Serum β<sub>2</sub>-Microglobulin and Prognosis of Patients with Renal Cell Carcinoma

Rasmuson, Torgny; Grankvist, Kjell; Ljungberg, Börje

doi:10.3109/02841869609109926

Cited by 24 publications

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“…Increased synthesis and release of h2M occur in several malignant diseases as indicated by an elevated serum or urine h2M concentration (10 -18). In addition, the level of h2M is one of the most important independent prognostic factors and survival predictors in some tumors, including renal cell carcinoma (12,14,16). Therefore, we hypothesized that h2M is not only a surrogate marker for tumor burden but also an important signaling molecule regulating renal cell carcinoma cell growth and behavior.…”

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confidence: 99%

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

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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...

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confidence: 99%

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

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“…Increased synthesis and release of 2-m, as indicated by elevated serum, plasma, or urine 2-m concentration, occurs in several malignant diseases, including prostate cancer, lung cancer, breast cancer, renal cell carcinoma (RCC), gastrointestinal and nasopharyngeal cancers, hepatocellular carcinoma, ovarian cancer, multiple myeloma, and lymphocytic malignancies such as non-Hodgkin's lymphoma, in addition to autoimmune and chronic infectious diseases [19, 21-29, 49, 50]. Furthermore, a number of studies have demonstrated that the level of serum 2-m is one of the most important independent prognostic factors and survival predictors for some tumors including RCC, multiple myeloma, and T-cell leukemia [22,24,28]. Overexpression of 2-m in tissue specimens assessed by immunohistochemical staining is also associated with tumor progression and poor prognosis in colorectal cancer and esophageal cancer [51,52].…”

Section: -M As a Biomarker For Cancersmentioning

confidence: 99%

“…Free 2-m protein is present at low levels in urine, serum, and other body fluids under normal conditions. A rise in 2-m concentration indicates abnormal conditions associated with various disorders [16][17][18][19][20][21][22][23][24][25][26]. Multiple lines of evidence show that 2-m is involved in cancer and other human malignancies.…”

Section: -M As a Biomarker For Cancersmentioning

confidence: 99%

“…After the MHC class I molecule binds an antigenic peptide, it is released to the cell surface where cytotoxic T lymphocytes recognize its peptides as originating from foreign proteins. The cell-associated form of 2-m is not anchored on the cell membrane, and therefore 2-m exhibits dissociation and equilibrium exchange with circulating soluble 2-m in the extracellular fluid where it is present at low levels in urine, serum, and other body fluids under physiologically relevant conditions, but is elevated with renal tubular failure, autoimmune disease, chronic infectious disease, and malignancies [16][17][18][19][20][21][22][23][24][25][26]41].…”

Section: Mhc Class I and 2-microglobulinmentioning

confidence: 99%

“…Elevated 2-m has been observed in patients with renal failure and autoimmune and infectious diseases [17,18]. Furthermore, increased synthesis and release of 2-m occurs in several malignant diseases including multiple myeloma, lymphoma, and solid tumors as indicated by elevated serum or urine 2-m concentrations [19][20][21][22][23][24][25][26]. Also, the level of 2-m is one of the most important independent prognostic factors and survival predictors for some cancers [22,[26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

