C-src enriched serum microvesicles are generated in malignant plasma cell dyscrasia
Plasma cell dyscrasias are immunosecretory disorders that can lead to hematological malignancies such as Multiple Myeloma (MM). MM accounts for 15% of all hematologic cancers, and those diagnosed with MM typically become severely ill and have a low life expectancy. Monoclonal immunoglobulin Free Lig...
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| Veröffentlicht in: | PloS one 2013-08, Vol.8 (8), p.e70811-e70811 |
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| creator | Di Noto, Giuseppe Paolini, Lucia Zendrini, Andrea Radeghieri, Annalisa Caimi, Luigi Ricotta, Doris |
| description | Plasma cell dyscrasias are immunosecretory disorders that can lead to hematological malignancies such as Multiple Myeloma (MM). MM accounts for 15% of all hematologic cancers, and those diagnosed with MM typically become severely ill and have a low life expectancy. Monoclonal immunoglobulin Free Light Chains (FLC) are present in the serum and urine of many patients with plasma cell diseases. The biological differences between monoclonal FLCs, produced under malignant or benign dyscrasias, has not yet been characterized. In the present study, we show that endothelial and heart muscle cell lines internalize kappa and lambda FLCs. After internalization, FLCs are rerouted in the extracellular space via microvesicles and exosomes that can be re-internalized in contiguous cells. Only FLCs secreted from malignant B Lymphocytes were carried in Hsp70, annexin V, and c-src positive vesicles. In both MM and AL Amyloidosis patients we observed an increase in microvesicle and exosome production. Isolated serum vesicles from MM, AL Amyloidosis and monoclonal gammopathy of undetermined significance (MGUS) patients contained FLCs. Furthermore MM and AL amyloidosis vesicles were strongly positive for Hsp70, annexin V, and c-src compared to MGUS and control patients. These are the first data implying that FLCs reroute via microvesicles in the blood stream, and also suggest a potential novel mechanism of c-src activation in plasma cell dyscrasia. |
| doi_str_mv | 10.1371/journal.pone.0070811 |
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MM accounts for 15% of all hematologic cancers, and those diagnosed with MM typically become severely ill and have a low life expectancy. Monoclonal immunoglobulin Free Light Chains (FLC) are present in the serum and urine of many patients with plasma cell diseases. The biological differences between monoclonal FLCs, produced under malignant or benign dyscrasias, has not yet been characterized. In the present study, we show that endothelial and heart muscle cell lines internalize kappa and lambda FLCs. After internalization, FLCs are rerouted in the extracellular space via microvesicles and exosomes that can be re-internalized in contiguous cells. Only FLCs secreted from malignant B Lymphocytes were carried in Hsp70, annexin V, and c-src positive vesicles. In both MM and AL Amyloidosis patients we observed an increase in microvesicle and exosome production. Isolated serum vesicles from MM, AL Amyloidosis and monoclonal gammopathy of undetermined significance (MGUS) patients contained FLCs. Furthermore MM and AL amyloidosis vesicles were strongly positive for Hsp70, annexin V, and c-src compared to MGUS and control patients. These are the first data implying that FLCs reroute via microvesicles in the blood stream, and also suggest a potential novel mechanism of c-src activation in plasma cell dyscrasia.