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Cancer Discov. 2015 Jan;5(1):52-63. doi: 10.1158/2159-8290.CD-14-0474. Epub 2014 Oct 31.

Mutant KRAS-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions.

Author information

1
Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida.
2
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
3
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
4
Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida. storz.peter@mayo.edu.

Abstract

Desmoplasia and an inflammatory environment are defining features of pancreatic cancer. Unclear is how pancreatic cells that undergo oncogenic transformation can cross-talk with immune cells and how this contributes to the development of pancreatic lesions. Here, we demonstrate that pancreatic acinar cells expressing mutant KRAS can expedite their transformation to a duct-like phenotype by inducing local inflammation. Specifically, we show that KRAS(G12D) induces the expression of intercellular adhesion molecule-1 (ICAM-1), which serves as chemoattractant for macrophages. Infiltrating macrophages amplify the formation of KRAS(G12D)-caused abnormal pancreatic structures by remodeling the extracellular matrix and providing cytokines such as TNF. Depletion of macrophages or treatment with a neutralizing antibody for ICAM-1 in mice expressing oncogenic Kras under an acinar cell-specific promoter resulted in both a decreased formation of abnormal structures and decreased progression of acinar-to-ductal metaplasia to pancreatic intraepithelial neoplastic lesions.

SIGNIFICANCE:

We here show that oncogenic KRAS in pancreatic acinar cells upregulates the expression of ICAM-1 to attract macrophages. Hence, our results reveal a direct cooperative mechanism between oncogenic Kras mutations and the inflammatory environment to drive the initiation of pancreatic cancer.

PMID:
25361845
PMCID:
PMC4293204
DOI:
10.1158/2159-8290.CD-14-0474
[Indexed for MEDLINE]
Free PMC Article

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