholar 

  18. Carmeliet P: Angiogenesis in health and disease. Nat Med 2003;9(6):653–660.

    Article  CAS  PubMed  Google Scholar 

  19. Couvelard A, O’Toole D, Leek R, Turley H, Sauvanet A, Degott C, Ruszniewski P, Belghiti J, Harris AL, Gatter K, Pezzella F: Expression of hypoxia-inducible factors is correlated with the presence of a fibrotic focus and angiogenesis in pancreatic ductal adenocarcinomas. Histopathology 2005;46(6):668–676.

    Article  CAS  PubMed  Google Scholar 

  20. Gatenby RA, Gillies RJ: A microenvironmental model of carcinogenesis. Nat Rev Cancer 2008;8(1):56–61.

    Article  CAS  PubMed  Google Scholar 

  21. Ceyhan GO, Giese NA, Erkan M, Kerscher AG, Wente MN, Giese T, Buchler MW, Friess H: The neurotrophic factor artemin promotes pancreatic cancer invasion. Ann Surg 2006;244(2):274–281.

    Article  PubMed  Google Scholar 

  22. Noto M, Miwa K, Kitagawa H, Kayahara M, Takamura H, Shimizu K, Ohta T: Pancreas head carcinoma: frequency of invasion to soft tissue adherent to the superior mesenteric artery. Am J Surg Pathol 2005;29(8):1056–1061.

    PubMed  Google Scholar 

  23. Balkwill F, Mantovani A: Inflammation and cancer: back to Virchow? Lancet 2001;357(9255):539–545.

    Article  CAS  PubMed  Google Scholar 

  24. Dvorak HF: Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986;315(26):1650–1659.

    Article  CAS  PubMed  Google Scholar 

  25. Whitcomb DC, Pogue-Geile K: Pancreatitis as a risk for pancreatic cancer. Gastroenterol Clin North Am 2002;31(2):663–678.

    Article  PubMed  Google Scholar 

  26. Dannenberg AJ, Subbaramaiah K: Targeting cyclooxygenase-2 in human neoplasia: rationale and promise. Cancer Cell 2003;4(6):431–436.

    Article  CAS  PubMed  Google Scholar 

  27. de Visser KE, Eichten A, Coussens LM: Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 2006;6(1):24–37.

    Article  CAS  PubMed  Google Scholar 

  28. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A: Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002;23(11):549–555.

    Article  CAS  PubMed  Google Scholar 

  29. Domagala W, Striker G, Szadowska A, Dukowicz A, Weber K, Osborn M: Cathepsin D in invasive ductal NOS breast carcinoma as defined by immunohistochemistry. No correlation with survival at 5 years. Am J Pathol 1992;141(5):1003–1012.

    CAS  PubMed  Google Scholar 

  30. Lin EY, Nguyen AV, Russell RG, Pollard JW: Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 2001;193(6):727–740.

    Article  CAS  PubMed  Google Scholar 

  31. Lewis CE, Pollard JW: Distinct role of macrophages in different tumor microenvironments. Cancer Res 2006;66(2):605–612.

    Article  CAS  PubMed  Google Scholar 

  32. Wilson TJ, Nannuru KC, Futakuchi M, Sadanandam A, Singh RK: Cathepsin G enhances mammary tumor-induced osteolysis by generating soluble receptor activator of nuclear factor-kappab ligand. Cancer Res 2008;68(14):5803–5811.

    Article  CAS  PubMed  Google Scholar 

  33. Sica A, Allavena P, Mantovani A: Cancer related inflammation: the macrophage connection. Cancer Lett 2008;267(2):204–215.

    Article  CAS  PubMed  Google Scholar 

  34. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313(5795):1960–1964.

    Article  CAS  PubMed  Google Scholar 

  35. Sica A, Schioppa T, Mantovani A, Allavena P: Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 2006;42(6):717–727.

    Article  CAS  PubMed  Google Scholar 

  36. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W: Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10(9):942–949.

    Article  CAS  PubMed  Google Scholar 

  37. Sica A, Bronte V: Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 2007;117(5):1155–1166.

    Article  CAS  PubMed  Google Scholar 

  38. Chu GC, Kimmelman AC, Hezel AF, DePinho RA: Stromal biology of pancreatic cancer. J Cell Biochem 2007;101(4):887–907.