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0070811</identifier><identifier>PMID: 23940647</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amyloidosis ; Angiogenesis ; Annexin A5 - metabolism ; Annexin V ; B cells ; Benign monoclonal gammopathy ; Binding sites ; Biology ; Cardiac muscle ; Cell activation ; Cell culture ; Disease ; Endothelial Cells - metabolism ; Endothelium, Vascular - pathology ; Enzyme Activation ; Exosomes ; Health aspects ; Heart ; Heat shock proteins ; HeLa Cells ; Hematology ; HSP70 Heat-Shock Proteins - metabolism ; Hsp70 protein ; Humans ; Immunoglobulin Light Chains - metabolism ; Immunoglobulins ; Internalization ; Life expectancy ; Life span ; Light ; Light chains ; Lymphocytes ; Lymphocytes B ; Medicine ; Multiple myeloma ; Muscles ; Paraproteinemia ; Paraproteinemias - blood ; Paraproteinemias - enzymology ; Patients ; Protein Transport ; Rodents ; Secretory Vesicles - enzymology ; Src protein ; src-Family Kinases - metabolism ; Urine ; Vesicles</subject><ispartof>PloS one, 2013-08, Vol.8 (8), p.e70811-e70811</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Di Noto et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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MM accounts for 15% of all hematologic cancers, and those diagnosed with MM typically become severely ill and have a low life expectancy. Monoclonal immunoglobulin Free Light Chains (FLC) are present in the serum and urine of many patients with plasma cell diseases. The biological differences between monoclonal FLCs, produced under malignant or benign dyscrasias, has not yet been characterized. In the present study, we show that endothelial and heart muscle cell lines internalize kappa and lambda FLCs. After internalization, FLCs are rerouted in the extracellular space via microvesicles and exosomes that can be re-internalized in contiguous cells. Only FLCs secreted from malignant B Lymphocytes were carried in Hsp70, annexin V, and c-src positive vesicles. In both MM and AL Amyloidosis patients we observed an increase in microvesicle and exosome production. Isolated serum vesicles from MM, AL Amyloidosis and monoclonal gammopathy of undetermined significance (MGUS) patients contained FLCs. Furthermore MM and AL amyloidosis vesicles were strongly positive for Hsp70, annexin V, and c-src compared to MGUS and control patients. These are the first data implying that FLCs reroute via microvesicles in the blood stream, and also suggest a potential novel mechanism of c-src activation in plasma cell dyscrasia.</description><subject>Amyloidosis</subject><subject>Angiogenesis</subject><subject>Annexin A5 - metabolism</subject><subject>Annexin V</subject><subject>B cells</subject><subject>Benign monoclonal gammopathy</subject><subject>Binding sites</subject><subject>Biology</subject><subject>Cardiac muscle</subject><subject>Cell activation</subject><subject>Cell culture</subject><subject>Disease</subject><subject>Endothelial Cells - metabolism</subject><subject>Endothelium, Vascular - pathology</subject><subject>Enzyme Activation</subject><subject>Exosomes</subject><subject>Health aspects</subject><subject>Heart</subject><subject>Heat shock proteins</subject><subject>HeLa Cells</subject><subject>Hematology</subject><subject>HSP70 Heat-Shock Proteins - metabolism</subject><subject>Hsp70 protein</subject><subject>Humans</subject><subject>Immunoglobulin Light Chains - metabolism</subject><subject>Immunoglobulins</subject><subject>Internalization</subject><subject>Life expectancy</subject><subject>Life span</subject><subject>Light</subject><subject>Light chains</subject><subject>Lymphocytes</subject><subject>Lymphocytes B</subject><subject>Medicine</subject><subject>Multiple myeloma</subject><subject>Muscles</subject><subject>Paraproteinemia</subject><subject>Paraproteinemias - blood</subject><subject>Paraproteinemias - enzymology</subject><subject>Patients</subject><subject>Protein Transport</subject><subject>Rodents</subject><subject>Secretory Vesicles - enzymology</subject><subject>Src protein</subject><subject>src-Family Kinases - metabolism</subject><subject>Urine</subject><subject>Vesicles</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl2L1DAUhoso7rr6D0QLgujFjPmapLkRlsGPgYUFV70NZ9LTTpa2GZN2cf-9qdNdprIX0ouU5DnvyXnzZtlLSpaUK_rh2g-hg2a59x0uCVGkoPRRdko1ZwvJCH989H-SPYvxmpAVL6R8mp0wrgWRQp1mV-tFDDbHLji7wzKPGIY2b50N_gajsw3GHALmNXYYoE-E6_IWGld30PX5voHYQm6xafLyNtoA0cHz7EkFTcQX03qW_fj86fv66-Li8stmfX6xsFKzfqH1VlCpK12uQBYlpUwXld0SRoAIaytegGCSCqqrbaFQSwXAVaXRgtoyWfKz7PVBd9_4aCY_oqGCEyYUZzQRmwNRerg2--BaCLfGgzN_N3yoDYR-nNIwgppwXXAmhJCpY0UZVcjFqkLCmExaH6duw7bF0mLXB2hmovOTzu1M7W8MV5wnr5PAu0kg-F8Dxt60Lo7OQYd-GO_NiKSKrFhC3_yDPjzdRNWQBnBd5VNfO4qac6GKZFxiE7V8gEpfiemZU3gql_ZnBe9nBYnp8XdfwxCj2Vx9-3_28uecfXvE7hCafhd9M_TOd3EOigOYQhhjwOreZErMmP07N8yYfTNlP5W9On6g-6K7sPM_Nor9HA</recordid><startdate>20130805</startdate><enddate>20130805</enddate><creator>Di Noto, Giuseppe</creator><creator>Paolini, Lucia</creator><creator>Zendrini, Andrea</creator><creator>Radeghieri, Annalisa</creator><creator>Caimi, Luigi</creator><creator>Ricotta, Doris</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130805</creationdate><title>C-src enriched serum microvesicles are generated in malignant plasma cell dyscrasia</title><author>Di Noto, Giuseppe ; Paolini, Lucia ; Zendrini, Andrea ; Radeghieri, Annalisa ; Caimi, Luigi ; Ricotta, Doris</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-99b4169f9d5a68d11298fcb020a04ccf38a4261419fb87e967aa37f9eca7b26d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Amyloidosis</topic><topic>Angiogenesis</topic><topic>Annexin A5 - 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MM accounts for 15% of all hematologic cancers, and those diagnosed with MM typically become severely ill and have a low life expectancy. Monoclonal immunoglobulin Free Light Chains (FLC) are present in the serum and urine of many patients with plasma cell diseases. The biological differences between monoclonal FLCs, produced under malignant or benign dyscrasias, has not yet been characterized. In the present study, we show that endothelial and heart muscle cell lines internalize kappa and lambda FLCs. After internalization, FLCs are rerouted in the extracellular space via microvesicles and exosomes that can be re-internalized in contiguous cells. Only FLCs secreted from malignant B Lymphocytes were carried in Hsp70, annexin V, and c-src positive vesicles. In both MM and AL Amyloidosis patients we observed an increase in microvesicle and exosome production. Isolated serum vesicles from MM, AL Amyloidosis and monoclonal gammopathy of undetermined significance (MGUS) patients contained FLCs. Furthermore MM and AL amyloidosis vesicles were strongly positive for Hsp70, annexin V, and c-src compared to MGUS and control patients. These are the first data implying that FLCs reroute via microvesicles in the blood stream, and also suggest a potential novel mechanism of c-src activation in plasma cell dyscrasia.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23940647</pmid><doi>10.1371/journal.pone.0070811</doi><tpages>e70811</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amyloidosis Angiogenesis Annexin A5 - metabolism Annexin V B cells Benign monoclonal gammopathy Binding sites Biology Cardiac muscle Cell activation Cell culture Disease Endothelial Cells - metabolism Endothelium, Vascular - pathology Enzyme Activation Exosomes Health aspects Heart Heat shock proteins HeLa Cells Hematology HSP70 Heat-Shock Proteins - metabolism Hsp70 protein Humans Immunoglobulin Light Chains - metabolism Immunoglobulins Internalization Life expectancy Life span Light Light chains Lymphocytes Lymphocytes B Medicine Multiple myeloma Muscles Paraproteinemia Paraproteinemias - blood Paraproteinemias - enzymology Patients Protein Transport Rodents Secretory Vesicles - enzymology Src protein src-Family Kinases - metabolism Urine Vesicles |
| title | C-src enriched serum microvesicles are generated in malignant plasma cell dyscrasia |
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