Differential CMS-Related Expression of Cell Surface Carbonic Anhydrases IX and XII in Colorectal Cancer Models—Implications for Therapy
Tumor-associated carbonic anhydrases IX (CAIX) and XII (CAXII) have long been in the spotlight as potential new targets for anti-cancer therapy. Recently, CAIX/CAXII specific inhibitor SLC-0111 has passed clinical phase I study and showed differential response among patients with colorectal cancer (...
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| Format: | Article |
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MDPI AG
2023-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/6/5797 |
| _version_ | 1797611145576579072 |
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| author | Arne Rotermund Sarah Brandt Martin S. Staege Jana Luetzkendorf Lutz P. Mueller Thomas Mueller |
| author_facet | Arne Rotermund Sarah Brandt Martin S. Staege Jana Luetzkendorf Lutz P. Mueller Thomas Mueller |
| author_sort | Arne Rotermund |
| collection | DOAJ |
| description | Tumor-associated carbonic anhydrases IX (CAIX) and XII (CAXII) have long been in the spotlight as potential new targets for anti-cancer therapy. Recently, CAIX/CAXII specific inhibitor SLC-0111 has passed clinical phase I study and showed differential response among patients with colorectal cancer (CRC). CRC can be classified into four different consensus molecular subgroups (CMS) showing unique expression patterns and molecular traits. We questioned whether there is a CMS-related CAIX/CAXII expression pattern in CRC predicting response. As such, we analyzed transcriptomic data of tumor samples for CA9/CA12 expression using Cancertool. Protein expression pattern was examined in preclinical models comprising cell lines, spheroids and xenograft tumors representing the CMS groups. Impact of CAIX/CAXII knockdown and SLC-0111 treatment was investigated in 2D and 3D cell culture. The transcriptomic data revealed a characteristic CMS-related CA9/CA12 expression pattern with pronounced co-expression of both CAs as a typical feature of CMS3 tumors. Protein expression in spheroid- and xenograft tumor tissue clearly differed, ranging from close to none (CMS1) to strong CAIX/CAXII co-expression in CMS3 models (HT29, LS174T). Accordingly, response to SLC-0111 analyzed in the spheroid model ranged from no (CMS1) to clear (CMS3), with moderate in CMS2 and mixed in CMS4. Furthermore, SLC-0111 positively affected impact of single and combined chemotherapeutic treatment of CMS3 spheroids. In addition, combined CAIX/CAXII knockdown and more effective treatment with SLC-0111 reduced clonogenic survival of CMS3 modelling single cells. In conclusion, the preclinical data support the clinical approach of targeted CAIX/CAXII inhibition by showing linkage of expression with response and suggest that patients with CMS3-classified tumors would most benefit from such treatment. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T06:24:40Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0427c2a07e144567bcdf2cbe176990ca2023-11-17T11:39:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-03-01246579710.3390/ijms24065797Differential CMS-Related Expression of Cell Surface Carbonic Anhydrases IX and XII in Colorectal Cancer Models—Implications for TherapyArne Rotermund0Sarah Brandt1Martin S. Staege2Jana Luetzkendorf3Lutz P. Mueller4Thomas Mueller5Department of Internal Medicine IV (Hematology/Oncology), Medical Faculty, Martin Luther University Halle-Wittenberg, 06120 Halle, GermanyDepartment of Internal Medicine IV (Hematology/Oncology), Medical Faculty, Martin Luther University Halle-Wittenberg, 06120 Halle, GermanyDepartment of Surgical and Conservative Pediatrics and Adolescent Medicine, Medical Faculty, Martin Luther University Halle-Wittenberg, 06120 Halle, GermanyDepartment of Internal Medicine IV (Hematology/Oncology), Medical Faculty, Martin Luther University Halle-Wittenberg, 06120 Halle, GermanyDepartment of Internal Medicine IV (Hematology/Oncology), Medical Faculty, Martin Luther University Halle-Wittenberg, 06120 Halle, GermanyDepartment of Internal Medicine IV (Hematology/Oncology), Medical Faculty, Martin Luther University Halle-Wittenberg, 06120 Halle, GermanyTumor-associated carbonic anhydrases IX (CAIX) and XII (CAXII) have long been in the spotlight as potential new targets for anti-cancer therapy. Recently, CAIX/CAXII specific inhibitor SLC-0111 has passed clinical phase I study and showed differential response among patients with colorectal cancer (CRC). CRC can be classified into four different consensus molecular subgroups (CMS) showing unique expression patterns and molecular traits. We questioned whether there is a CMS-related CAIX/CAXII expression pattern in CRC predicting response. As such, we analyzed transcriptomic data of tumor samples for CA9/CA12 expression using Cancertool. Protein expression pattern was examined in preclinical models comprising cell lines, spheroids and xenograft tumors representing the CMS groups. Impact of CAIX/CAXII knockdown and SLC-0111 treatment was investigated in 2D and 3D cell culture. The transcriptomic data revealed a characteristic CMS-related CA9/CA12 expression pattern with pronounced co-expression of both CAs as a typical feature of CMS3 tumors. Protein expression in spheroid- and xenograft tumor tissue clearly differed, ranging from close to none (CMS1) to strong CAIX/CAXII co-expression in CMS3 models (HT29, LS174T). Accordingly, response to SLC-0111 analyzed in the spheroid model ranged from no (CMS1) to clear (CMS3), with moderate in CMS2 and mixed in CMS4. Furthermore, SLC-0111 positively affected impact of single and combined chemotherapeutic treatment of CMS3 spheroids. In addition, combined CAIX/CAXII knockdown and more effective treatment with SLC-0111 reduced clonogenic survival of CMS3 modelling single cells. In conclusion, the preclinical data support the clinical approach of targeted CAIX/CAXII inhibition by showing linkage of expression with response and suggest that patients with CMS3-classified tumors would most benefit from such treatment.https://www.mdpi.com/1422-0067/24/6/5797carbonic anhydrasescolorectal cancerconsensus molecular subtypesCMSSLC-0111targeted inhibition of carbonic anhydrases |
| spellingShingle | Arne Rotermund Sarah Brandt Martin S. Staege Jana Luetzkendorf Lutz P. Mueller Thomas Mueller Differential CMS-Related Expression of Cell Surface Carbonic Anhydrases IX and XII in Colorectal Cancer Models—Implications for Therapy International Journal of Molecular Sciences carbonic anhydrases colorectal cancer consensus molecular subtypes CMS SLC-0111 targeted inhibition of carbonic anhydrases |
| title | Differential CMS-Related Expression of Cell Surface Carbonic Anhydrases IX and XII in Colorectal Cancer Models—Implications for Therapy |
| title_full | Differential CMS-Related Expression of Cell Surface Carbonic Anhydrases IX and XII in Colorectal Cancer Models—Implications for Therapy |
| title_fullStr | Differential CMS-Related Expression of Cell Surface Carbonic Anhydrases IX and XII in Colorectal Cancer Models—Implications for Therapy |
| title_full_unstemmed | Differential CMS-Related Expression of Cell Surface Carbonic Anhydrases IX and XII in Colorectal Cancer Models—Implications for Therapy |
| title_short | Differential CMS-Related Expression of Cell Surface Carbonic Anhydrases IX and XII in Colorectal Cancer Models—Implications for Therapy |
| title_sort | differential cms related expression of cell surface carbonic anhydrases ix and xii in colorectal cancer models implications for therapy |
| topic | carbonic anhydrases colorectal cancer consensus molecular subtypes CMS SLC-0111 targeted inhibition of carbonic anhydrases |
| url | https://www.mdpi.com/1422-0067/24/6/5797 |
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