title: Involvement of host stroma cells and tissue fibrosis in pancreatic tumor development in transgenic mice.
abstract: BACKGROUND
  Stroma cells and extracellular matrix (ECM) components provide the pivotal microenvironment for tumor development. The study aimed to evaluate the importance of the pancreatic stroma for tumor development.
  
  
  METHODS
  Pancreatic tumor cells were implanted subcutaneously into green fluorescent protein transgenic mice, and stroma cells invading the tumors were identified through immunohistochemistry. Inhibition of tumor invasion by stroma cells was achieved with halofuginone, an inhibitor of TGFβ/Smad3 signaling, alone or in combination with chemotherapy. The origin of tumor ECM was evaluated with species-specific collagen I antibodies and in situ hybridization of collagen α1(I) gene. Pancreatic fibrosis was induced by cerulean injection and tumors by spleen injection of pancreatic tumor cells.
  
  
  RESULTS
  Inhibition of stroma cell infiltration and reduction of tumor ECM levels by halofuginone inhibited development of tumors derived from mouse and human pancreatic cancer cells. Halofuginone reduced the number only of stroma myofibroblasts expressing both contractile and collagen biosynthesis markers. Both stroma myofibroblasts and tumor cells generated ECM that contributes to tumor growth. Combination of treatments that inhibit stroma cell infiltration, cause apoptosis of myofibroblasts and inhibit Smad3 phosphorylation, with chemotherapy that increases tumor-cell apoptosis without affecting Smad3 phosphorylation was more efficacious than either treatment alone. More tumors developed in fibrotic than in normal pancreas, and prevention of tissue fibrosis greatly reduced tumor development.
  
  
  CONCLUSIONS
  The utmost importance of tissue fibrosis and of stroma cells for tumor development presents potential new therapy targets, suggesting combination therapy against stroma and neoplastic cells as a treatment of choice.
authors: Institute of Animal Sciences, The Volcani Center, Bet Dagan, Israel.
authors: Itai
authors: I
authors: Spector
authors: Yael
authors: Y
authors: Zilberstein
authors: Adi
authors: A
authors: Lavy
authors: Arnon
authors: A
authors: Nagler
authors: Olga
authors: O
authors: Genin
authors: Mark
authors: M
authors: Pines
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002108:Ceruletide / Q000009:adverse effects; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000187:drug effects / Q000473:pathology; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D010880:Piperidines / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
chemical_list: D016588:Anticarcinogenic Agents; D010880:Piperidines; D052999:Quinazolinones; D002108:Ceruletide; D003094:Collagen; C010176:halofuginone