Researchers from the Mayo Clinic in Jacksonville, Florida, have uncovered the link between oncogenic pancreatic acinar cells and the inflammation that facilitates its cancerous progression.
Peter Storz, PhD
Recognizing that early detection and treatment is the key to combating pancreatic cancer, often an aggressive malignancy, researchers from the Mayo Clinic in Jacksonville, Florida, have uncovered the link between oncogenic pancreatic acinar cells and the inflammation that facilitates its cancerous progression.
Peter Storz, PhD, professor of cancer cell biology and lead author on a recent publication inCancer Discovery, said, “Understanding the crosstalk between acinar cells withKRASmutations and the microenvironment of those cells is key to developing targeted strategies to prevent and treat this cancer.”
OncogenicKRASmutations drive the transition of pancreatic acinar cells to proliferative duct-like cells, precursors to pancreatic intraepithelial neoplastic lesions (PanINs).KRASencodes a small GTPase that cycles between GTP-bound active and GDP-bound inactive states. Constitutive activation of the mutant protein, prevalent in several cancers, leads to sustained proliferation, metabolic reprogramming, remodelling of the microenvironment, cell migration, and metastasis. In pancreatic cells,KRASmutations initiate acinar-to-ductal metaplasia (ADM), and several additional mutations (eg, in tumor suppressor genes) occur in the progression from precancerous lesion to cancer. Evidence also points to the role of inflammation in cancer development.
KRASmutations activate well-defined signalling pathways in the ADM process, but Storz and colleagues investigated whether or not mutantKRASis also involved in triggering local inflammation. Indeed, they found that cells withKRASmutations induce the expression of intercellular adhesion molecule-1 (ICAM-1), which acts as a chemoattractant for macrophages.
Macrophages secrete matrix-degrading enzymes and cytokines that drive the ADM process. The researchers showed that depleting macrophages and neutralizing ICAM-1 have similar effects: reduction of precancerous lesions.
“Pancreatic cancer develops from these lesions, so if we understand how the lesions come about, we may be able to stop the cancer train altogether,” says Storz.
In a series of experiments, the researchers elucidated the interaction betweenKRAS-mutant cells, macrophages, ICAM-1, and cancer progression. They first showed that in animal models depleted of macrophages, the number of neoplastic lesions decreased significantly. They demonstrated that inKRAS-mutant acinar cells, ICAM-1 expression (mRNA) increased 100-fold compared with normal cells. In Transwell assays, they showed that recombinant soluble ICAM-1 induced migration of macrophage cells, and ICAM-1 neutralizing antibodies block the chemoattraction.
To test the ability of neutralizing antibodies to block chemoattraction in vivo, the investigators treatedKRAS-mutant mice with anti-ICAM-1 antibody for 11 weeks. Neutralization of ICAM-1 was associated with decreased macrophage infiltration into the pancreas and reduction in the number of abnormal lesions. The effect was nearly identical to that of macrophage depletion.
The results indicate that in acinar cells, activatingKRASmutations cause the chemoattraction of macrophage cells via expression of ICAM-1.
“We show a direct link betweenKRASmutations and the inflammatory environment that drives the initiation of pancreatic cancer,” said Storz.
The role of ICAM-1 in pancreatic cancer progression has implications for early detection of disease and well as potential early treatment. Pancreatitis patients have been found to have high levels of circulating ICAM-1, suggesting potential as a marker for pancreatic disease. In combination with markers for advanced PanINs, ICAM-1 could predict preneoplastic lesions. In these patients with increased risk for developing pancreatic cancer, neutralizing antibodies might prevent progression of precancerous lesions.
The researchers point to their animal studies as aproof-of-principlefor the clinical use of ICAM-1 antibodies in humans. A neutralizing antibody specific for ICAM-1, Enlimomab, has already been developed for treatment of stroke, rheumatoid arthritis, and other disorders.
Liou GY, Doppler H, Necela B, et al. Mutant Kras-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions.Cancer Discov