    Article  CAS  PubMed  Google Scholar 

  39. Esposito I, Kleeff J, Bischoff SC, Fischer L, Collecchi P, Iorio M, Bevilacqua G, Buchler MW, Friess H: The stem cell factor-c-kit system and mast cells in human pancreatic cancer. Lab Invest 2002;82(11):1481–1492.

    CAS  PubMed  Google Scholar 

  40. Esposito I, Friess H, Kappeler A, Shrikhande S, Kleeff J, Ramesh H, Zimmermann A, Buchler MW: Mast cell distribution and activation in chronic pancreatitis. Hum Pathol 2001;32(11):1174–1183.

    Article  CAS  PubMed  Google Scholar 

  41. Sattler M, Salgia R: Targeting c-Kit mutations: basic science to novel therapies. Leuk Res 2004;28(Suppl 1): S11–S20.

    Article  CAS  PubMed  Google Scholar 

  42. Gulubova MV: Structural examination of tryptase- and chymase-positive mast cells in livers, containing metastases from gastrointestinal cancers. Clin Exp Metastasis 2003;20(7):611–620.

    Article  CAS  PubMed  Google Scholar 

  43. Gordon JR, Galli SJ: Promotion of mouse fibroblast collagen gene expression by mast cells stimulated via the Fc epsilon RI. Role for mast cell-derived transforming growth factor beta and tumor necrosis factor alpha. J Exp Med 1994;180(6):2027–2037.

    Article  CAS  PubMed  Google Scholar 

  44. Albrecht M, Frungieri MB, Kunz L, Ramsch R, Meineke V, Kohn FM, Mayerhofer A: Divergent effects of the major mast cell products histamine, tryptase and TNF-alpha on human fibroblast behaviour. Cell Mol Life Sci 2005;62(23):2867–2876.

    Article  CAS  PubMed  Google Scholar 

  45. Gaca MD, Pickering JA, Arthur MJ, Benyon RC: Human and rat hepatic stellate cells produce stem cell factor: a possible mechanism for mast cell recruitment in liver fibrosis. J Hepatol 1999;30(5):850–858.

    Article  CAS  PubMed  Google Scholar 

  46. Zimnoch L, Szynaka B, Puchalski Z: Mast cells and pancreatic stellate cells in chronic pancreatitis with differently intensified fibrosis. Hepatogastroenterology 2002;49(46):1135–1138.

    PubMed  Google Scholar 

  47. Monti P, Leone BE, Marchesi F, Balzano G, Zerbi A, Scaltrini F, Pasquali C, Calori G, Pessi F, Sperti C, Di Carlo V, Allavena P, Piemonti L: The CC chemokine MCP-1/CCL2 in pancreatic cancer progression: regulation of expression and potential mechanisms of antimalignant activity. Cancer Res 2003;63(21):7451–7461.

    CAS  PubMed  Google Scholar 

  48. Kleeff J, Kusama T, Rossi DL, Ishiwata T, Maruyama H, Friess H, Buchler MW, Zlotnik A, Korc M: Detection and localization of Mip-3alpha/LARC/Exodus, a macrophage proinflammatory chemokine, and its CCR6 receptor in human pancreatic cancer. Int J Cancer 1999;81(4): 650–7.

    Article  CAS  PubMed  Google Scholar 

  49. Balaz P, Friess H, Kondo Y, Zhu Z, Zimmermann A, Buchler MW: Human macrophage metalloelastase worsens the prognosis of pancreatic cancer. Ann Surg 2002;235(4):519–527.

    Article  PubMed  Google Scholar 

  50. Aoyagi Y, Oda T, Kinoshita T, Nakahashi C, Hasebe T, Ohkohchi N, Ochiai A: Overexpression of TGF-beta by infiltrated granulocytes correlates with the expression of collagen mrna in pancreatic cancer. Br J Cancer 2004;91(7):1316–1326.

