Skip to main content

Advertisement

Log in

Interplay of Tumor Microenvironment Cell Types with Parenchymal Cells in Pancreatic Cancer Development and Therapeutic Implications

  • REVIEW ARTICLE
  • Published:
Journal of Gastrointestinal Cancer Aims and scope Submit manuscript

Abstract

Introduction

The process of “induction,” namely, the formation of a tissue by the functional interaction between the epithelial layer and the stroma, is key for the development of many organs, in particular to the pancreas.

Discussion

In diseases like pancreatic cancer, most studies performed to date, in the area of pancreatic cancer, have focused on studying epithelial cells and their contribution to this disease. Strikingly, until recently, the stroma that surrounds cancer cells in pancreatic tumors (desmoplastic reaction–tumor microenvironment) has remained an underrepresented area of research. However, several laboratories are increasingly posing questions as what is the role of this tumor microenvironment in the development and progression of this fatal disease. Therefore, in the current article, we define and describe the components of this desmoplastic reaction and the pancreatic tumor microenvironment and briefly review advances being made. More importantly, we highlight the urgent need of research in this field.

Conclusion

We anticipate that, because of the paucity of knowledge on this subject, studies on the pancreatic tumor microenvironment will bring new concepts which will ultimately impact in designing new diagnosis and treatment for this disease.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96. doi:10.3322/CA.2007.0010.

    Article  PubMed  Google Scholar 

  2. Schneider G, Hamacher R, Eser S, Friess H, Schmid RM, Saur D. Molecular biology of pancreatic cancer—new aspects and targets. Anticancer Res. 2008;28:1541–50.

    PubMed  CAS  Google Scholar 

  3. Sipos B, Frank S, Gress T, Hahn S, Kloppel G. Pancreatic intraepithelial neoplasia revisited and updated. Pancreatology. 2008;9:45–54. doi:10.1159/000178874.

    Article  PubMed  Google Scholar 

  4. Algul H, Schmid RM. Pancreatic cancer: a plea for good and comprehensive morphological studies. Eur J Gastroenterol Hepatol. 2008;20:713–5. doi:10.1097/MEG.0b013e3282f9460e.

    Article  PubMed  Google Scholar 

  5. Miyamoto Y, Maitra A, Ghosh B, Zechner U, Argani P, Iacobuzio-Donahue CA, et al. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell. 2003;3:565–76. doi:10.1016/S1535-6108(03)00140-5.

    Article  PubMed  CAS  Google Scholar 

  6. Mulkeen AL, Yoo PS, Cha C. Less common neoplasms of the pancreas. World J Gastroenterol. 2006;12:3180–5.

    PubMed  Google Scholar 

  7. Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C. The significance of unstable chromosomes in colorectal cancer. Nat Rev Cancer. 2003;3:695–701. doi:10.1038/nrc1165.

    Article  PubMed  CAS  Google Scholar 

  8. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6:392–401. doi:10.1038/nrc1877.

    Article  PubMed  CAS  Google Scholar 

  9. Jaster R. Molecular regulation of pancreatic stellate cell function. Mol Cancer. 2004;3:26. doi:10.1186/1476-4598-3-26.

    Article  PubMed  Google Scholar 

  10. Senoo H, Kojima N, Sato M. Vitamin A-storing cells (stellate cells). Vitam Horm. 2007;75:131–59. doi:10.1016/S0083-6729(06)75006-3.

    Article  PubMed  CAS  Google Scholar 

  11. Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A, et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998;115:421–32. doi:10.1016/S0016-5085(98)70209-4.

    Article  PubMed  CAS  Google Scholar 

  12. Omary MB, Lugea A, Lowe AW, Pandol SJ. The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest. 2007;117:50–9. doi:10.1172/JCI30082.

    Article  PubMed  CAS  Google Scholar 

  13. Apte MV, Park S, Phillips PA, Santucci N, Goldstein D, Kumar RK, et al. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas. 2004;29:179–87. doi:10.1097/00006676-200410000-00002.

    Article  PubMed  CAS  Google Scholar 

  14. Bachem MG, Zhou Z, Zhou S, Siech M. Role of stellate cells in pancreatic fibrogenesis associated with acute and chronic pancreatitis. J Gastroenterol Hepatol. 2006;21(Suppl 3):S92–6. doi:10.1111/j.1440-1746.2006.04592.x.

    Article  PubMed  CAS  Google Scholar 

  15. Thuneberg L. One hundred years of interstitial cells of Cajal. Microsc Res Tech. 1999;47:223–38. doi:10.1002/(SICI)1097-0029(19991115)47:4<223::AID-JEMT2>3.0.CO;2-C.

