Claudin-4 SPECT imaging allows detection of aplastic lesions in a mouse model of breast cancer
The expression of claudin-4, a protein involved in tight junction complexes, is widely dysregulated in epithelial malignancies. Claudin-4 is overexpressed in several premalignant precursor lesions, including those of cancers of the breast, pancreas, and prostate, and is associated with poor survival...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Society of Nuclear Medicine
2015
|
| _version_ | 1797075565930348544 |
|---|---|
| author | Mosley, M Knight, J Neesse, A Michl, P Iezzi, M Kersemans, V Cornelissen, B |
| author_facet | Mosley, M Knight, J Neesse, A Michl, P Iezzi, M Kersemans, V Cornelissen, B |
| author_sort | Mosley, M |
| collection | OXFORD |
| description | The expression of claudin-4, a protein involved in tight junction complexes, is widely dysregulated in epithelial malignancies. Claudin-4 is overexpressed in several premalignant precursor lesions, including those of cancers of the breast, pancreas, and prostate, and is associated with poor survival. A noncytotoxic C-terminal fragment of Clostridium perfringens enterotoxin (cCPE) is a natural ligand for claudin-4. Here, we demonstrate whole-body quantitative SPECT imaging of preneoplastic breast cancer tissue using (111)In-labeled cCPE.cCPE.GST or GST (GST is glutathione S-transferase) was conjugated to the metal ion chelator benzyl-diethylenetriaminepentaacetic acid to allow (111)In radiolabeling. The affinity of radiolabeled cCPE.GST for claudin-4 was confirmed using claudin-4-expressing MDA-MB-468 and SQ20b cells, compared with claudin-4-negative HT1080 cells. In vivo SPECT imaging was performed using athymic mice bearing MDA-MB-468 or HT1080 xenografts and using genetically modified BALB/neuT mice, which spontaneously develop claudin-4-expressing breast cancer lesions.The uptake of (111)In-cCPE.GST in claudin-4-positive MDA-MB-468 xenograft tumors in athymic mice was significantly higher than in (111)In-GST or claudin-4-negative HT1080 tumors (6.72 ± 0.18 vs. 3.88 ± 1.00 vs. 2.36 ± 1.25 percentage injected dose per gram [%ID/g]; P < 0.0001). No other significant differences were observed in any of the examined organs. BALB/neuT mice, expressing rat neuT under mmtv promotor control, spontaneously developed tumorous lesions within their mammary fat pads over the course of 130 d. Overt mammary tumors were claudin-4-positive, and (111)In-cCPE.GST uptake was 3.2 ± 0.70 %ID/g, significantly higher than (111)In-GST (1.00 ± 0.60 %ID/g; P < 0.05). Mammary fat pads in mice aged 80 d bore claudin-4-positive aplastic lesions and accumulated (111)In-cCPE.GST (3.17 ± 0.51 %ID/g) but not (111)In-GST (0.99 ± 0.39 %ID/g; P < 0.001).Taken together, (111)In-cCPE.GST targets claudin-4 expression in frank tumors and preneoplastic tissue, and cCPE imaging may be used as an early detection tool for breast, prostate, and pancreatic cancer. |
| first_indexed | 2024-03-06T23:52:07Z |
| format | Journal article |
| id | oxford-uuid:72f4d701-0dc3-4623-be59-91532e6b8179 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:52:07Z |
| publishDate | 2015 |
| publisher | Society of Nuclear Medicine |
| record_format | dspace |
