Mutant KRAS–Induced Expression of ICAM-1 in Pancreatic Acinar Cells Causes Attraction of Macrophages to Expedite the Formation of Precancerous Lesions

Abstract

Desmoplasia and an inflammatory environment are defining features of pancreatic cancer. Unclear is how pancreatic cells that undergo oncogenic transformation can crosstalk 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 KrasG12D induces the expression of intercellular adhesion molecule-1 (ICAM-1), which serves as chemoattractant for macrophages. Infiltrating macrophages amplify the formation of KrasG12D-caused abnormal pancreatic structures by re-modulating the extracellular matrix and providing cytokines such as tumor necrosis factor (TNF). Depletion of macrophages or treatment with a neutralizing antibody for ICAM-1 in mice expressing oncogenic Kras under an acinar cell-specific promoter both resulted in a decreased formation of abnormal structures and decreased progression of ADM to PanIN lesions.

Role of liver ICAM-1 in metastasis

“…IL-6 has been also implicated in the differentiation of human monocytes to M2 macrophages (102), a mechanism that probably also occurs in liver and is related to tumor progression (103). Interestingly, the infiltration of macrophages was reduced in ICAM-1 knockout mice in a model of renal injury (104), which is consistent with another report linking ICAM-1 blockage with a reduction in macrophage infiltration in precancerous pancreatic lesions (105). It is tempting to speculate that the same phenomenon may occur in the liver, as macrophages express LFA-1 and MUC-1, which are well known ICAM-1 ligands, suggesting that ICAM-1 is a key mediator in the recruitment of tumor-promoting macrophages.…”

“…Other authors have linked the increased expression of ICAM-1 with the infiltration of TAMs in renal carcinoma (128). Furthermore, this ICAM-1-mediated infiltration was also augmented in pancreatic cancer and correlated with the formation of precancerous lesions (105). Moreover, ICAM-1 silencing in C26 tumor-bearing mice resulted in decreased myeloid infiltration in metastatic liver lesions (56).…”

Inducible RasGEF1B circular RNA is a positive regulator of ICAM-1 in the TLR4/LPS pathway

“…25,26 Physiologically, ICAM-1 is expressed at a low basal level, 27 however during inflammatory and immune responses, ICAM-1 level increased substantially and aberrantly at sites of inflammation contributing to a number of inflammation-related diseases and injuries such as endotoxin-induced airway disease 28,29 and asthma, 27,30 arthritis, 31 ulcerative colitis 32 and chronic cholangiopathies. 21 In cancer, ICAM-1 has been mainly implicated in local inflammatory tumor microenvironment, 33 tumor progression and metastasis. 34 The molecular mechanisms underlying the transcriptional regulation of ICAM-1 gene has an important implication in term of inflammatoryrelated diseases.…”

Pancreatic cancer: from bench to bedside

“…Gene mutation is the key to the occurrence of cancer, and more than 95% of pancreatic cancer patients have KRAS mutations. Liou found a direct link between KRAS mutations and inflammatory environment (9). The study on the new factor of pancreatic cancer, provides a new basis for the differential diagnosis of pancreatic cancer risk and the development of new therapy, shows that when assessing the risk of pancreatic cancer in individuals, it is necessary to evaluate the history of the pancreatic cancer and other malignant diseases in the family (10).…”