Researchers have developed an animal model of pancreatic cancer that closely resembles the disease in humans, a step considered necessary for understanding disease progression and for developing techniques to detect and treat the cancer, according to a study in Cancer Cell (2005;7:469–483).
“Basically the challenges with pancreatic cancer are twofold and they both stem largely from the same reason,” said lead author Sunil R. Hingorani, MD, PhD, an instructor in the Departments of Medicine and Cancer Biology at the University of Pennsylvania.
“Number one, the disease is essentially incurable; and secondly, we can't biopsy the pancreas very easily.”
The researchers, led by Dr. Hingorani and David A. Tuveson, MD, PhD, Assistant Professor in the Departments of Medicine and Cancer Biology, engineered mice to express two mutated genes commonly associated with pancreatic cancer—the tumor-suppressor Trp53 R172H and the oncogene Kras G12D.
Expression of Trp53 R172H in the context of Kras G12D incited the development of pancreatic ductal carcinoma that mirrored the primary clinical, histopathological, and genomic features of the disease in humans.
“The significant finding is this would appear to represent what appears to be a faithful model of human pancreatic cancer beginning from the earliest, preinvasive disease to invasive and widely metastatic disease,” Dr. Hingorani said.
In the study, funded in part by the NIH, NCI, the National Pancreas Foundation, and an AACR-PanCAN Career Development Award, the majority of the mice developed cachexia, abdominal distention, and biliary and small bowel obstruction, all clinical hallmarks of pancreatic disease in humans.
The pattern and frequency of metastasis also mirrored that seen in human disease, with the disease spreading to the liver, lungs, diaphragm, and adrenals. In the animals, 63% had liver metastases, compared with 60% to 80% of humans with the disease, and 45% had lung metastases, compared with 50% to 60% of humans with pancreatic cancer.
Overexpression of members of the ErbB family of receptor tyrosine kinases and their associated ligands, particularly ErbB1/Egfr and ErbB2/Her2, have been implicated in pancreatic tumorigenesis and suggested as potential therapeutic targets, the authors wrote.
However, when studying preinvasive, invasive, and metastatic lesions for expression of these receptors, there is a surprising degree of heterogeneity in the expression patterns that spanned stages of progression, states of differentiation, and individual lesions of similar differentiation within the same tissue, the researchers said.
Combinations of additional mutations in critical tumor suppressor gene pathways did not cause the heterogeneity, suggesting the existence of distinct genetic routes to invasive disease.
Another mark of the correlation between the model and human disease was the presence of genomic instability in the mice. A high degree of genomic, including chromosomal, instability is a key feature of human pancreatic cancer.