Immunoreactivity and proliferative actions of β2 microglobulin on human bone-derived cells in vitro

Evans, Dean B.; Thavarajah, M.; Kanis, John А.

doi:10.1016/0006-291x(91)91635-p

Cited by 26 publications

(21 citation statements)

References 35 publications

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“…In particular, β2-M was reported as a growth factor and signaling molecule in cancer cells [45-47]. It is also known to be able to trigger the EMT phenomenon as well as being capable of activating stromal cells, such as osteoblasts [48] and osteoclast [49]. The significant increase in this molecule in our breast cancer samples with microcalcifications suggests its possible role both in mesenchymal transformation and in the production of microcalcifications.…”

Section: Discussionmentioning

confidence: 87%

Microcalcifications in breast cancer: an active phenomenon mediated by epithelial cells with mesenchymal characteristics

et al. 2014

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BackgroundMammary microcalcifications have a crucial role in breast cancer detection, but the processes that induce their formation are unknown. Moreover, recent studies have described the occurrence of the epithelial–mesenchymal transition (EMT) in breast cancer, but its role is not defined. In this study, we hypothesized that epithelial cells acquire mesenchymal characteristics and become capable of producing breast microcalcifications.MethodsBreast sample biopsies with microcalcifications underwent energy dispersive X-ray microanalysis to better define the elemental composition of the microcalcifications. Breast sample biopsies without microcalcifications were used as controls. The ultrastructural phenotype of breast cells near to calcium deposits was also investigated to verify EMT in relation to breast microcalcifications. The mesenchymal phenotype and tissue mineralization were studied by immunostaining for vimentin, BMP-2, β2-microglobulin, β-catenin and osteopontin (OPN).ResultsThe complex formation of calcium hydroxyapatite was strictly associated with malignant lesions whereas calcium-oxalate is mainly reported in benign lesions. Notably, for the first time, we observed the presence of magnesium-substituted hydroxyapatite, which was frequently noted in breast cancer but never found in benign lesions. Morphological studies demonstrated that epithelial cells with mesenchymal characteristics were significantly increased in infiltrating carcinomas with microcalcifications and in cells with ultrastructural features typical of osteoblasts close to microcalcifications. These data were strengthened by the rate of cells expressing molecules typically involved during physiological mineralization (i.e. BMP-2, OPN) that discriminated infiltrating carcinomas with microcalcifications from those without microcalcifications.ConclusionsWe found significant differences in the elemental composition of calcifications between benign and malignant lesions. Observations of cell phenotype led us to hypothesize that under specific stimuli, mammary cells, which despite retaining a minimal epithelial phenotype (confirmed by cytokeratin expression), may acquire some mesenchymal characteristics transforming themselves into cells with an osteoblast-like phenotype, and are able to contribute to the production of breast microcalcifications.

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Section: Discussionmentioning

confidence: 87%

Microcalcifications in breast cancer: an active phenomenon mediated by epithelial cells with mesenchymal characteristics

et al. 2014

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“…In tissue culture, B2M is mitogenic for prostate cancer cells and osteoblasts (27,28). More recently, B2M has been identified as an autocrine factor that stimulates expression of bone-specific proteins in prostate cancer cells (29).…”

Section: Discussionmentioning

confidence: 99%

β-2-Microglobulin Is an Androgen-Regulated Secreted Protein Elevated in Serum of Patients with Advanced Prostate Cancer

