Prolactin Receptor-Mediated Internalization of Imaging Agents Detects Epithelial Ovarian Cancer with Enhanced Sensitivity and Specificity
Poor prognosis of ovarian cancer, the deadliest of the gynecologic malignancies, reflects major limitations associated with detection and diagnosis. Current methods lack high sensitivity to detect small tumors and high specificity to distinguish malignant from benign tissue, both impeding diagnosis...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2017-04, Vol.77 (7), p.1684-1696 |
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| creator | Sundaram, Karthik M Zhang, Yilin Mitra, Anirban K Kouadio, Jean-Louis K Gwin, Katja Kossiakoff, Anthony A Roman, Brian B Lengyel, Ernst Piccirilli, Joseph A |
| description | Poor prognosis of ovarian cancer, the deadliest of the gynecologic malignancies, reflects major limitations associated with detection and diagnosis. Current methods lack high sensitivity to detect small tumors and high specificity to distinguish malignant from benign tissue, both impeding diagnosis of early and metastatic cancer stages and leading to costly and invasive surgeries. Tissue microarray analysis revealed that >98% of ovarian cancers express the prolactin receptor (PRLR), forming the basis of a new molecular imaging strategy. We fused human placental lactogen (hPL), a specific and tight binding PRLR ligand, to magnetic resonance imaging (gadolinium) and near-infrared fluorescence imaging agents. Both in tissue culture and in mouse models, these imaging bioconjugates underwent selective internalization into ovarian cancer cells via PRLR-mediated endocytosis. Compared with current clinical MRI techniques, this targeted approach yielded both enhanced signal-to-noise ratio from accumulation of signal via selective internalization and improved specificity conferred by PRLR upregulation in malignant ovarian cancer. These features endow PRLR-targeted imaging with the potential to transform ovarian cancer detection.
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| doi_str_mv | 10.1158/0008-5472.CAN-16-1454 |
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.</description><subject>Animal models</subject><subject>Animals</subject><subject>Carcinoma, Ovarian Epithelial</subject><subject>Cell culture</subject><subject>Cell Line, Tumor</subject><subject>Diagnosis</subject><subject>Endocytosis</subject><subject>Female</subject><subject>Fluorescence</subject><subject>Gadolinium</subject><subject>Gadolinium DTPA</subject><subject>Humans</subject><subject>I.R. radiation</subject><subject>Infrared imaging</subject><subject>Internalization</subject><subject>Invasiveness</subject><subject>Magnetic resonance imaging</subject><subject>Magnetic Resonance Imaging - methods</subject><subject>Metastases</subject><subject>Mice</subject><subject>Neoplasms, Glandular and Epithelial - diagnostic imaging</subject><subject>Neoplasms, Glandular and Epithelial - metabolism</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Ovarian cancer</subject><subject>Ovarian Neoplasms - diagnostic imaging</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>Placenta</subject><subject>Placental Lactogen - metabolism</subject><subject>Prolactin</subject><subject>Prolactin - metabolism</subject><subject>Receptors, Prolactin - analysis</subject><subject>Receptors, Prolactin - physiology</subject><subject>Rodents</subject><subject>Sensitivity</subject><subject>Sensitivity and Specificity</subject><subject>Tissue analysis</subject><subject>Tissue Array Analysis</subject><subject>Tissue culture</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkd1uEzEQhS0EoqHwCCBL3HCzxT_rtfcGKQoBIhWK-Lm2vN7ZxNXG3tpOUHkD3hqvWiLganw03xx55iD0nJILSoV6TQhRlaglu1gtP1W0qWgt6gdoQQVXlaxr8RAtTswZepLSdZGCEvEYnTHFCBNULdCvzzGMxmbn8RewMOUQq4_QO5OhxxufIXozup8mu-BxGPBmb7bOb_FyCz4n_BYy2FLXk8s7GJ0Z8dXRRGc8XhlvIeIfpYHXfjerHn8Fn1x2R5dvsfFFT2Dd4GzRT9GjwYwJnt3Xc_T93frb6kN1efV-s1peVrbmba5kw_tGWsEG23ImVNvxbuBEshp6WR6cSytBcTCyJ20_sK5ryiQd5NCrFiQ_R2_ufKdDt4felj2iGfUU3d7EWx2M0_92vNvpbTjqclgiGloMXt0bxHBzgJT13iUL42g8hEPSVDUtpa1oeEFf_odeh8N80UK1irNaFsdCiTvKxpBShOH0GUr0HLaeg9RzkLqErWmj57DL3Iu_NzlN_UmX_waBU6iM</recordid><startdate>20170401</startdate><enddate>20170401</enddate><creator>Sundaram, Karthik M</creator><creator>Zhang, Yilin</creator><creator>Mitra, Anirban K</creator><creator>Kouadio, Jean-Louis K</creator><creator>Gwin, Katja</creator><creator>Kossiakoff, Anthony A</creator><creator>Roman, Brian B</creator><creator>Lengyel, Ernst</creator><creator>Piccirilli, Joseph A</creator><general>American Association for Cancer Research, Inc</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>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170401</creationdate><title>Prolactin Receptor-Mediated Internalization of Imaging Agents Detects Epithelial Ovarian Cancer with Enhanced Sensitivity and Specificity</title><author>Sundaram, Karthik M ; Zhang, Yilin ; Mitra, Anirban K ; Kouadio, Jean-Louis