Urokinase and macrophages in tumour angiogenesis

Hildenbrand, Ralf; Dilger, I.; Hörlin, A; Stutte, H. J.

doi:10.1038/bjc.1995.419

Cited by 109 publications

(61 citation statements)

References 26 publications

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“…Others have reported a moderate association between angiogenesis and uPA (r ¼ 0.85), as well as PAI-1 (r ¼ 0.74) (Hildenbrand et al, 1995). This might be explained from the fewer (n ¼ 42) patients investigated in those studies, from correlating uPA from the periphery of the tumour specimen with the angiogenesis, and from estimating angiogenesis by the microvessel density method.…”

Section: Molecular and Cellular Pathologymentioning

confidence: 92%

Independent prognostic value of angiogenesis and the level of plasminogen activator inhibitor type 1 in breast cancer patients

et al. 2003

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Tumour angiogenesis and the levels of plasminogen activator inhibitor type 1 (PAI-1) are both informative prognostic markers in breast cancer. In cell cultures and in animal model systems, PAI-1 has a proangiogenic effect. To evaluate the interrelationship of angiogenesis and the PAI-1 level in breast cancer, we have evaluated the prognostic value of those factors in a total of 228 patients with primary, unilateral, invasive breast cancer, evaluated at a median follow-up time of 12 years. Microvessels were immunohistochemically stained by antibodies against CD34 and quantitated by the Chalkley counting technique. The levels of PAI-1 and its target proteinase uPA in tumour extracts were analysed by ELISA. The Chalkley count was not correlated with the levels of uPA or PAI-1. High values of uPA, PAI-1, and Chalkley count were all significantly correlated with a shorter recurrence-free survival and overall survival. In the multivariate analysis, the uPA level did not show independent prognostic impact for any of the analysed end points. In contrast, the risk of recurrence was independently and significantly predicted by both the PAI-1 level and the Chalkley count, with a hazard ratio (95% CI) of 1.6 (1.01-2.69) and 1.4 (1.02-1.81), respectively. For overall survival, the Chalkley count, but not PAI-1, was of significant independent prognostic value. The risk of death was 1.7 (1.30-2.15) for Chalkley counts in the upper tertile compared to the lower one. We conclude that the PAI-1 level and the Chalkley count are independent prognostic markers for recurrence-free survival in patients with primary breast cancer, suggesting that the prognostic impact of PAI-1 is not only based on its involvement in angiogenesis.

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Section: Molecular and Cellular Pathologymentioning

confidence: 92%

Independent prognostic value of angiogenesis and the level of plasminogen activator inhibitor type 1 in breast cancer patients

et al. 2003

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“…Previously we have determined a strong correlation between uPA levels in tumor tissue extracts and Ki67-associated proliferation rate in breast cancer (18). This prompted us to investigate the mitogenic activity of uPA in the breast cancer cell line, MDA-MB-231, in detail.…”

Section: Discussionmentioning

confidence: 99%

Urokinase-type plasminogen activator induces proliferation in breast cancer cells

Gandhari

Arens²,

Majety³

et al. 2006

Int J Oncol

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Abstract. Urokinase-type plasminogen activator (uPA) is implicated in various pathophysiological processes, including extracellular matrix turnover, cell migration and invasion. Our study aimed to determine the role of uPA in both proliferation and mitogen-activated protein kinase (MAPK) pathway. Hence, we analyzed the effects induced by exogeneous addition of domain-specific uPA antibodies and uPAinteracting molecules on proliferation of uPA-suppressed MDA-MB-231 breast cancer cells. uPA expression was reduced to 53% by stable transfection with an antisense/ vector construct and to 65% by siRNA transfection. Immunocytochemical Ki67 staining and flow cytometry (S-phase) analysis indicated a strong decrease of cellular proliferation activity (35% and 38%, respectively). Exogenous addition of high molecular weight-uPA (HMW-uPA) or incubation with the amino terminal fragment (ATF), which lacks the enzymatic activity of uPA, lead to increased cell proliferation. A strong increase of proliferation was absent when the monoclonal antiuPAR antibody IIIF10 (blocking uPA binding site), soluble uPAR (scavenger effect) and phosphatidyl-inositol-specific phopholipase C (PI-PLC, degrading uPAR) was added prior to the addition of HMW-uPA. In conclusion, HMW-uPA and ATF induce proliferation of breast cancer cells by binding to uPAR. Thereby, integrins situated adjacent to uPAR carry the signals into the cell, thus stimulating proliferation that is mediated via the MAPK pathway.

