Following the report of an antibody IL-17RB which proved to ease the metastasis of pancreatic cancer back in 2015, Dr. Wen-Hwa Lee’s group made another breakthrough in the study regarding pancreatic ductal adenocarcinoma (PDAC), which is a ferocious kind of pancreatic cancer. In the latest Cell Metabolism journal, the group pinpointed the cause and effect of pancreatic cancer, which can shed lights for prevention and treatment of the disease.
Pancreatic cancer is one of the toughest cancer diseases. One reason is due to its non-specific low key symptoms at early onset: upper abdominal pain, back pain, lack of appetite, fatigue, or weight loss, none is considered a clear indication. Usually it is due to drastic weight loss in a short time that finally draws the doctor’s attention, and usually, that is already at terminal stages. From the medical records, the researchers found out around eighty percent of the cases already have metastasis when pancreatic cancer is identified, only twenty percent are considered treatable by operations, and yet, eighty percent of the successfully treated patients would still have a comeback or metastasis eventually.
It seems that only when the mechanism of the pancreatic cancer is well understood, can an effective therapeutic be developed. Better yet, if we know the cause, perhaps we can do the right thing to avoid it.
KRAS is a gene known to enhance cell growth, it is also reputable in causing cancer cell growth when KRAS has a defect.
Dr. Chun-Mei Hu is an assistant research specialist who is in charge of the animal core facility in GRC. Dr. Hu has also participated in the Lee’s pancreatic cancer research and wanted to make a thorough study to understand how pancreatic cancer cell grows. By going through the pathological records, she found out a whopping 94% of KRAS defects reported among the PDAC cancer cases, this being a clue too significant to ignore, she wanted to find out, what exactly happened to have caused the KRAS gene mutation in pancreatic cells? Could it be the root cause?
From the biopsy obtained from the collaborators Dr. Yu-Ting Chang, Ming-Chu Chang, and Yung-Ming Jeng of Taiwan University Hospital, they identified another interesting clue. By observing normal pancreatic tissues and intestinal tissues from pancreatic cancer patients with diabetics, and normal pancreatic tissues and intestinal tissues from non-diabetic pancreatic cancer patients, only normal pancreatic tissues with the diabetic condition have significantly higher KRAS gene mutation than the other three tissue samples. Mice tests also showed if fed with high sugar high fat diet for a long period of time, their blood sugar tends to be high. However, after examining the pancreas, colon, intestine, liver, lung and kidney tissues, only the tissues from the pancreas appeared to have DNA damage and KRAS gene mutation.
Since pancreas is responsible for metabolism, the team figured it must be during the process of digesting and something went wrong to have caused DNA damage so that somewhere along the way, crooked KRAS genes made the cells went out of control.
To find out what exactly is the triggering element, they conducted a series of cell experiments treated with high concentrations of glucose, glutamine (a representative for amino acids), or palmitic acid (a representative for saturated fatty acids) separately. The result showed only when fed with high concentrations of glucose would the pancreatic cells have genetic mutation!
Then, they needed to dig into the pancreatic cells to see the molecular mechanism. The observed a significant decrease of dNTP within the cells when there are lots of glucose inside the cells. dNTP (deoxy-ribonucleoside triphosphate) is a type of nucleotide transformed from glucose intakes inside our body. dNTP is important in DNA repli-cation and repair.
Lastly, after a series of tracking, the team determined that when there are excess amount of glucose absorbed into the pancreatic cells, a glycosylation process would kick in, as a result, this post-translational modification specifically compromised the ribonucleotide reductase (RNR) activity, leading to deficiency in dNTP pools.
Simply put, in the make of the upper stream component dNTP, the necessary element RNR were disturbed by the excess amount of glucose and twisted its original function. Due to decrease of dNTP pools, the genomic process of pancreatic cells might cause replication stress to increase mutations including oncogenic KRAS mutation.
Once the KRAS gene had a mutation, defected pancreatic cells are unleashed and keep splitting and growing on a fast pace, and resulted in pancreatic cancers.
Their study also indicates that, although the excessive glucose triggers the glycosyla-tion and blocks the self-repair mechanism, such scenario only happens to pancreatic cells, not the lung cancer cells, nor the colon cancer cells, although these two diseases have a strong correlation with diabetics.
This study confirmed the fact that too much glucose adds the burden to the frontline metabolism actions in pancreas and caused the cancer. The bottom line is, in order to protect the pancreas, avoid high sugar diets!
The research article can be read online at the Cell Journal website: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30069-5
ABOUT THE PANCREAS CANCER
Pancreas hides deeply inside our abdomen, surrounded by liver, stomach, colon, intestine, and bladder. It has the responsibility to provide insulin and digestive enzymes for our body to carry out the digestion work. The main function of our digestive system is to divide what we ate into smaller pieces and then transform the food into different kinds of chemical ele-ments that can be used by other organ
There are two functional groups in our pancreas, the endocrine and exocrine. Tiny isles be-long to the endocrine system that make the insulin and glucagon, and then send them away to our body parts through blood. The exocrine glands make substances and send them out through ducts to the intestine to further divide carbohydrates, proteins, and fats.
Statistically, of all pancreatic cancers treated, 5% are originated from the pancreatic isles, the remaining 95% all happen in the pancreatic ducts, and are referred to as pancreatic ductal adenocarcinoma (PDAC). PDAC is considered a harder to treat cancer, the average survival rate is around 3 to 6 months after diagonosis.