Although not common, pancreatic cancer is an extremely lethal disease, with a mere 11.5% relative survival rate after five years. Due to the limited presence of early symptoms, diagnosis usually occurs during the later stages when treatment becomes more challenging. Various precancerous lesions, such as PanINs, intraductal papillary mucinous neoplasms, and mucinous cystic neoplasms, could potentially lead to pancreatic cancer.

The identification of effective approaches for the early detection, prevention, and treatment of pancreatic cancer hinges upon comprehending the evolution of pancreatic tissue from a normal to a precancerous to a cancerous state.

“Unfortunately, it has been difficult to understand the baseline characteristics of the pancreas due to a lack of normal pancreatic tissue available for research,” comments co-corresponding author Marina Pasca di Magliano.

“Since there is no reason to biopsy or resect a physiologically normal pancreas, researchers have had to rely on the tissue surrounding pancreatic tumors as the so-called normal,” adds co-corresponding author Timothy Frankel. “However, it is clear that the tissue adjacent to tumors is very abnormal looking and is not a reliable surrogate for true, healthy pancreatic tissue.”

The authors collaborated with Gift of Life Michigan to acquire normal pancreatic tissue samples from 30 recently deceased donors who were unsuitable for transplantation. These donors, who did not have any pancreatic diseases and ranged in age from 20 to 70 years old, included 20 males and 10 females of varying races, with approximately two-thirds being white and one-third African American. The pancreata were procured post-brain death and preserved using a technique that maintained blood flow until resection, followed by immediate cooling to minimize warm ischemic time and preserve the cellular and transcriptomic profile of the tissue.

The authors collaborated with Gift of Life Michigan to procure 30 healthy pancreata from recently deceased donors who were not deemed suitable for organ transplantation. The aim was to characterize normal pancreatic tissue. Since the pancreata were donated after brain death, the blood flow was sustained until the organs were excised and rapidly cooled. This process reduced the warm ischemic time and helped maintain the cellular and transcriptomic profile of the tissue.

The donors, who did not suffer from any pancreatic ailments, were aged between 20 and 70 years at the time of their demise. There were 20 male and 10 female donors, with approximately two-thirds being White, one-third being African American, and one donor each of Asian and unknown race.

The researchers conducted histopathologic analyses on tissue samples obtained from multiple regions of the pancreas. The results showed that PanINs were present in 18 of the 30 pancreata obtained from donors of various age and racial backgrounds.

Further analysis of the tissue adjacent to the PanIN lesions demonstrated that the microenvironment in these regions contained high levels of fibroblasts, myeloid cells, and T cells. This indicated a significant difference between the PanIN microenvironment and that of the normal pancreatic tissue.

The authors sought to compare the microenvironment and gene expression of PanINs from healthy donors with that of pancreatic tumors. To achieve this, they analyzed and compared the data obtained from the PanINs with previously published data on pancreatic cancer cells.

The results indicated that while PanINs and pancreatic tumors had different microenvironments, they exhibited similar gene expression patterns.

Additionally, the microenvironment of pancreatic tumors contained fewer acinar and endothelial cells but had a higher concentration of macrophages and CD4+ T cells compared to that of the PanIN microenvironment.

First author Eileen Carpenter summarized that the analysis of real normal pancreata revealed the frequent presence of PanINs in individuals of diverse age and race. The findings indicated that PanINs may have already acquired some malignant cell features. The results contradict the belief that PanINs invariably progress to cancer, especially considering the rarity of pancreatic cancer.

“Prior efforts at early detection have focused on finding the PanIN lesions, with the assumption that individuals with PanINs would be the ones at risk of developing pancreatic cancer,” points out Frakel, “but our findings suggest that additional factors are involved.”

“Understanding why some PanINs evolve to cancer and others do not will be important to accurately predict who is at risk of pancreatic cancer and to develop techniques for cancer interception,” Pasca di Magliano adds. “The composition of the microenvironments surrounding PanINs might be a key factor.”

The authors acknowledged that the study had limitations, including the inability to track changes in the pancreas over time or evaluate the effects of therapeutic interventions. Pasca di Magliano noted that the examined tissue only represented a momentary snapshot of the pancreas at the time of the donor’s death. Another limitation was the small sample size of the study.

Source: 10.1158/2159-8290.CD-23-0013 

Image Credit: Getty