K ; Gwin, Katja ; Kossiakoff, Anthony A ; Roman, Brian B ; Lengyel, Ernst ; Piccirilli, Joseph A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c439t-763d67c52fc932589b3bf30724ed7f30337c7e83ea7d09df2bb6c431f7fd89e73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Carcinoma, Ovarian Epithelial</topic><topic>Cell culture</topic><topic>Cell Line, Tumor</topic><topic>Diagnosis</topic><topic>Endocytosis</topic><topic>Female</topic><topic>Fluorescence</topic><topic>Gadolinium</topic><topic>Gadolinium DTPA</topic><topic>Humans</topic><topic>I.R. radiation</topic><topic>Infrared imaging</topic><topic>Internalization</topic><topic>Invasiveness</topic><topic>Magnetic resonance imaging</topic><topic>Magnetic Resonance Imaging - methods</topic><topic>Metastases</topic><topic>Mice</topic><topic>Neoplasms, Glandular and Epithelial - diagnostic imaging</topic><topic>Neoplasms, Glandular and Epithelial - metabolism</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Ovarian cancer</topic><topic>Ovarian Neoplasms - diagnostic imaging</topic><topic>Ovarian Neoplasms - metabolism</topic><topic>Placenta</topic><topic>Placental Lactogen - metabolism</topic><topic>Prolactin</topic><topic>Prolactin - metabolism</topic><topic>Receptors, Prolactin - analysis</topic><topic>Receptors, Prolactin - physiology</topic><topic>Rodents</topic><topic>Sensitivity</topic><topic>Sensitivity and Specificity</topic><topic>Tissue analysis</topic><topic>Tissue Array Analysis</topic><topic>Tissue culture</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sundaram, Karthik M</creatorcontrib><creatorcontrib>Zhang, Yilin</creatorcontrib><creatorcontrib>Mitra, Anirban K</creatorcontrib><creatorcontrib>Kouadio, Jean-Louis K</creatorcontrib><creatorcontrib>Gwin, Katja</creatorcontrib><creatorcontrib>Kossiakoff, Anthony A</creatorcontrib><creatorcontrib>Roman, Brian B</creatorcontrib><creatorcontrib>Lengyel, Ernst</creatorcontrib><creatorcontrib>Piccirilli, Joseph A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sundaram, Karthik M</au><au>Zhang, Yilin</au><au>Mitra, Anirban K</au><au>Kouadio, Jean-Louis K</au><au>Gwin, Katja</au><au>Kossiakoff, Anthony A</au><au>Roman, Brian B</au><au>Lengyel, Ernst</au><au>Piccirilli, Joseph A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prolactin Receptor-Mediated Internalization of Imaging Agents Detects Epithelial Ovarian Cancer with Enhanced Sensitivity and Specificity</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2017-04-01</date><risdate>2017</risdate><volume>77</volume><issue>7</issue><spage>1684</spage><epage>1696</epage><pages>1684-1696</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><abstract>Poor prognosis of ovarian cancer, the deadliest of the gynecologic malignancies, reflects major limitations associated with detection and diagnosis. Current methods lack high sensitivity to detect small tumors and high specificity to distinguish malignant from benign tissue, both impeding diagnosis of early and metastatic cancer stages and leading to costly and invasive surgeries. Tissue microarray analysis revealed that >98% of ovarian cancers express the prolactin receptor (PRLR), forming the basis of a new molecular imaging strategy. We fused human placental lactogen (hPL), a specific and tight binding PRLR ligand, to magnetic resonance imaging (gadolinium) and near-infrared fluorescence imaging agents. Both in tissue culture and in mouse models, these imaging bioconjugates underwent selective internalization into ovarian cancer cells via PRLR-mediated endocytosis. Compared with current clinical MRI techniques, this targeted approach yielded both enhanced signal-to-noise ratio from accumulation of signal via selective internalization and improved specificity conferred by PRLR upregulation in malignant ovarian cancer. These features endow PRLR-targeted imaging with the potential to transform ovarian cancer detection.
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| subjects | Animal models Animals Carcinoma, Ovarian Epithelial Cell culture Cell Line, Tumor Diagnosis Endocytosis Female Fluorescence Gadolinium Gadolinium DTPA Humans I.R. radiation Infrared imaging Internalization Invasiveness Magnetic resonance imaging Magnetic Resonance Imaging - methods Metastases Mice Neoplasms, Glandular and Epithelial - diagnostic imaging Neoplasms, Glandular and Epithelial - metabolism NMR Nuclear magnetic resonance Ovarian cancer Ovarian Neoplasms - diagnostic imaging Ovarian Neoplasms - metabolism Placenta Placental Lactogen - metabolism Prolactin Prolactin - metabolism Receptors, Prolactin - analysis Receptors, Prolactin - physiology Rodents Sensitivity Sensitivity and Specificity Tissue analysis Tissue Array Analysis Tissue culture Tumors |
| title | Prolactin Receptor-Mediated Internalization of Imaging Agents Detects Epithelial Ovarian Cancer with Enhanced Sensitivity and Specificity |
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