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Tumor-Stromal Interactions in Invasion and Metastases

  • Mert Erkan
  • Irene Esposito
  • Helmut Friess
  • Jörg Kleeff

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.

Keywords

Vascular Endothelial Growth Factor Pancreatic Cancer Chronic Pancreatitis Pancreatic Cancer Cell Stellate Cell 
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.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Mert Erkan
    • 1
  • Irene Esposito
    • 2
  • Helmut Friess
    • 1
  • Jörg Kleeff
    • 1
  1. 1.Technical University of MunichMunichGermany
  2. 2.Institute of Pathology, InselspitalUniversity of Bern Switzerland

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