Tumor hypoxia correlates with metastatic tumor growth of pancreatic cancer in an orthotopic murine model.
BACKGROUND
The role of tumor hypoxia has become a major focus in cancer research since it influences both local and systemic tumor growth. Oxygen measurements taken in human pancreatic cancer have shown extremely low oxygen tension. The aim of this study was to develop an orthotopic model for pancreatic cancer that mimics the specific tumor microenvironment and to evaluate the role of tumor oxygenation in local tumor growth and systemic dissemination in this model.


METHODS
We used two established human pancreatic cancer cell lines for xenobiotic tumor induction. After subcutaneous tumor formation one small tumor piece was transplanted into the pancreatic parenchyma of mice of the different study groups. Upon orthotopic tumor induction tumor oxygenation was measured with the Eppendorf histograph. Histological evaluation was performed with pimonidazole, an in vivo marker of hypoxia.


RESULTS
The tumor take rate was 100% in this model. Metastatic tumor dissemination occurred within the abdominal cavity, and distant metastasis were observed in the lung parenchyma. Oxygen measurements taken in various abdominal organs and xenograft tumor showed a high variation between different organs and xenografted tumors. Tumor oxygenation correlated well with the metastatic score in this model. Furthermore hypoxia was found both in the tumor center and also at the rim of a growing tumor mass. A high number of hypoxic cells were detectable in metastases located in the lung parenchyma.


CONCLUSIONS
This study provides experimental evidence that tumor hypoxia influences metastatic disease progression and supports recent assumptions that tumor hypoxia is actively involved in progression of pancreatic cancer. It further demonstrates that tumor hypoxia is not only found in the center of a tumor mass, but also occurs at the invasion front.
Büchler
Peter
P
Department of Surgery, The David Geffen School of Medicine at UCLA, University of California-Los Angeles, Los Angeles, California, USA. peter.buechler@med.uni-heidelberg.de
Reber
Howard A
HA
Lavey
Robert S
RS
Tomlinson
James
J
Büchler
Markus W
MW
Friess
Helmut
H
Hines
Oscar J
OJ
D000008:Abdominal Neoplasms / Q000556:secondary*; D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009593:Nitroimidazoles / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D010313:Partial Pressure; D013194:Staining and Labeling
D009593:Nitroimidazoles; C033815:pimonidazole; D010100:Oxygen