| spelling | oxford-uuid:72f4d701-0dc3-4623-be59-91532e6b81792022-03-26T19:53:27ZClaudin-4 SPECT imaging allows detection of aplastic lesions in a mouse model of breast cancerJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:72f4d701-0dc3-4623-be59-91532e6b8179EnglishSymplectic Elements at OxfordSociety of Nuclear Medicine2015Mosley, MKnight, JNeesse, AMichl, PIezzi, MKersemans, VCornelissen, BThe expression of claudin-4, a protein involved in tight junction complexes, is widely dysregulated in epithelial malignancies. Claudin-4 is overexpressed in several premalignant precursor lesions, including those of cancers of the breast, pancreas, and prostate, and is associated with poor survival. A noncytotoxic C-terminal fragment of Clostridium perfringens enterotoxin (cCPE) is a natural ligand for claudin-4. Here, we demonstrate whole-body quantitative SPECT imaging of preneoplastic breast cancer tissue using (111)In-labeled cCPE.cCPE.GST or GST (GST is glutathione S-transferase) was conjugated to the metal ion chelator benzyl-diethylenetriaminepentaacetic acid to allow (111)In radiolabeling. The affinity of radiolabeled cCPE.GST for claudin-4 was confirmed using claudin-4-expressing MDA-MB-468 and SQ20b cells, compared with claudin-4-negative HT1080 cells. In vivo SPECT imaging was performed using athymic mice bearing MDA-MB-468 or HT1080 xenografts and using genetically modified BALB/neuT mice, which spontaneously develop claudin-4-expressing breast cancer lesions.The uptake of (111)In-cCPE.GST in claudin-4-positive MDA-MB-468 xenograft tumors in athymic mice was significantly higher than in (111)In-GST or claudin-4-negative HT1080 tumors (6.72 ± 0.18 vs. 3.88 ± 1.00 vs. 2.36 ± 1.25 percentage injected dose per gram [%ID/g]; P < 0.0001). No other significant differences were observed in any of the examined organs. BALB/neuT mice, expressing rat neuT under mmtv promotor control, spontaneously developed tumorous lesions within their mammary fat pads over the course of 130 d. Overt mammary tumors were claudin-4-positive, and (111)In-cCPE.GST uptake was 3.2 ± 0.70 %ID/g, significantly higher than (111)In-GST (1.00 ± 0.60 %ID/g; P < 0.05). Mammary fat pads in mice aged 80 d bore claudin-4-positive aplastic lesions and accumulated (111)In-cCPE.GST (3.17 ± 0.51 %ID/g) but not (111)In-GST (0.99 ± 0.39 %ID/g; P < 0.001).Taken together, (111)In-cCPE.GST targets claudin-4 expression in frank tumors and preneoplastic tissue, and cCPE imaging may be used as an early detection tool for breast, prostate, and pancreatic cancer. |
| spellingShingle | Mosley, M Knight, J Neesse, A Michl, P Iezzi, M Kersemans, V Cornelissen, B Claudin-4 SPECT imaging allows detection of aplastic lesions in a mouse model of breast cancer |
| title | Claudin-4 SPECT imaging allows detection of aplastic lesions in a mouse model of breast cancer |
| title_full | Claudin-4 SPECT imaging allows detection of aplastic lesions in a mouse model of breast cancer |
| title_fullStr | Claudin-4 SPECT imaging allows detection of aplastic lesions in a mouse model of breast cancer |
| title_full_unstemmed | Claudin-4 SPECT imaging allows detection of aplastic lesions in a mouse model of breast cancer |
| title_short | Claudin-4 SPECT imaging allows detection of aplastic lesions in a mouse model of breast cancer |
| title_sort | claudin 4 spect imaging allows detection of aplastic lesions in a mouse model of breast cancer |
| work_keys_str_mv | AT mosleym claudin4spectimagingallowsdetectionofaplasticlesionsinamousemodelofbreastcancer AT knightj claudin4spectimagingallowsdetectionofaplasticlesionsinamousemodelofbreastcancer AT neessea claudin4spectimagingallowsdetectionofaplasticlesionsinamousemodelofbreastcancer AT michlp claudin4spectimagingallowsdetectionofaplasticlesionsinamousemodelofbreastcancer AT iezzim claudin4spectimagingallowsdetectionofaplasticlesionsinamousemodelofbreastcancer AT kersemansv claudin4spectimagingallowsdetectionofaplasticlesionsinamousemodelofbreastcancer AT cornelissenb claudin4spectimagingallowsdetectionofaplasticlesionsinamousemodelofbreastcancer |