Editors' ChoiceCancer Immunology

Mutant KRAS triggers an inflammatory attraction

Sci. Signal.  27 Jan 2015:
Vol. 8, Issue 361, pp. ec20
DOI: 10.1126/scisignal.aaa7496

Inflammation induces the formation of hyperplastic lesions in the pancreas and promotes their progression to malignant pancreatic ductal adenocarcinoma. By depleting macrophages with an intravenous injection of gadolinium chloride, Liou et al. found that macrophages promoted the development of precancerous lesions in a genetic mouse model of KRAS-mutant pancreatic cancer. In tissue samples from patients with acinar-to-ductal metaplasia (ADM) pancreatic lesions, intercellular adhesion molecule-1 (ICAM-1) was abundant in the lesions but not in the adjacent normal epithelial cells. In mice, macrophage infiltration into ADM lesions and the expression of the gene encoding ICAM-1 in acinar cells was increased in KRAS-mutant compared with wild-type pancreas tissue. ICAM-1 has both a membrane-bound form and a secreted, soluble form. Expressing KRASG12D in cultured primary mouse acinar cells increased the abundance of ICAM-1 at the mRNA and protein levels in cells and the abundance of soluble ICAM-1 in the supernatant. The expression of ICAM-1 in HeLa cells induced the secretion of soluble ICAM-1 and attracted RAW264.7 macrophages in coculture. Macrophages are classified as either M1 or M2, which have proinflammatory or suppressive function, respectively. In a transwell assay, recombinant soluble ICAM-1 or isolated KRASG12D mouse acinar cells induced the migration of isolated M1 but not M2 macrophages. A neutralizing antibody against ICAM-1 prevented the migration of M1 macrophages in the acinar cell transwell assay and decreased the infiltration of macrophages and the size and progression of ADM lesions in mice. Macrophages secrete matrix metalloproteinases (MMPs), which may facilitate tumor growth and metastasis. In situ zymography revealed extracellular matrix degradation in KRAS-mutant ADM lesions, which had increased abundance of MMP9 compared with controls. The findings indicate that mutant KRAS induces pancreatic cells to attract proinflammatory macrophages and that blocking this intercellular signal may prevent the progression of precancerous lesions.

G.-Y. Liou, H. Döppler, B. Necela, B. Edenfield, L. Zhang, D. W. Dawson, P. Storz, Mutant KRAS-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions. Cancer Discov. 5, 52–63 (2015). [PubMed]