Researchers have identified a new marker associated with one of the deadliest cancers in the United States, which could lead to earlier diagnosis and treatment options.
At the University of California – San Diego, scientists studied mice genetically modified to reflect the early stages of pancreatic cancer, a disease that claims nearly 90% of patients within five years of diagnosis.
When examining cells under a microscope, they observed that cell stress and inflammation might signal the onset of the disease. This condition may trigger cancer cells to activate a protein called STAT3, known for helping tumors survive and resist treatment.
STAT3, in turn, activates another protein, Integrin β3 (ITGB3), in both mouse and human cells, fueling the growth of pancreatic ductal adenocarcinoma (PDAC), which is the most common type of pancreatic cancer.
This chain reaction results in PDAC spreading more rapidly and becoming tougher to treat. Interestingly, inflammation and cellular stress caused by chemotherapy can further activate STAT3, increasing ITGB3 levels and exacerbating the spread of the disease.
Given these findings, researchers are optimistic that blocking STAT3 could potentially halt tumor formation while pancreatic cancer is still in its initial stages.
Since most pancreatic cancers are detected only after they have already progressed, this discovery could enhance overall survival rates.
David Cheresh, a study author and pathologist at UC San Diego, mentioned that because STAT3 plays a significant role in numerous cancers and regulates many genes, the team delved deeper into which specific genes relate to cancer development, progression, and drug resistance.
Additionally, the researchers believe these findings could pave the way for early treatments for lung, breast, and skin cancers.
Each year, pancreatic cancer affects about 67,000 Americans and causes around 52,000 deaths. Unfortunately, the disease is often diagnosed only in advanced stages—three or four—due to its vague symptoms, which might be mistaken for less serious issues like irritable bowel syndrome (IBS).
By the time it reaches stage four, the five-year survival rate plummets to just 3%, making the condition nearly incurable. The exact causes of pancreatic cancer remain unclear, though smoking, obesity, and diabetes are believed to heighten the risk by promoting harmful inflammation that may lead to cellular mutations.
In a study published in the journal Cell Reports, researchers engineered mice to carry a mutation in the KRAS gene, which increases the likelihood of developing lung, colorectal, and pancreatic cancers. This approach aimed to mimic early pancreatic cancer in humans.
The team found that in the presence of inflammatory proteins and stress from low oxygen levels—factors that enhance the invasiveness and treatment resistance of cancer cells—STAT3 activates ITGB3 in both mouse and human pancreatic cells, driving the growth of these cancer cells.
This created a detrimental cycle between STAT3 and ITGB3, intensifying tumor aggressiveness and facilitating its spread.
However, when the research team administered cancer drugs aimed at targeting STAT3 in the early stages, they observed a slowdown in cancer development, leading to less aggressive tumors and preventing their spread to other organs.
Overall, STAT3 prompts the activation of ten genes, including ITGB3, which the researchers have termed the “STRESS UP” gene signature.
The team believes that recognizing this STRESS UP signal early could help predict whether precancerous cells will evolve into pancreatic cancer and indicate how aggressive a tumor might be. Cheresh stated, “Awareness of this gene signature in patients could be incredibly useful, as there are existing medications that target STAT3 activation and consequently inhibit the expression of these STRESS UP genes in cancer cells.”
He added that the STRESS UP identifier might be a foundation for developing early screening tools for pancreatic cancer, which currently has no means of detection until symptoms arise.
Next, the team intends to investigate molecules that could inhibit inflammation from activating ITGB3, not only in pancreatic cancer but also in other types that can impact tissue surfaces, such as lung, breast, and skin cancers.
