US researchers have developed the first animal model that clearly defines cancer metastasises in all the same places that human pancreatic cancer spreads to such as the liver, lungs, diaphragm, and adrenal glands.
The model, which is certain to be the most accurate representation of pancreatic cancer progression in the human body, is likely to form a basis for new drug therapies for this type of cancer that has a one-year survival rate after chemotherapy of only 17 to 28 per cent of patients, according to the National Cancer Institute.
"With a model that can generate the full spectrum of disease, from preinvasive to invasive and metastastic lesions, we can begin to tease out the events that are linked to the progression of pancreatic cancer," explains Sunil Hingorani, one of the lead investigators.
"In trying to understand what events are required to create and support invasive and metastatic disease, we hope to translate our findings into better therapies," Hingorani added.
Scientists from the departments of medicine and cancer biology at the University of Pennsylvania School of Medicine, engineered mice to express two mutant genes associated with pancreatic cancer, Kras, an oncogene, and p53, a well-studied tumour suppressor.
The investigators linked physiological, cellular, and genomic changes due to mutations in Kras and p53 in the mice to changes similar to that observed in pancreatic cancer patients.
The disease that develops in the Kras and p53 mutant mouse model demonstrated distinct similarities to human pancreatic cancer at multiple levels. Clinical symptoms in the mutant mice mirrored those displayed in pancreatic cancer patients, such as abdominal swelling and muscle loss.
The frequency of metastases to these various organ sites was also highly similar to that seen in humans. In human patients, 60 to 80 per cent develop metastases to the liver; and 50 to 60 per cent developed metastases to the lungs. In the genetically modified animals, 63 per cent displayed liver metastases, and 45 per cent displayed lung metastases-further emphasising the accuracy of this model in mimicking human pancreatic cancer.
To further understand the progression of pancreatic cancer, Hingorani and colleagues studied cell lines derived from primary tumour and metastasised cells. From this, the researchers established the occurrence of genomic instability in the mouse model. Genomic instability-continuous formation of mutated chromosomes-leads to widespread genetic changes throughout the affected cells.
Genomic instability is seen in many human epithelial cancers, including pancreatic cancer, and is thought to be a driving force in the transition from local tumour growth to metastases of cancers.
In the pancreatic tumours and metastases from the mouse model, the investigators characterised other molecules implicated in pancreatic cancer. Often, the expression of molecules such as growth factors and their receptors will offer possible targets for treatment.
The researchers also discovered a high degree of heterogeneity in expression among these key molecules across the specimens. After ruling out the likelihood that this variability resulted from additional acquired mutations in known key tumour suppressor pathways.
"There may actually be unique genetic routes to pancreatic cancer, such that not all pancreatic cancers are equivalent," Hingorani suggested. Hingorani along with co-lead investigator, David Tuveson, report their findings in the May issue of Cancer Cell.
The disease, the 14th most common cancer worldwide, has a poor survival rate because the illness is usually only detected in its later stages. Pancreatic cancer is rarely diagnosed in its early stages because symptoms such as unexplained weight loss, nausea, diarrhoea, weakness, jaundice and back pain only occur when the illness is more advanced.
Each year approximately 216,000 new cases of pancreatic cancer are diagnosed and 213,000 die from the illness, according to the International Agency for Research on Cancer (IARC) in France.
There is no effective screening program for the illness, most cases of which occur in developed countries. In about 10 per cent cases there is a genetic component. Smoking is one of the main risk factors for the illness.
This drug is one of a group of chemotherapy drugs called anti metabolites, which are similar to normal body molecules but are slightly different in structure. These differences mean that anti-metabolites stop cells working properly instead of helping them. Anti-metabolites often stop cells making and repairing DNA.
Whilst currently the best option, Gemcitabine (Gemzar) is not as effective as it could be due to its method of delivery and lack of precision in targeting the pancreas. This results in a median survival of approximately six months. However, it should be noted that even the best combinational treatments still only result in median survival of 1 year at the most.