    Article  PubMed  CAS  Google Scholar 

  16. Popescu LM, Hinescu ME, Ionescu N, Ciontea SM, Cretoiu D, Ardelean C. Interstitial cells of Cajal in pancreas. J Cell Mol Med. 2005;9:169–90. doi:10.1111/j.1582-4934.2005.tb00347.x.

    Article  PubMed  CAS  Google Scholar 

  17. Zhang L, Notohara K, Levy MJ, Chari ST, Smyrk TC. IgG4-positive plasma cell infiltration in the diagnosis of autoimmune pancreatitis. Mod Pathol. 2007;20:23–8. doi:10.1038/modpathol.3800689.

    Article  PubMed  CAS  Google Scholar 

  18. Clark CE, Beatty GL, Vonderheide RH. Immunosurveillance of pancreatic adenocarcinoma: insights from genetically engineered mouse models of cancer. Cancer Lett. 2008;279:1–7.

    Article  PubMed  Google Scholar 

  19. Guerra C, Schuhmacher AJ, Canamero M, Grippo PJ, Verdaguer L, Perez-Gallego L, et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell. 2007;11:291–302. doi:10.1016/j.ccr.2007.01.012.

    Article  PubMed  CAS  Google Scholar 

  20. Monti P, Leone BE, Marchesi F, Balzano G, Zerbi A, Scaltrini F, et al. The CC chemokine MCP-1/CCL2 in pancreatic cancer progression: regulation of expression and potential mechanisms of antimalignant activity. Cancer Res. 2003;63:7451–61.

    PubMed  CAS  Google Scholar 

  21. Mytar B, Baj-Krzyworzeka M, Majka M, Stankiewicz D, Zembala M. Human monocytes both enhance and inhibit the growth of human pancreatic cancer in SCID mice. Anticancer Res. 2008;28:187–92.

    PubMed  Google Scholar 

  22. Esposito I, Menicagli M, Funel N, Bergmann F, Boggi U, Mosca F, et al. Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol. 2004;57:630–6. doi:10.1136/jcp. 2003.014498.

    Article  PubMed  CAS  Google Scholar 

  23. Stefani AL, Basso D, Panozzo MP, Greco E, Mazza S, Zancanaro F, et al. Cytokines modulate MIA PaCa 2 and CAPAN-1 adhesion to extracellular matrix proteins. Pancreas. 1999;19:362–9. doi:10.1097/00006676-199911000-00007.

    Article  PubMed  CAS  Google Scholar 

  24. Calderon B, Suri A, Miller MJ, Unanue ER. Dendritic cells in islets of Langerhans constitutively present beta cell-derived peptides bound to their class II MHC molecules. Proc Natl Acad Sci U S A. 2008;105:6121–6. doi:10.1073/pnas.0801973105.

    Article  PubMed  CAS  Google Scholar 

  25. Takaori K. Current understanding of precursors to pancreatic cancer. J Hepatobiliary Pancreat Surg. 2007;14:217–23. doi:10.1007/s00534-006-1165-6.

    Article  PubMed  Google Scholar 

  26. Mahadevan D, Von Hoff DD. Tumor–stroma interactions in pancreatic ductal adenocarcinoma. Mol Cancer Ther. 2007;6:1186–97. doi:10.1158/1535-7163.MCT-06-0686.

    Article  PubMed  CAS  Google Scholar 

  27. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70. doi:10.1016/S0092-8674(00)81683-9.

    Article  PubMed  CAS  Google Scholar 

  28. Natalwala A, Spychal R, Tselepis C. Epithelial–mesenchymal transition mediated tumourigenesis in the gastrointestinal tract. World J Gastroenterol. 2008;14:3792–7. doi:10.3748/wjg.14.3792.

    Article  PubMed  CAS  Google Scholar 

  29. Zhu Z, Kleeff J, Kayed H, Wang L, Korc M, Buchler MW, et al. Nerve growth factor and enhancement of proliferation, invasion, and tumorigenicity of pancreatic cancer cells. Mol Carcinog. 2002;35:138–47. doi:10.1002/mc.10083.

    Article  PubMed  CAS  Google Scholar 

  30. Eibl G, Reber HA. A xenograft nude mouse model for perineural invasion and recurrence in pancreatic cancer. Pancreas. 2005;31:258–62. doi:10.1097/01.mpa.0000175176.40045.0f.

    Article  PubMed  Google Scholar 

  31. Ceyhan GO, Bergmann F, Kadihasanoglu M, Altintas B, Demir IE, Hinz U, et al. Pancreatic neuropathy and neuropathic pain—a comprehensive pathomorphological study of 546 cases. Gastroenterology. 2009;136:177.e1–86.e1.