    Article  CAS  PubMed  Google Scholar 

  51. Fukunaga A, Miyamoto M, Cho Y, Murakami S, Kawarada Y, Oshikiri T, Kato K, Kurokawa T, Suzuoki M, Nakakubo Y, Hiraoka K, Itoh T, Morikawa T, Okushiba S, Kondo S, Katoh H: CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas 2004;28(1):e26–e31.

    Article  PubMed  Google Scholar 

  52. Hiraoka N, Onozato K, Kosuge T, Hirohashi S: Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 2006;12(18):5423–5434.

    Article  CAS  PubMed  Google Scholar 

  53. Nummer D, Suri-Payer E, Schmitz-Winnenthal H, Bonertz A, Galindo L, Antolovich D, Koch M, Buchler M, Weitz J, Schirrmacher V, Beckhove P: Role of tumor endothelium in CD4+ CD25+ regulatory T cell infiltration of human pancreatic carcinoma. J Natl Cancer Inst 2007;99(15):1188–1199.

    Article  CAS  PubMed  Google Scholar 

  54. Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH: Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 2007;67(19):9518–9527.

    Article  CAS  PubMed  Google Scholar 

  55. Bachem MG, Schunemann M, Ramadani M, Siech M, Beger H, Buck A, Zhou S, Schmid-Kotsas A, Adler G: Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 2005;128(4):907–921.

    Article  CAS  PubMed  Google Scholar 

  56. Mollenhauer J, Roether I, Kern HF: Distribution of extracellular matrix proteins in pancreatic ductal adenocarcinoma and its influence on tumor cell proliferation in vitro. Pancreas 1987;2(1):14–24.

    Article  CAS  PubMed  Google Scholar 

  57. Omary MB, Lugea A, Lowe AW, Pandol SJ: The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest 2007;117(1):50–59.

    Article  CAS  PubMed  Google Scholar 

  58. Watari N, Hotta Y, Mabuchi Y: Morphological studies on a vitamin A-storing cell and its complex with macrophage observed in mouse pancreatic tissues following excess vitamin A administration. Okajimas Folia Anat Jpn 1982;58(4–6):837–858.

    CAS  PubMed  Google Scholar 

  59. Lohr M, Trautmann B, Gottler M, Peters S, Zauner I, Maillet B, Kloppel G: Human ductal adenocarcinomas of the pancreas express extracellular matrix proteins. Br J Cancer 1994;69(1):144–151.

    CAS  PubMed  Google Scholar 

  60. Gress TM, Menke A, Bachem M, Muller-Pillasch F, Ellenrieder V, Weidenbach H, Wagner M, Adler G: Role of extracellular matrix in pancreatic diseases. Digestion 1998;59(6):625–637.

    Article  CAS  PubMed  Google Scholar 

  61. Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA, Pirola RC, Wilson JS: Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 1998;43(1):128–133.

    Article  CAS  PubMed  Google Scholar 

  62. Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A, Siech M, Beger H, Grunert A, Adler G: Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 1998;115(2):421–432.

    Article  CAS  PubMed  Google Scholar 

  63. Farrow B, Albo D, Berger DH: The role of the tumor microenvironment in the progression of pancreatic cancer. J Surg Res 2008;149(2):319–328.

    Article  PubMed  Google Scholar 

  64. Friedman SL: Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008;88(1):125–172.

    Article  CAS  PubMed  Google Scholar 

  65. Bachem MG, Zhou S, Buck K, Schneiderhan W, Siech M: Pancreatic stellate cells-role in pancreas cancer. Langenbecks Arch Surg 2008;393(6):891–900.

    Article  PubMed  Google Scholar 

  66. Erkan M, Michalski CW, Rieder S, Reiser-Erkan C, Abiatari I, Kolb A, Giese NA, Esposito I, Friess H, Kleeff J: The Activated Stroma Index Is a Novel and Independent Prognostic Marker in Pancreatic Ductal Adenocarcinoma. Clin Gastroenterol Hepatol 2008; 6(10):1155–1161.

    Google Scholar 

  67. Schedin P, Elias A: Multistep tumorigenesis and the microenvironment. Breast Cancer Res 2004; 6(2):93–101.

    Article  CAS  PubMed  Google Scholar 

  68. Ingber DE, Madri JA, Jamieson JD: Role of basal lamina in neoplastic disorganization of tissue architecture. Proc Natl Acad Sci U S A 1981;78(6):3901–3905.