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Test Article

2014

ScienceOpen Research

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2-microglobulin ( 2-m) has become the focus of intense scrutiny since the discovery of its undesirable roles promoting osteomimicry and cancer progression. 2-m is a well-known housekeeping protein that forms complexes with the heavy chain of major histocompatibility complex class I molecules, which are heterodimeric cell surface proteins that present antigenic peptides to cytotoxic T cells. On recognition of foreign peptide antigens on cell surfaces, T cells actively bind and lyse antigen-presenting cancer cells. In addition to its roles in tumor immunity, 2-m has two different functions in cancer cells, either tumor promoting or tumor suppressing, in cancer cell context-dependent manner. Our studies have demonstrated that 2-m is involved extensively in the functional regulation of growth, survival, apoptosis, and even metastasis of cancer cells. We found that 2-m is a soluble growth factor and a pleiotropic signaling molecule which interacts with its receptor, hemochromatosis protein, to modulate epithelial-to-mesenchymal transition (EMT) through iron-responsive pathways. Specific antibodies against 2-m have remarkable tumoricidal activity in cancer, through 2-m action on iron flux, alterations of intracellular reactive oxygen species, DNA damage and repair enzyme activities, -catenin activation and cadherin switching, and tumor responsiveness to hypoxia. These novel functions of 2-m and 2-m signaling may be common to several solid tumors including human lung, breast, renal, and prostate cancers. Our experimental results could lead to the development of a novel class of antibody-based pharmaceutical agents for cancer growth control. In this review, we briefly summarize the recent data regarding 2-m as a promising new cancer therapeutic target and discuss antagonizing this therapeutic target with antibody therapy for the treatment of localized and disseminated cancers.Keywords: Anti-2-m antibody, apoptosis, 2-microglobulin ( 2-m), osteomimicry. INTRODUCTION2-microglobulin ( 2-m), a well-known housekeeping gene, is a nonglycosylated protein with a low molecular weight of 12-kDa. This 99-amino acid residue protein is synthesized by all nucleated cells. It has been identified as a major structural component of amyloid fibrils deposited in dialysis-related amyloidosis, a common and serious complication in patients receiving hemodialysis for more than 10 years [1, 2]. 2-m forms a small invariable light chain subunit of the major histocompatibility complex (MHC) class I antigen, also known as human leukocyte antigen (HLA), on the cell surface of nucleated cells. 2-m is an important structural protein in the regulation of host immune recognition of self and non-self antigens by CD8 + T lymphocytes and for immunoglobulin transport and iron metabolism [3][4][5][6]. Some animal studies have reported that even when no MHC class I antigens could be detected on cells and the animals were grossly deficient in CD4 -CD8 + T cells, which normally mediate cytotoxic T cell function, the homozygotes appeared normal [7,8]....

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Killing tumor cells through their surface β₂‐microglobulin or major histocompatibility complex class I molecules

Yang

2010

Cancer

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Targeted antibody-based therapy has been used successfully to treat cancers. Recent studies have demonstrated that tumor cells treated with antibodies specific for b 2 -microglobulin (b 2 M) or major histocompatibility complex (MHC) class I molecules undergo apoptosis in vitro and in vivo (mouse models). Antibodies against b 2 M or MHC class I induce tumor cell apoptosis by 1) recruiting MHC class I molecules to lipid rafts and activating LYN kinase and the signal-transducing enzyme phospholipase C-c2-dependent c-Jun N-terminal kinase signaling pathway and 2) expelling interleukin 6 and insulin-like growth factor 1 receptors out of lipid rafts and inhibiting the growth and survival factor-induced activation of the phosphatidylinositol 3-kinase/Akt and extracellular signal-related kinase pathways. Consequently, mitochondrial integrity is compromised, and the caspase-9-dependent cascade is activated in treated tumor cells. However, although b 2 M and MHC class I are expressed on normal hematopoietic cells, which is a potential safety concern, the monoclonal antibodies were selective to tumor cells and did not damage normal cells in vitro or in human-like mouse models. These findings suggest that targeting b 2 M or MHC class I by using antibodies or other agents offers a potential therapeutic approach for b 2 M/MHC class I-expressing malignancies.

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Serum β₂-Microglobulin and Prognosis of Patients with Renal Cell Carcinoma

Cited by 24 publications

References 21 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

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Killing tumor cells through their surface β₂‐microglobulin or major histocompatibility complex class I molecules

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Serum β2-Microglobulin and Prognosis of Patients with Renal Cell Carcinoma

Cited by 24 publications

References 21 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

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Killing tumor cells through their surface β2‐microglobulin or major histocompatibility complex class I molecules

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Serum β₂-Microglobulin and Prognosis of Patients with Renal Cell Carcinoma

Killing tumor cells through their surface β₂‐microglobulin or major histocompatibility complex class I molecules