    Article  Google Scholar 

  32. Shimizu K. Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis. J Gastroenterol. 2008;43:823–32. doi:10.1007/s00535-008-2249-7.

    Article  PubMed  CAS  Google Scholar 

  33. Phillips PA, McCarroll JA, Park S, Wu MJ, Pirola R, Korsten M, et al. Rat pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix turnover. Gut. 2003;52:275–82. doi:10.1136/gut.52.2.275.

    Article  PubMed  CAS  Google Scholar 

  34. Farrow B, Albo D, Berger DH. The role of the tumor microenvironment in the progression of pancreatic cancer. J Surg Res. 2008;149:319–28. doi:10.1016/j.jss.2007.12.757.

    Article  PubMed  Google Scholar 

  35. Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res. 2005;97:512–23. doi:10.1161/01.RES.0000182903.16652.d7.

    Article  PubMed  CAS  Google Scholar 

  36. Cartwright T, Richards DA, Boehm KA. Cancer of the pancreas: are we making progress? A review of studies in the US Oncology Research Network. Cancer Control. 2008;15:308–13.

    PubMed  Google Scholar 

  37. El-Rayes BF, Ali S, Philip PA, Sarkar FH. Protein kinase C: a target for therapy in pancreatic cancer. Pancreas. 2008;36:346–52. doi:10.1097/MPA.0b013e31815ceaf7.

    Article  PubMed  CAS  Google Scholar 

  38. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960–6. doi:10.1200/JCO.2006.07.9525.

    Article  PubMed  CAS  Google Scholar 

  39. Danovi SA, Wong HH, Lemoine NR. Targeted therapies for pancreatic cancer. Br Med Bull. 2008;87:97–130. doi:10.1093/bmb/ldn027.

    Article  PubMed  CAS  Google Scholar 

  40. Gaspar NJ, Li L, Kapoun AM, Medicherla S, Reddy M, Li G, et al. Inhibition of transforming growth factor beta signaling reduces pancreatic adenocarcinoma growth and invasiveness. Mol Pharmacol. 2007;72:152–61. doi:10.1124/mol.106.029025.

    Article  PubMed  CAS  Google Scholar 

  41. Aikawa T, Gunn J, Spong SM, Klaus SJ, Korc M. Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer. Mol Cancer Ther. 2006;5:1108–16. doi:10.1158/1535-7163.MCT-05-0516.

    Article  PubMed  CAS  Google Scholar 

  42. Baluk P, Hashizume H, McDonald DM. Cellular abnormalities of blood vessels as targets in cancer. Curr Opin Genet Dev. 2005;15:102–11. doi:10.1016/j.gde.2004.12.005.

    Article  PubMed  CAS  Google Scholar 

  43. Kindler H, Niedzwiecki D, Hollis D. 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. J Clin Oncol. 2007;25:4508. (abstract).

    Google Scholar 

  44. Spano JP, Chodkiewicz C, Maurel J, Wong R, Wasan H, Barone C, et al. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet. 2008;371:2101–8. doi:10.1016/S0140-6736(08)60661-3.

    Article  PubMed  CAS  Google Scholar 

  45. Cao Y, Cao R, Hedlund EM. Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways. J Mol Med. 2008;86:785–9. doi:10.1007/s00109-008-0337-z.

    Article  PubMed  CAS  Google Scholar 

  46. Cao R, Bjorndahl MA, Religa P, Clasper S, Garvin S, Galter D, et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell. 2004;6:333–45. doi:10.1016/j.ccr.2004.08.034.

    Article  PubMed  CAS  Google Scholar 

  47. Gautschi O, Heighway J, Mack PC, Purnell PR, Lara PN Jr, Gandara DR. Aurora kinases as anticancer drug targets. Clin Cancer Res. 2008;14:1639–48. doi:10.1158/1078-0432.CCR-07-2179.

    Article  PubMed  CAS  Google Scholar 

  48. Simeone DM. Pancreatic cancer stem cells: implications for the treatment of pancreatic cancer. Clin Cancer Res. 2008;14:5646–8. doi:10.1158/1078-0432.CCR-08-0584.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Vijay Shah.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guturu, P., Shah, V. & Urrutia, R. Interplay of Tumor Microenvironment Cell Types with Parenchymal Cells in Pancreatic Cancer Development and Therapeutic Implications. J Gastrointest Canc 40, 1–9 (2009). https://doi.org/10.1007/s12029-009-9071-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12029-009-9071-1

Keywords

Navigation