    Article  CAS  PubMed  Google Scholar 

  69. Sohara N, Znoyko I, Levy MT, Trojanowska M, Reuben A: Reversal of activation of human myofibroblast-like cells by culture on a basement membrane-like substrate. J Hepatol 2002;37(2):214–221.

    Article  CAS  PubMed  Google Scholar 

  70. Vonlaufen A, Joshi S, Qu C, Phillips PA, Xu Z, Parker NR, Toi CS, Pirola RC, Wilson JS, Goldstein D, Apte MV: Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res 2008;68(7):2085–2093.

    Article  CAS  PubMed  Google Scholar 

  71. Schneiderhan W, Diaz F, Fundel M, Zhou S, Siech M, Hasel C, Moller P, Gschwend JE, Seufferlein T, Gress T, Adler G, Bachem MG: Pancreatic stellate cells are an important source of MMP-2 in human pancreatic cancer and accelerate tumor progression in a murine xenograft model and CAM assay. J Cell Sci 2007;120512–519.(Pt 3):

    Article  CAS  PubMed  Google Scholar 

  72. Korc M: Pancreatic cancer-associated stroma production. Am J Surg 2007;194(4 Suppl):S84–S86.

    Article  CAS  PubMed  Google Scholar 

  73. Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE: CEACAM6 gene silencing impairs anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells. Oncogene 2004;23(2):465–473.

    Article  CAS  PubMed  Google Scholar 

  74. Lohr M, Schmidt C, Ringel J, Kluth M, Muller P, Nizze H, Jesnowski R: Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res 2001;61(2):550–555.

    CAS  PubMed  Google Scholar 

  75. Paget S: The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 1989;8(2):98–101.

    CAS  PubMed  Google Scholar 

  76. Guerra C, Schuhmacher AJ, Canamero M, Grippo PJ, Verdaguer L, Perez-Gallego L, Dubus P, Sandgren EP, Barbacid M: Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 2007;11(3):291–302.

    Article  CAS  PubMed  Google Scholar 

  77. Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR: Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 1999;59(19):5002–5011.

    CAS  PubMed  Google Scholar 

  78. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ: Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001;292(5516):468–472.

    Article  CAS  PubMed  Google Scholar 

  79. Kleeff J, Beckhove P, Esposito I, Herzig S, Huber PE, Lohr JM, Friess H: Pancreatic cancer microenvironment. Int J Cancer 2007;121(4):699–705.

    Article  CAS  PubMed  Google Scholar 

  80. Jain RK: Transport of molecules in the tumor interstitium: a review. Cancer Res 1987;47(12):3039–3051.

    CAS  PubMed  Google Scholar 

  81. Schuch G, Kisker O, Atala A, Soker S: Pancreatic tumor growth is regulated by the balance between positive and negative modulators of angiogenesis. Angiogenesis 2002;5(3):181–190.

    Article  CAS  PubMed  Google Scholar 

  82. Kindler HL, Niedzwiecki D, Hollis D, Oraefo E, Schrag D, Hurwitz H, McLeod HL, Mulcahy MF, Schilsky RL, Goldberg RM: Cancer and Leukemia Group B, A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis of Cancer and Leukemia Group B (CALGB), in 43rd ASCO Annual Meeting. 2007: Chicago, IL.

    Google Scholar 

  83. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 1990;61(5):759–767.

    Article  CAS  PubMed  Google Scholar 

  84. Tuveson DA, Hingorani SR: Ductal pancreatic cancer in humans and mice. Cold Spring Harb Symp Quant Biol 2005;70:65–72.

    Article  CAS  PubMed  Google Scholar 

  85. Tarin D, Price JE, Kettlewell MG, Souter RG, Vass AC, Crossley B: Mechanisms of human tumor metastasis studied in patients with peritoneovenous shunts. Cancer Res 1984;44(8):3584–3592.

