Tumor-derived intercellular adhesion molecule-1 mediates tumor-associated leukocyte infiltration in orthotopic pancreatic xenografts

Abstract

Tumor infiltration of immune cells (polymorphonuclear cells [PMNs] and macrophages) was initially thought to be an attempt by the host organism to combat malignancy. It appears, however, that certain subsets of chronically activated immune cells likely promote tumor growth, facilitate tumor cell survival and aid in metastasis. The association between tumor cells and tumor-associated PMNs has been demonstrated in several types of cancer, but the presence of tumor-associated PMNs in pancreatic cancer has not been well studied in vivo. Intercellular adhesion molecule-1 (ICAM-1) functions in cell-cell and cell-extracellular matrix adhesion and has a physiological role in PMN tight adhesion of leukocytes via interaction with the ligands LFA-1 and Mac-1. Increased ICAM-1 expression correlates with poor prognosis in pancreatic cancer. Therefore, the aim of this study was to investigate the function of ICAM-1 and tumor-associated PMNs in pancreatic cancer progression using ICAM-1-null (ICAM-1(-/-)) mice. We hypothesize that ICAM-1 null mice have decreased pancreatic cancer progression. Surprisingly, there is no significant difference in pancreatic cancer progression in wild-type versus ICAM-1 null mice. Interestingly, we found that tumor-derived ICAM-1 co-localizes with host PMNs at the leading edge of the tumor in ICAM-1 null mice. These results suggest that tumor-derived ICAM-1 is a sufficient ligand for tumor-associated PMNs and may play a role in subsequent tumor growth and metastasis.

Activation state of stromal inflammatory cells in murine metastatic pancreatic adenocarcinoma

“…TAMs and TANs are uniquely equipped to provide growth factors, angiogenic factors, and enzymes capable of breaking down the extracellular matrix and facilitating the metastatic process (36). Using a model of metastases that creates a hepatic dominant metastatic pattern, as observed in human pancreatic adenocarcinoma (35), we have demonstrated that TAMs express a "procancer" alternatively activated phenotype, as evidenced by a marked increase in expression of CD206 and CD163 in the hepatic metastatic tumor microenvironment. These data demonstrate that TAMs in the tumor microenvironment are AAMs in an in vivo model, which corroborates prior hypothesis papers (10,31) and in vitro studies (39).…”

“…All studies were performed under the guidelines of an approved protocol of the University of Colorado at Denver Institutional Animal Care and Use Committee (IACUC). After acclimation, mice underwent general anesthesia and were inoculated by a subcapsular splenic injection of 2.5 ϫ 10 5 Pan02 cells (35), control mice did not receive tumor inoculation. Mice were clinically followed (2), weighed 3 times weekly, and killed 5 wk after injection of tumor cells or earlier if there were clinical deterioration per IACUC regulations.…”

“…Neutrophils are also key contributors of tumor MMP-9 (9). Our laboratory has recently shown an increase in TANs at the leading edge of tumors in a transgenic murine model of pancreatic adenocarcinoma (35). Like TAMs, TANs have the ability to secrete growth factors that may sustain tumorigenesis (12), as well as factors that have the potential to facilitate angiogenesis and metastasis, such as VEGF, MMPs, and other proteases (10,19,37), which break down the basement membrane, allowing tumor cells to invade surrounding tissue and spread distantly (35).…”

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

“…In pancreatic cancer cell lines it was shown that ICAM-1 expression was significantly-increased as compared to normal pancreatic cells (37). Moreover, the ICAM-1 expression status was linked to the poor prognosis of pancreatic cancer (38). Although our data show that in human tissue ICAM-1 expression mainly occurs in regions of ADM and decreases in regions of PanINs (Fig.…”

Advanced technologies for studying circulating tumor cells at the protein level

“…Its expression on CTCs has been found to encourage their transendothelial migration in melanoma [95], pancreatic [96] and breast cancers [97] by promoting their interaction with neutrophils [98,99].…”