The prognostic value of serum β 2 microglobulin compared with other presentation features in myelomatosis

Cuzick, Jack; Cooper, Edward H.; MacLennan, Ian C. M.

doi:10.1038/bjc.1985.140

Cited by 83 publications

(37 citation statements)

References 13 publications

(19 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This observation supports the conclusion that h2M plays an important role in regulating the growth and survival of cancer cells, and it seems compatible with the clinical data that high levels of serum h2M are associated with high tumor burden and poor prognosis (14,28,29). In addition, h2M-mediated cell growth was associated with cell cycle progression.…”

Section: Discussionsupporting

confidence: 90%

β2-Microglobulin Promotes the Growth of Human Renal Cell Carcinoma through the Activation of the Protein Kinase A, Cyclic AMP–Responsive Element-Binding Protein, and Vascular Endothelial Growth Factor Axis

Nomura

Huang

Zhau

et al. 2006

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: h 2 -Microglobulin (h2M), a soluble protein secreted by cancer and host inflammatory cells, has various biological functions, including antigen presentation. Because aberrant expression of h2M has been reported in human renal cell carcinoma, we investigated the effects of h2M overexpression on cancer cell growth and analyzed its molecular signaling pathway. Experimental Design: We established clonal cell lines that overexpressed h2M in human renal cell carcinoma (SN12C) cells and then examined cell growth in vitro and in vivo and studied the h2M-mediated downstream cell signaling pathway. Results: Our results showed that h2M expression positively correlates with (a) in vitro growth on plastic dishes and as Matrigel colonies, (b) cell invasion and migration in Boyden chambers, and (c) vascular endothelial growth factor (VEGF) expression and secretion by cells. We found, in addition, that h2M mediates its action through increased phosphorylation of cyclic AMPr esponsive element-binding protein (CREB) via the protein kinase A-CREB axis, resulting in increased VEGF expression and secretion. In convergence with this signal axis, h2M overexpression also activated both phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. h2M overexpression induced accelerated growth of SN12C in mouse subcutis and bone. Interrupting the h2M signaling pathway using small interfering RNA led to apoptosis with increased activation of caspase-3 and caspase-9 and cleaved poly(ADP-ribose) polymerase. Conclusions: Our results showed for the first time that the h2M-protein kinase A-CREB-VEGF signaling axis plays a crucial role in support of renal cell carcinoma growth and progression and reveals a novel therapeutic target. b 2 -Microglobulin (b2M), a well-known housekeeping gene, is a 12-kDa nonglycosylated polypeptide composed of 100 amino acids. h2M is synthesized by all nucleated cells and forms complexes with the heavy chain of MHC class I (1). MHC class I or HLA antigen plays an important role in tumor immunity because cancer cells present peptides that are degraded by proteasome but still recognized by cytotoxic T cells (2 -4). The expression of MHC class I antigen has been observed in some cancer cells, but down-regulation or loss of HLA molecules on the surface of cancer cells is often associated with the progression of several tumor types (5 -8) due in part to the ability of cancer cells to evade host immune surveillance and subsequent elimination by cytotoxic T cells. However, the biological functions of h2M in cancer and bone metastasis are still unknown.h2M protein expression by normal and cancer cells and its clinical usefulness has been the subject of investigation for the past two decades. With few of these studies showing a direct mitogenic action of h2M (9), no study has attempted to delineate the potential signaling function of h2M in cancer cells. h2M is a soluble factor synthesized and secreted by cancer and inflammatory cells. Increased synthesis and release of h2M occur in seve...

show abstract

Section: Discussionsupporting

confidence: 90%

β2-Microglobulin Promotes the Growth of Human Renal Cell Carcinoma through the Activation of the Protein Kinase A, Cyclic AMP–Responsive Element-Binding Protein, and Vascular Endothelial Growth Factor Axis

Nomura

Huang

Zhau

et al. 2006

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Recently, some new parameters, such as thymidine kinase (Simonsson et al, 1985), T-cell subsets (San Miguel et al, 1985), plasma cell morphology (Greipp et al, 1985), plasma cell antigens (Ruiz Arguelles et al, 1984;San Miguel et al, 1987), plasma cell labelling index and beta-2-microglobulin (Bataille et al, 1984;Brenning et al, 1986;Cuzick et al, 1985;Van Dobbenburgh et al, 1985) have emerged as possible prognostic factors in multiple myeloma. Of all these, the latter has been the most extensively analysed, being assessed in most studies as an important prognostic variable (Bataille et al, 1984;Brenning et al, 1986;Cuzick et al, 1985).…”

