Stromal expression of urokinase‐type plasminogen activator receptor (uPAR) is associated with invasive growth in primary liver cancer

Abstract

Aims/Buckground: Expression of urokinase-type plasminogen activator receptor (uPAR) was studied in 25 hepatocellular carcinomas (HCCs) and seven cholangiocellular carcinomas (CCCs) by immunohistochemistry. Methods und Results: uPAR was expressed mostly by host cells distributed along the tumour-host interface in all cases of HCC and CCC, and its expression was higher in CCC. These uPAR-positive cells were identified as macrophages by observation of serial sections stained for CD68, a marker for macrophages. Cancer cells were positive for uPAR in only one case of poorly differentiated HCC with sarcomatous changes and in three cases of CCC. Hepatocellular carcinomas were classified into two types: those with a fibrous capsule (expansive type) and those without a fibrous capsule (invasive type). Invasive-type HCCs showed more prominent expression of uPAR by macrophages than expansive HCCs (p<O.OOl), to approximately the same degree as that of CCC. Extrahepatic metastasis was observed in two of 16 expansive HCCs, five of nine invasive HCCs and six of seven CCCs. Conclusions: Our findings suggest that uPAR expression mainly by macrophages is associated with invasive growth of cancer cells into the surrounding tissue in primary carcinoma of

Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor‐1 in colon cancer liver metastases

“…Expression of uPAR in colon cancer liver metastases has not previously been reported. In hepatocellular carcinomas it has been found that uPAR mRNA and protein is expressed primarily in stromal macrophages and myofibroblasts as well as in few cancer cells 28–30…”

CD10+ fibroblasts are more involved in the progression of hilar/extrahepatic cholangiocarcinoma than of peripheral intrahepatic cholangiocarcinoma

“…We have previously revealed the aberrant expression of laminin γ2 chain, which is an extracellular matrix protein and considered to be processed by MMP‐2 in CC 26 . MMPs and tissue inhibitor of MMPs are expressed in tumour cells and/or tumour‐associated stroma, having the role of degrading extracellular matrix proteins and regulating invasion and metastasis in CC 27–30 . CD10 creates a microenvironment that facilitates cancer cell invasion and metastasis, as well as MMPs, due to the structural similarity of CD10 to MMPs 31,32 .…”

“…26 MMPs and tissue inhibitor of MMPs are expressed in tumour cells and ⁄ or tumour-associated stroma, having the role of degrading extracellular matrix proteins and regulating invasion and metastasis in CC. [27][28][29][30] CD10 creates a microenvironment that facilitates cancer cell invasion and metastasis, as well as MMPs, due to the structural similarity of CD10 to MMPs. 31,32 Dawson et al 16 have revealed that CD10 contributes to the synthesis and inactivation of endothelin-1, a mitogenic peptide in prostatic cancer, and have implicated CD10 as a mediator of tumour invasion via tumour-stromal interactions.…”

In vivo antitumor activity by dual stromal and tumor-targeted oncolytic measles viruses

“…We have previously developed and characterized novel, species specific oncolytic MVs fully retargeted against the human or murine urokinase receptor (uPAR) [17,18], a GPI-anchored cell surface receptor, which is overexpressed in tumor and particularly in stromal cells, and whose role in tumor-stromal interactions and cancer progression are well established [19][20][21][22][23][24][25]. We demonstrated that systemic 10 3 10 4 10 5 10 6 10 3 10 4 10 5 10 6 10 3 10 4 10 5 10 6 10 3 10 4 10 5 10 6 10 3 10 4 10 5 10 6 10 3 10 4 10 5 10 6 10 2 10 3 10 4 10 5 10 2 10 3 10 4 10 5 10 2 10 3 10 4 10 5 10 2 10 3 10 4 10 5 10 2 10 3 10 4 10 5 10 2 10 3 10 4 10 5 10 2 10 3 10 4 10 5 administration of species specific, human (MV-huPA) or murine (MV-muPA) uPAR retargeted MVs is safe, successfully targets tumor tissues over non-cancer tissues, and is associated with significant tumor delaying effects in primary or metastatic, xenograft, and syngeneic cancer models, respectively [18,26].…”