Search

Heparin affin regulatory peptide (HARP) and midkine (MK) are growth factors, expressed in carcinomas, neuroblastomas and gliomas. In this study, we measured the levels of HARP and MK in plasma samples from 77 cancer patients. The patients had advanced tumors with loco-regional (n=18) or metastatic (n=49) diseases and 10 patients have their diseases limited to the primary site. HARP and MK plasma concentrations were significantly higher in all of these different subgroups of cancer patients (P<0.05 in all cases), when compared to healthy controls (n=30). Neither HARP nor MK levels were significantly different between patients with loco-regional and metastatic tumors (P=0.203 and 0.242, respectively). Moreover, a strong correlation between the elevations of the plasma levels of these two proteins (r2=0.546) in these cancer patients was found. Measurements of these secreted angiogenic growth factors may be useful for evaluation of cancer diagnosis.

Among the proteases involved in the tumor invasion process, components of the plasminogen activator system (plasminogen activator type-urokinase uPA, its membrane receptor uPAR and its two inhibitors PAI-1 and PAI-2) appear to define high risk patients in primary breast cancer. As individual analysis of each component of the plasminogen activator system does not reflect the complex interactions between the different components, we studied the prognostic impact of a dissemination risk index combining the four variables. We found that this index was the most powerful prognostic factor, particularly in node-negative patients.

It is now clearly established that proteolytic enzymes, and in particular plasminogen activator (uPA), play an important role in breaking down the extracellular matrix, which is considered to be a step in metastasis formation. Plasminogen activators are controlled at various levels. Two inhibitors, PAI-1 and PAI-2, have been identified, the latter being more specific for uPA. In attempts to determine their prognostic value, it is essential to investigate the relative importance of these parameters and their interactions. We used an immunoenzymatic method to assay uPA, PAI-1 and PAI-2 antigens in cytosols prepared from 314 primary breast tumors. The patients were followed up for a minimum of six years and all relevant clinical and laboratory findings had been recorded. Univariate analysis confirmed the poor outcome of patients whose tumors contained large amounts of uPA and PAI-1. In addition, low levels of PAI-2 correlated with shorter disease-free survival in the overall population (P = 0.02), post-menopausal women (P = 0.02) and women without lymph node involvement (P = 0.02). Multivariate analysis using the "Main Effects" Cox model identified node involvement, macroscopic tumor size and PAI-2 as significant variables. The "interactive" Cox model, taking into account interactions between uPA and its two inhibitors, identified a first subgroup with a very poor prognosis associating either high levels of PAI-1 with low levels of PAI-2 in the overall population as well as following stratification for axillary node negative disease, or high levels of uPA with low levels of PAI-2 in the group of menopausal women. We conclude that PAI-1 provides the same prognostic informations as uPA, and does not appear to play its role as an inhibitor. In contrast, PAI-2 increased the prognostic value of both uPA, particularly in post-menopausal women, as well as PAI-1 in a subgroup of axillary node negative patients.

The activities of selected glycolytic enzymes in breast tumor tissues were examined based on earlier studies showing a relationship between therapy and/or prognosis of breast cancer and tissue enzyme. In the present study, five glycolytic enzymatic activities (pyruvate kinase [PK], glucose-6-phosphate dehydrogenase [G6PD], phosphohexose-isomerase [PHI], lactate dehydrogenase [LDH], and 6-phospho-glucocate dehydrogenase [6PGD]) were measured in the cytosol (105,000 g) of 57 breast carcinomas and 22 benign breast lesions. Nucleic acids and DNA were also determined. The results were related to the wet weight of the tissue, to total and tissue cytosol proteins, and to DNA. The various means of expressing the results were compared. The correlations were satisfactory except for PHI and LDH. In these cases, this might have been due to blood contamination. The enzyme activities content was lower in the benign breast lesions than in the breast carcinomas irrespective of the way the results were expressed.