Plasma proteasome level is a potential marker in patients with solid tumors and hemopoietic malignancies

Abstract

BACKGROUND Proteasomes are nonlysosomal proteolytic structures that have been implicated in cell growth and differentiation. Abnormal expression levels of proteasomes have been described in tumor cells, and proteasomes can be detected and measured in plasma. The objective of this study was to characterize differences in proteasome levels between normal, healthy donors and patients with neoplastic disease and to correlate the findings with clinical status and other biologic markers of disease spread. METHODS Plasma proteasome levels were measured using a sandwich enzyme‐linked immunosorbent assay in normal donors (n = 73 donors) and in patients with solid tumors (n = 20 patients), acute leukemia (n = 35 patients), myeloproliferative (n = 37 patients) and myelodysplastic (n = 19 patients) syndromes, chronic lymphocytic leukemia (n = 44 patients), non‐Hodgkin lymphoma (n =104 patients), Hodgkin disease (n = 14 patients), other lymphoid disorders (n = 17 patients), and multiple myeloma (n = 27 patients). RESULTS In the normal donors, the plasma proteasome concentration was 2356 ng/mL ± 127 ng/mL. Patients with solid tumors exhibited a significantly higher value (7589 ng/mL ± 2124 ng/mL), similar to the patients with myeloproliferative (4099 ng/mL ± 498 ng/mL) and myelodysplastic (2922 ng/mL ± 322 ng/mL) syndromes. Patients with lymphoproliferative disorders, in contrast, had significantly lower values than normal donors (1751 ng/mL ± 107 ng/mL), except those in aggressive phase of the disease. This low level persisted in patients who were in complete remission. Proteasome levels decreased during the initial phase of treatment. Although there was a significant correlation with serum lactic dehydrogenase levels, frequent discrepancies were noted. There was no correlation with C‐reactive protein or β2‐microglobulin levels, even in the group of patients with multiple myeloma. CONCLUSIONS The plasma proteasome level is a potential new tool for the monitoring of patients with neoplastic disease. It is not correlated solely with cell lysis and may be involved in the pathophysiology of disease progression. Cancer 2001;92:2493–500. © 2001 American Cancer Society.

Circulating Proteasomes Are Functional and Have a Subtype Pattern Distinct from 20S Proteasomes in Major Blood Cells

“…Similarly increased concentrations of circulating proteasomes were detected in plasma of patients with solid tumors, myeloproliferative and myelodysplastic syndromes (4 ), various autoimmune diseases (3 ), metastatic malignant melanoma or severe psoriasis (5 ), and critical illness with sepsis and trauma (6 ). Chemotherapeutic treatment of patients with acute leukemia decreased or even normalized concentrations of circulating proteasomes (2,4 ). Patients with chronic lymphoid malignancies had subnormal concentrations of circulating proteasomes, except for patients with progressing disease, who had increased concentrations (4 ).…”

“…The finding that the concentration of circulating proteasomes increases dramatically in patients suffering from various diseases including autoimmune diseases (3,4 ) suggests that an increased amount of circulating proteasomes can be regarded as a marker of cells damaged under these pathologic conditions. We compared the pattern of proteasome subtypes in circulating proteasomes for patients with autoimmune disease with that found in healthy controls.…”

“…Wada et al (2 ) used ELISA to measured the concentrations of circulating proteasomes in sera from patients with hematologic malignancies and with various liver diseases and found that they were substantially higher than circulating proteasome in plasma of healthy patients. Similarly increased concentrations of circulating proteasomes were detected in plasma of patients with solid tumors, myeloproliferative and myelodysplastic syndromes (4 ), various autoimmune diseases (3 ), metastatic malignant melanoma or severe psoriasis (5 ), and critical illness with sepsis and trauma (6 ). Chemotherapeutic treatment of patients with acute leukemia decreased or even normalized concentrations of circulating proteasomes (2,4 ).…”

Therapeutic Targets in Extracellular Protein Deposition Diseases

“…While the concentration of plasma proteasome has been measured at between 2.1-2.4 g/mL [76], this is 300 times less abundant than inside cells [77]. Moreover, proteasomal degradation requires ATP which is around 1000 times less abundant extracellularly [78].…”

Proteasome Activity as New Approach to the Management of Multiple Myeloma

“…Furthermore, several recent studies have indicated that the measurement of proteasome concentration in the serum or plasma using an enzyme-linked immunosorbent assay (ELISA) can be a new approach to diagnosis, prognosis and monitoring of anticancer treatment of patients with haematological malignancies and certain solid tumours [9][10][11][12]. The latest research has established that plasma proteasome concentration correlates with advanced disease in MM and that it may be an independent prognostic factor for survival [12].…”