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

Abstract

Metastatic growth and invasion by colon cancer cells in the liver requires the ability of the cancer cells to interact with the new tissue environment. Plasmin(ogen) is activated on cell surfaces by urokinase-type PA (uPA), and is regulated by uPAR and plasminogen activator inhibitor-1 (PAI-1). To compare the expression patterns of uPA, uPAR and PAI-1 in colon cancer with that in their liver metastases, we analysed matched samples from 14 patients. In all 14 primary colon cancers, we found upregulation of uPAR, uPA mRNA and PAI-1 in primarily stromal cells at the invasive front. In 5 of the 14 liver metastases, we found intense expression of uPAR, uPA-mRNA and PAI-1 in primarily stromal cells at the metastases periphery, and in an expression pattern similar to that found in the primary tumours. In the remaining 9 liver metastases, uPAR and uPA-mRNA were only seen associated with the presence of necrosis within the liver metastases. In addition, PAI-1-immunoreactivity was in all liver metastases seen in hepatocytes at the metastases periphery. Interestingly, the former 5 liver metastases positive for uPAR, uPA mRNA and PAI-1 at the metastasis periphery all had a predominantly desmoplastic reaction, whereas 8 of the remaining 9 showed direct contact between the cancer cells and the liver parenchyma. We conclude that there are 2 distinct patterns of expression of uPAR, uPA and PAI-1 in colon cancer liver metastases and that these correlate closely with 2 morphological growth patterns. These findings may have implication for the treatment of patients with metastatic disease.

Prognosis in adenocarcinomas of lower oesophagus, gastro‐oesophageal junction and cardia evaluated by uPAR‐immunohistochemistry

“…34 In colorectal adenocarcinomas, gastric carcinomas and breast carcinomas uPAR is localised to macrophages and myofibroblasts as well as to some cancer cells. 9,17,35 In squamous cell carcinoma (SCC) of the oral cavity, the receptor is predominantly observed in macrophages but also in fibroblasts and neutrophils. 36,37 uPAR-positive neoplastic cells found in areas with incipient and invasive SCC are in addition reported to express laminin-5c2, 37 which is a marker for invasiveness.…”

“…Immunoperoxidase staining was done as previously described. 9,17 The primary antibodies were incubated at the following dilutions: uPAR pAb (2.8 lg/ml), uPAR mAb, R2 (0.86 lg/ml), R4 (5.1 lg/ml), CD68, PG-M1, 1:100 and a-SMA, 1:200.…”

“…9 In brief, paraffin sections of 3 lm were deparaffinised and pretreated in Target Retrieval Solution (code S1699, Dako) for 15 min at 98 C. The mAbs against cytokeratin (1:100) was labelled with Zenon 488, the mAb against CD68, clone KP1 (1:100) was labelled with Zenon 594, the mAb against a-SMA (1:100) was labelled with Zenon 647 and uPAR pAb, (2.8 lg/ ml) was detected with Cy3-conjugated goat anti-rabbit IgG.…”

“…9 Antisense and sense uPAR-riboprobes were generated from plasmids pHUR04 and pHUR06 27 and adjusted to 500,000 cpm/ll.…”

“…The high malignant potential of these tumours may be related to matrix-degrading proteolytic activities that facilitate their migration across anatomical barriers and are known as important factors in other types of carcinomas of the gastro-intestinal tract, and in particular in the colon. 8,9 Plasminogen is locally converted into plasmin on cell surfaces by urokinase-type plasminogen activator (uPA) bound to its receptor uPAR. 10 The activity of uPA and tissue-type plasminogen activator is regulated by plasminogen activator inhibitors (PAI).…”