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et al. 2007

Clinical Cancer Research

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Purpose: A better understanding of secreted proteins may lead to the discovery of new biomarkers, which, along with prostate-specific antigen (PSA), may be useful in the diagnosis and treatment of prostate cancer patients. Experimental Design: Conditioned medium was collected from LNCaP cells following stimulation with methyltrienolone (R1881), 17h-estradiol (estradiol), or interleukin-6 and analyzed for differential protein expression with surface-enhanced laser desorption/ionization-time of flight mass spectrometry. Quantitative reverse transcription-PCR, immunoblots, and ELISA were used to measure h-2-microglobulin (B2M) message and protein levels in cells, conditioned medium, and serum. Results: Surface-enhanced laser desorption/ionization-time of flight revealed that many peaks were induced or repressed following stimulation with R1881or estradiol. A peak of interest centered at 11.8 kDa was chosen for additional analysis. Immunodepletion identified the peak of interest as B2M. Reverse transcription-PCR and immunoblots confirmed that PSA and B2M were induced by R1881. However, unlike PSA, B2M was not increased on stimulation with estradiol or interleukin-6. Human B2M is identified in the serum of mice bearing human prostate cancer xenograft. B2M is expressed in human prostate cancer cell lines and tissues. Serum B2M levels are elevated in patients with metastatic, androgen-independent prostate cancer. Conclusions: B2M is a secreted protein expressed in prostate cancer, which is more specific for androgen stimulation than PSA under the conditions tested. Additional studies are warranted to explore if B2M is as useful marker for prostate cancer. Identification of proteins secreted from cancer cells in preclinical models may be a useful strategy for biomarker discovery.Most serum biomarkers routinely used in the diagnosis and treatment of cancer are cell surface or secreted proteins expressed by both benign and malignant tissue. As these proteins are generally found at low abundance, highly sensitive tests (such as ELISAs) are required to measure biomarker levels in peripheral blood. However, the limited sensitivity and specificity of these tests often restricts their clinical utility. For example, prostate-specific antigen (PSA) is an androgenregulated secreted protein that is expressed by both normal and malignant prostate epithelial cells, which is widely used as a serum marker for prostate cancer (1). Occult prostate cancers may be found in f25% of patients with PSA levels in the generally accepted reference range (V4 ng/mL; ref. 2). Most, but not all, patients with metastatic prostate cancer show elevated levels of PSA, which is often used as a marker to guide treatment decisions. However, the validity of PSA as a surrogate to predict overall survival in advanced prostate cancer remains controversial (3,4). Therefore, additional biomarkers may be useful in the diagnosis and treatment of patients with prostate cancer.Serum-based protein profiling with mass spectrometry (MS) is a promising technolo...

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“…Hence, h2M may be useful as a prognostic and therapeutic response indicator for cancer patients. h2M is a mitogen and is capable of increasing the growth of human osteoblasts (22), human prostate cancer PC3 cells, and rat stromal cells (23) and to regulate the expression of hormone/growth factor receptors (epidermal growth factor receptor, insulin receptor, and IGF-I and IGF-II receptors) and the interaction with their ligands (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

β2-Microglobulin Is a Signaling and Growth-Promoting Factor for Human Prostate Cancer Bone Metastasis

et al. 2006

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The protein factor B2-microglobulin (B2M), purified from the conditioned medium of human prostate cancer cell lines, stimulated growth and enhanced osteocalcin (OC) and bone sialoprotein (BSP) gene expression in human prostate cancer cells by activating a cyclic AMP (cAMP)-dependent protein kinase A signaling pathway. When B2M was overexpressed in prostate cancer cells, it induced explosive tumor growth in mouse bone through increased phosphorylated cAMPresponsive element binding protein (CREB) and activated CREB target gene expression, including OC, BSP, cyclin A, cyclin D1, and vascular endothelial growth factor. Interrupting the B2M downstream signaling pathway by injection of the B2M small interfering RNA liposome complex produced an effective regression of previously established prostate tumors in mouse bone through increased apoptosis as shown by immunohistochemistry and activation of caspase-9, caspase-3, and cleavage of poly(ADP-ribose) polymerase. These results suggest that B2M signaling is an attractive new therapeutic target for the treatment of lethal prostate cancer bone metastasis. (Cancer Res 2006; 66(18): 9108-16)

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Immunoreactivity and proliferative actions of β2 microglobulin on human bone-derived cells in vitro

Cited by 26 publications

References 35 publications

Microcalcifications in breast cancer: an active phenomenon mediated by epithelial cells with mesenchymal characteristics

Microcalcifications in breast cancer: an active phenomenon mediated by epithelial cells with mesenchymal characteristics

β-2-Microglobulin Is an Androgen-Regulated Secreted Protein Elevated in Serum of Patients with Advanced Prostate Cancer

β2-Microglobulin Is a Signaling and Growth-Promoting Factor for Human Prostate Cancer Bone Metastasis

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