Pancreatic cancer is a rare disease, accounting for about 3% of all cancers in the United States. It is the deadliest of all solid malignancies, accounting for about 7% of all cancer deaths each year, and carries a 5-year survival rate of just 11.5%. According to the American Cancer Society, in 2023, over 64,000 people will be diagnosed with the disease and more than 50,500 will die of the cancer.
Studies show that the development of pancreatic cancer may be preceded by several precancer lesions, including pancreatic intraepithelial neoplasia (PanIN) lesions, intraductal papillary mucinous neoplasms, and mucinous cystic neoplasms.
A study by Carpenter et al published in Cancer Discovery comparing healthy pancreases from deceased donors of diverse age and race to pancreatic cancer and peritumoral tissue discovered that pancreatic intraepithelial neoplasia (PanIN) lesions were found in a majority of the donor pancreases and that these lesions contained features of pancreatic cancer. Additional research is needed to identify mechanisms that inhibit or promote PanIN progression to malignancy to potentially detect pancreatic cancer in its early stages and find effective therapeutic strategies.
Study Methodology
The researchers partnered with Gift of Life Michigan to collect healthy pancreases from 30 recently deceased donors for whom no suitable transplant recipients were identified. The donors—20 males and 10 females—were between the ages of 20 and 70. Approximately two-thirds were White, one-third were Black, one donor was Asian, and one donor was of unknown race. The donors were all prescreened via cross-sectional imaging and lab values prior to organ recovery and were found to have no identifiable pathology in the pancreas.
Blood flow in the organ was maintained until the pancreas could be resected and immediately cooled, which limited warm ischemic time and helped preserve the cellular and transcriptomic profile of the tissue.
Results
The researchers performed histopathologic analyses from various regions of the pancreas and found the presence of PanINs in 18 of the 30 donor pancreases. Analysis of the tissue immediately surrounding the PanIN lesions showed that the PanIN microenvironment was rich in fibroblasts, myeloid cells, and T cells, making it distinct from that of histologically normal pancreatic tissue.
To understand how the PanIN lesions of healthy donors compared with pancreatic tumors, the authors compared the microenvironment and gene expression of PanINs with previously published data on pancreatic cancer cells. They found that PanINs and pancreatic tumors had distinct microenvironments, but similar gene expression patterns. Compared with the PanIN microenvironment, the tumor microenvironment had lower levels of acinar and endothelial cells and a greater proportion of macrophages and CD4-positive T cells.
“Precursor lesions to pancreatic cancer are poorly characterized. We analyzed donor pancreata and discovered that precursor lesions are detected at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell intrinsic factors that restrain, or, conversely, promote, malignant progression,” concluded the study authors.
Clinical Significance
“Understanding how pancreatic tissue evolves as it transitions from normal to precancerous to cancerous will be key to identifying strategies for early detection, prevention, and treatment of pancreatic cancer,” said lead study investigator Marina Pasca di Magliano, PhD, Professor of Surgery and Professor of Cell and Developmental Biology at Michigan Medicine at the University of Michigan Medical School in Ann Arbor. “Unfortunately, it has been difficult to understand the baseline characteristics of the pancreas due to a lack of normal pancreatic tissue available for research. 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. The composition of the microenvironments surrounding PanINs might be a key factor.”
Disclosure: Funding for this study was provided by the National Institutes of Health, the Veterans Affairs Biomedical Laboratory and Research Development Awards, the American College of Gastroenterology, the Rackham International Student Fellowship, the CCSG Bioinformatics Shared Resource, the Association for Academic Surgery, and the Joel J. Roslyn Award. For full disclosures of the study authors, visit aacrjournals.org/cancerdiscovery.