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“…However, microglia/macrophages express high levels of a range of proteolytic enzymes including CatS which may augment the proteolytic activity of the tumor cells and promote invasion by modifying the extracellular matrix. [41][42][43] To assess tumor cell expression and a potential role in invasion in the absence of other cell types, we have used astrocytoma cultures. We found no correlation between intracellular CatS activity and grade of the tumor of origin.…”

Section: Discussionmentioning

confidence: 99%

The Clinical Significance of Cathepsin S Expression in Human Astrocytomas

Flannery¹,

Gibson²,

Mirakhur³

et al. 2003

The American Journal of Pathology

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Early local invasion by astrocytoma cells results in tumor recurrence even after apparent total surgical resection, leading to the poor prognosis associated with malignant astrocytomas. Proteolytic enzymes have been implicated in facilitating tumor cell invasion and the current study was designed to characterize the expression of the cysteine proteinase cathepsin S (CatS) in astrocytomas and examine its potential role in invasion. Immunohistochemical analysis of biopsies demonstrated that CatS was expressed in astrocytoma cells but absent from normal astrocytes, oligodendrocytes, neurones and endothelial cells. Microglial cells and macrophages were also positive. Assays of specific activity in 59 astrocytoma biopsies confirmed CatS expression and in addition demonstrated that the highest levels of activity were expressed in grade IV tumors. CatS activity was also present in astrocytoma cells in vitro and the extracellular levels of activity were highest in cultures derived from grade IV tumors. In vitro invasion assays were carried out using the U251MG cell line and the invasion rate was reduced by up to 61% in the presence of the selective CatS inhibitor 4-Morpholineurea-LeuHomoPhe-vinylsulphone. We conclude that CatS expression is up-regulated in astrocytoma cells and provide evidence for a potential role for CatS in invasion. Astrocytomas are the commonest primary brain tumors and within this group the malignant grade III and IV tumors predominate (anaplastic astrocytomas and glioblastomas). Despite their non-metastatic nature, prognosis is poor because tumor infiltration of surrounding brain leads to recurrence even after apparently radical surgery. Multiple stereotactic biopsies of astrocytomas have demonstrated isolated tumor cells at considerable distances from the main tumor mass, 1 and recent investigations 2 have shown that tumor cells may be cultured from histologically normal brain at a distance greater than 4 cm from the gross tumor. Astrocytoma invasion is an active process that involves interactions with the host extracellular matrix (ECM), proteolytic modification of the ECM, and migration of the tumor cells into the modified matrix. 3 Members of the metalloproteinase, serine proteinase, and cysteine proteinase superfamilies have been linked to glioma invasion. 4 The cysteine proteinase cathepsin B (CatB) is expressed in gliomas in vitro 5 and immunohistochemical studies have demonstrated its presence in astrocytomas and glioblastomas in contrast to its absence from astrocytes in normal brain. 6,7 The expression and activity of CatB is higher in anaplastic astrocytomas and glioblastomas compared with low-grade tumors and normal brain 8 and high levels of CatB are positively correlated with poor survival. 9 Human glioblastoma cell lines also exhibit higher levels of CatB expression than lower grade astrocytomas 10 and the functional relevance of the enzyme is confirmed by a marked reduction in in vitro invasiveness of a glioblastoma cell line transfected with antisense CatB cDNA. 11 There is evide...

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Urokinase and macrophages in tumour angiogenesis

Cited by 109 publications

References 26 publications

Independent prognostic value of angiogenesis and the level of plasminogen activator inhibitor type 1 in breast cancer patients

Independent prognostic value of angiogenesis and the level of plasminogen activator inhibitor type 1 in breast cancer patients

Urokinase-type plasminogen activator induces proliferation in breast cancer cells

The Clinical Significance of Cathepsin S Expression in Human Astrocytomas

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