    CAS  PubMed  Google Scholar 

  86. Bernards R, Weinberg RA: A progression puzzle. Nature 2002;418(6900):823.

    Article  CAS  PubMed  Google Scholar 

  87. Pianka ER: On r- AND K-SELECTION. American Naturalist 1970;104:592–597.

    Article  Google Scholar 

  88. Barcellos-Hoff MH, Ravani SA: Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res 2000;60(5):1254–1260.

    CAS  PubMed  Google Scholar 

  89. Ishikawa O, Ohigashi H, Imaoka S, Sasaki Y, Iwanaga T, Matayoshi Y, Inoue T: Is the long-term survival rate improved by preoperative irradiation prior to Whipple’s procedure for adenocarcinoma of the pancreatic head? Arch Surg 1994;129(10):1075–1080.

    CAS  PubMed  Google Scholar 

  90. Valtieri M, Sorrentino A: The mesenchymal stromal cell contribution to homeostasis. J Cell Physiol 2008;217(2):296–300.

    Article  CAS  PubMed  Google Scholar 

  91. Ceyhan GO, Bergmann F, Kadihasanoglu M, Erkan M, Park W, Hinz U, Giese T, Muller MW, Buchler MW, Giese NA, Friess H: The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis. Gut 2007;56(4):534–544.

    Article  CAS  PubMed  Google Scholar 

  92. Reiser-Erkan C, Gaa J, Kleeff J: T1 Pancreatic Cancer With Lymph Node Metastasis and Perineural Invasion of the Celiac Trunk. Clin Gastroenterol Hepatol 2008;6(11):e41–e42.

    Google Scholar 

  93. Pierce GB, Speers WC: Tumors as caricatures of the process of tissue renewal: prospects for therapy by directing differentiation. Cancer Res 1988;48(8):1996–2004.

    CAS  PubMed  Google Scholar 

  94. Watanabe I, Hasebe T, Sasaki S, Konishi M, Inoue K, Nakagohri T, Oda T, Mukai K, Kinoshita T: Advanced pancreatic ductal cancer: fibrotic focus and beta-catenin expression correlate with outcome. Pancreas 2003;26(4):326–333.

    Article  CAS  PubMed  Google Scholar 

  95. Hartel M, Di Mola FF, Gardini A, Zimmermann A, Di Sebastiano P, Guweidhi A, Innocenti P, Giese T, Giese N, Buchler MW, Friess H: Desmoplastic reaction influences pancreatic cancer growth behavior. World J Surg 2004;28(8):818–825.

    Article  PubMed  Google Scholar 

  96. Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M, Buckels JA: A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002;87(2):161–167.

    Article  CAS  PubMed  Google Scholar 

  97. Sund M, Zeisberg M, Kalluri R: Endogenous stimulators and inhibitors of angiogenesis in gastrointestinal cancers: basic science to clinical application. Gastroenterology 2005;129(6):2076–2091.

    Article  CAS  PubMed  Google Scholar 

  98. Ohuchida K, Mizumoto K, Murakami M, Qian LW, Sato N, Nagai E, Matsumoto K, Nakamura T, Tanaka M: Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res 2004;64(9):3215–3222.

    Article  CAS  PubMed  Google Scholar 

  99. Loeffler M, Kruger JA, Niethammer AG, Reisfeld RA: Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest 2006;116(7):1955–1962.

    Article  CAS  PubMed  Google Scholar 

  100. Russo FP, Alison MR, Bigger BW, Amofah E, Florou A, Amin F, Bou-Gharios G, Jeffery R, Iredale JP, Forbes SJ: The bone marrow functionally contributes to liver fibrosis. Gastroenterology 2006;130(6):1807–1821.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Technical University of Munich, Munich, Germany

    Mert Erkan, Helmut Friess & Jörg Kleeff

  2. Institute of Pathology, Inselspital, University of Bern,  , Switzerland

    Irene Esposito

Authors
  1. Mert Erkan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irene Esposito
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Helmut Friess
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jörg Kleeff
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this entry

Cite this entry

Erkan, M., Esposito, I., Friess, H., Kleeff, J. (2010). Tumor-Stromal Interactions in Invasion and Metastases. In: Pancreatic Cancer. Springer, New York, NY. https://doi.org/10.1007/978-0-387-77498-5_23

Download citation

Publish with us

Policies and ethics

Search

Navigation