High tPA-expression in primary melanoma of the limb correlates with good prognosis

Abstract

To investigate whether the course of primary melanoma disease correlates with expression of the various components of the proteolytic plasminogen activation (PA) system, immunohistochemical stainings for activators of plasminogen (tissue type (tPA) and urokinase type (uPA)), inhibitors of plasminogen activation (type 1 (PAI-1) and type 2 (PAI-2)) and the receptor for uPA (uPAR) were performed on 214 routinely processed melanoma lesions. All lesions were primary cutaneous melanomas, minimally 1.5 mm thick, and derived from patients with only local disease at the moment of diagnosis (clinically stage II (T 3–4 N 0 M 0), American Joint Committee on Cancer). Median patient follow-up was 6.1 years. Single variables as immunohistochemical staining results (extent of tumour cell staining, pattern of tumour cell staining and for some components also staining of stromal cells), histopathological and clinical parameters as well as treatment variables were analysed in order to assess their prognostic importance, in terms of time to recurrence, time to distant metastasis and duration of survival. The extent of tPA tumour cell positivity, categorized as 0–5%, 6–50% and 51–100%, appeared to be of importance for these end-points. Lesions with 51–100% tPA-positive tumour cells were found to have the best prognosis, whereas lesions with 6–50% tPA-positive tumour cells had the worst. Moreover, the prognostic significance of Breslow thickness, microscopic ulceration and sex was confirmed in this study. Multivariate analyses, incorporating these relevant factors, showed that the extent of tPA tumour cell positivity was an independent prognostic factor for distant metastasis-free interval (P= 0.012) and for the duration of survival (P= 0.043). © 2000 CancerResearch Campaign

Biomarkers: The Useful and the Not So Useful—An Assessment of Molecular Prognostic Markers for Cutaneous Melanoma

“…Here are included five different integrins (−α3, −α4, −α5, and −α6 (Natali et al , 1991; Schadendorf et al , 1993, 1995a; Danen et al , 1994) as well as −β5 (Danen et al , 1995)), integrinlinked kinase, an intracellular nonreceptor tyrosine kinase associated with the cytoplasmic tails of integrin-β1 and integrin-β3 and activated upon disruptions to integrin-mediated cell-matrix adhesion (McDonald et al , 2008), four non-integrin-based extracellular matrix component receptors (galectin-1 (Zubieta et al , 2006); galectin-3 (Vereecken et al , 2005; Prieto et al , 2006; Zubieta et al , 2006); 67 kDa laminin receptor (Vacca et al , 1993); and lysosome-associated membrane protein-1 (Kuzbicki et al , 2006a)), and six proteases and protease regulators (cathepsin D (Podhajcer et al , 1995); pepsinogen C (Quintela et al , 2001); heparanase-1 (Murry et al , 2005); MMP-14 (Hofmann et al , 2000; Kurschat et al , 2002); extracellular MMP-inducer EMMPRIN (van den Oord et al , 1997); and plasminogen-activator inhibitor-1 (Ferrier et al , 2000)). Notable among this set is that, for all but one protein, the direction of differential expression with lesion severity is consistent with that established from cell- and animal-based experimental data (Table 3).…”

Gene expression profiling and clinical outcome in melanoma: in search of novel prognostic factors

“…In contrast to benign nevi, where proteolysis is tissue type PA (tPA)-mediated and restricted to blood vessels, plasminogen activation in malignant lesions is both urokinase-type PA (uPA) and tPA mediated. Unlike the uPA system, extensive tPA expression of melanoma cells appears to correlate with a more favorable prognosis in stage II patients [27]. Melanoma cells may express matrix metalloprotease (MMP)-1, MMP-2 (gelatinase A), MMP-9 (gelatinase B), MMP-13 and MT1-MMP, as well as their tissue inhibitors (TI) TIMP-1, TIMP-2 and TIMP-3.…”

Gene expression profiling reveals molecular marker candidates of laryngeal squamous cell carcinoma

“…In contrast to PLAU, for which considerable evidence indicates that up-regulation of the enzyme correlates with tumor aggression, several observations suggest that high PLAT levels correlate with good prognosis in melanoma and breast cancer, whereas lower PLAT levels have been associated with malignant tumors (69,70). These findings suggest that an increase in either PLAT activity or expression levels is beneficial, possibly due to the overstimulation of plasmin generation by PLAT that induces the degradation of the pro-angiogenic fibrin matrix, resulting in the inhibition of angiogenesis (71,72).…”