Section: Resultsmentioning

confidence: 99%

Prognostic factors and classification in multiple myeloma

Miguel¹,

Sánchez²,

Gonzalez³

1989

Br J Cancer

View full text Add to dashboard Cite

Summary Analyses of prognostic factors have allowed the design of staging systems in different haematological disorders. In a series of 220 patients with multiple myeloma, univariate analysis showed that nine parameters had a significant adverse effect on survival; poor performance status (Karnowsky scaling system < 70%), infections before diagnosis, renal impairment (assessed either by creatinine clearance > 2 mg dl 1 or urea > 40 mg dl 1), serum calcium ( > O0 mg dl 1), severe anaemia ( < 8.5 g dl 1), the presence of Bence-Jones proteinuria, failure to achieve complete remission, more than 40% plasma cells in bone marrow and a low paraprotein index (monoclonal component/% plasma cells: P < 0.09). In addition, this index correlated significantly with all the other prognostic factors except performance status. The best combination of disease characteristics selected by means of the Cox regression proportional hazards method were performance status and creatinine levels. Additionally, by factor analysis of principal components we obtained a regression equation that included creatinine levels, haemoglobin, performance status and paraprotein index. Using this it was possible to separate the series of patients into three risk categories: A (65 patients), B (69 patients) and C (65 patients

show abstract

“…This study once again reinforcing the opinion that serum f2m level an extremely powerful prognostic factor in myelomatosis. (Cuzick et al, 1985). Thomale and Nass (1983) have suggested that modified nucleoside excretion in cancer results from a combination of intrinsic alterations in enzymatic activity and secondary events resulting from the overall metabolism of the host as the tumour grows.…”

Section: Discussionmentioning

confidence: 99%

“…More recently the serum f2-microglobulin level has been confirmed to be a powerful prognostic indicator (Child et al, 1983;Bataille et al, 1984, Cuzick et al, 1985. Nevertheless, the variation of the course of the disease within the subsets defined by combinations of these indicators warrants further study to try to improve our predictions at the individual patient level.…”

mentioning

confidence: 95%

Urinary pseudouridine excretion in myelomatosis

Sorensen¹,

Brown²,

Cooper³

et al. 1985

Br J Cancer

Self Cite

View full text Add to dashboard Cite

Sunmary Urinary ql excretion is independent of the main indices of tumour activity in myelomatosis (serum paraprotein, serum ,B2-microglobulin, serum creatinine and urinary light chain production). The mean (±s.d.) at presentation was 40.7 + 22.6 nmol . ,umol ucr 1, compared to 25.4 + 4.8 nmol . gmol ucr-in controls. Urinary levels at presentation are significantly related to prognosis, the higher the level the poorer the prognosis. However, when these levels have been stratified according to the corresponding level of serum /B2 m, the level adds little as a prognostic factor.Several biochemical indices have been found to be valuable as guides to prognosis in myelomatosis, they include serum creatinine, paraprotein urinary free light chain excretion and haemoglobin levels (Durie & Salmon, 1975). More recently the serum f2-microglobulin level has been confirmed to be a powerful prognostic indicator (Child et al., 1983;Bataille et al., 1984, Cuzick et al., 1985. Nevertheless, the variation of the course of the disease within the subsets defined by combinations of these indicators warrants further study to try to improve our predictions at the individual patient level.There is growing evidence that the increased urinary excretion of modified nucleosides is a common feature of many types of advanced cancers including lymphomas (Salvatore et al., 1983;Rasmunson et al., 1983). The modified nucleosides are produced by post-transcriptional enzymatic action; tRNA contains the highest and most varied number of modified nucleosides. No retrieval pathway exists for these compounds, ensuring that they are not randomly inserted into the macromolecules (Borek, 1983;Dirheimer, 1983). The catabolites of tRNA are excreted into the urine without reabsorption and consist of pseudouridine (i/) and possibly as many as 50 methylated nucleosides. Pseudouridine is generally excreted in concentrations of 10 to 100 times that of other modified nucleosides both in healthy subjects and cancer patients. There are previous reports indicating that l excretion levels tends to carry as much information in terms of its relation to tumour mass and activity as a formal analysis of the spectrum of modified nucleosides (Rasmunson et al., 1983); but others favour the simultaneous analysis of several nucleosides Heldman et al., 1983).In this paper we report the levels of urninary / excretion in myelomatosis, determine its role as a prognostic indicator alone, and investigate whether it can add information once the patients have been stratified for serum f2m levels. Materials and methods PatientsThe 264 patients were all entered into the Medical The urinary nucleosides were first isolated by affinity chromatography on boronate Affi-gel 667 obtained from Bioard (Watford, UK), as described by Gehrke et al. (1978). Pseudouridine was then assayed by reverse phase chromatography on a 300 x 5 mm Spherisorb 5 ODS column in conjunction with an Applied Chromatography Systems HPLC apparatus, and the absorbance monitored at 254 nm, 0.1 AUFS, 20 M1 of reconst...

show abstract

The prognostic value of serum β 2 microglobulin compared with other presentation features in myelomatosis

Cited by 83 publications

References 13 publications

β2-Microglobulin Promotes the Growth of Human Renal Cell Carcinoma through the Activation of the Protein Kinase A, Cyclic AMP–Responsive Element-Binding Protein, and Vascular Endothelial Growth Factor Axis

β2-Microglobulin Promotes the Growth of Human Renal Cell Carcinoma through the Activation of the Protein Kinase A, Cyclic AMP–Responsive Element-Binding Protein, and Vascular Endothelial Growth Factor Axis

Prognostic factors and classification in multiple myeloma

Urinary pseudouridine excretion in myelomatosis

Contact Info

Product

Resources

About