Timp2 loss-of-function mutation and TIMP2 treatment in a murine model of NSCLC: Modulation of immunosuppression and oncogenic signaling
Mounting evidence suggests that the tissue inhibitor of metalloproteinases-2 (TIMP2) can reduce tumor burden and metastasis. However, the demonstration of such anti-tumor activity and associated mechanisms using in vivo tumor models is lacking. The effects of a Timp2 functional mutation and administ...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-03-01
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| Series: | Translational Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523325000403 |
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| author | David Peeney Sarvesh Kumar Tej Pratap Singh Yueqin Liu Sandra M. Jensen Ananda Chowdhury Sasha Coates-Park Joshua Rich Sadeechya Gurung Yu Fan Daoud Meerzaman William G. Stetler-Stevenson |
| author_facet | David Peeney Sarvesh Kumar Tej Pratap Singh Yueqin Liu Sandra M. Jensen Ananda Chowdhury Sasha Coates-Park Joshua Rich Sadeechya Gurung Yu Fan Daoud Meerzaman William G. Stetler-Stevenson |
| author_sort | David Peeney |
| collection | DOAJ |
| description | Mounting evidence suggests that the tissue inhibitor of metalloproteinases-2 (TIMP2) can reduce tumor burden and metastasis. However, the demonstration of such anti-tumor activity and associated mechanisms using in vivo tumor models is lacking. The effects of a Timp2 functional mutation and administration of recombinant TIMP2 were examined in both orthotopic and heterotopic murine models of lung cancer using C57Bl/6 syngeneic Lewis Lung 2-luciferase 2 cells (LL2-Luc2) cells. Mice harboring a functional mutation of TIMP2 (mT2) display markedly increased primary lung tumor growth, increased mortality, enriched vasculature, and enhanced infiltration of pro-tumorigenic, immunosuppressive myeloid cells. Treatment with recombinant TIMP2 reduced primary tumor growth in both mutant and wild-type (wt) mice. Comparison of transcriptional profiles of lung tissues from tumor-free, wt versus mT2 mice reveals only minor changes. However, lung tumor-bearing mice of both genotypes demonstrate significant genotype-dependent changes in gene expression following treatment with TIMP. In tumor-bearing wt mice, TIMP2 treatment reduced the expression of upstream oncogenic mediators, whereas treatment of mT2 mice resulted in an immunomodulatory phenotype. A heterotopic subcutaneous model generating metastatic pulmonary tumors demonstrated that daily administration of recombinant TIMP2 significantly reduces the expression of heat shock proteins, suggesting a reduction of cell-stress responses. In summary, we describe how TIMP2 exerts novel, anti-tumor effects in a murine model of lung cancer and that rTIMP2 treatment supports a normalizing effect on the tumor microenvironment. Our findings show that TIMP2 treatment demonstrates significant potential as an adjuvant in the treatment of NSCLC. |
| format | Article |
| id | doaj-art-459dae0592c5485d916d86497152124e |
| institution | Kabale University |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-459dae0592c5485d916d86497152124e2025-02-04T04:10:22ZengElsevierTranslational Oncology1936-52332025-03-0153102309Timp2 loss-of-function mutation and TIMP2 treatment in a murine model of NSCLC: Modulation of immunosuppression and oncogenic signalingDavid Peeney0Sarvesh Kumar1Tej Pratap Singh2Yueqin Liu3Sandra M. Jensen4Ananda Chowdhury5Sasha Coates-Park6Joshua Rich7Sadeechya Gurung8Yu Fan9Daoud Meerzaman10William G. Stetler-Stevenson11Extracellular Matrix Pathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, MD 20892, USA; Corresponding authors at: Extracellular Matrix Pathology Section, Laboratory of Pathology, National Cancer Institute, NIH, Building 10-CRC/6B05, 10 Center Drive, Bethesda, MD-20892. USA.Extracellular Matrix Pathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, MD 20892, USALaboratory of Molecular Immunology, National Institute for Allergy, and Infectious Disease (NIAID), Bethesda, MD 20892, USAExtracellular Matrix Pathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, MD 20892, USAExtracellular Matrix Pathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, MD 20892, USAExtracellular Matrix Pathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, MD 20892, USAExtracellular Matrix Pathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, MD 20892, USAExtracellular Matrix Pathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, MD 20892, USAExtracellular Matrix Pathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, MD 20892, USAComputational Genomics and Bioinformatics Group, Center for Biomedical Informatics & Information Technology, National Cancer Institute, Rockville, MD 20850, USAComputational Genomics and Bioinformatics Group, Center for Biomedical Informatics & Information Technology, National Cancer Institute, Rockville, MD 20850, USAExtracellular Matrix Pathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, MD 20892, USA; Corresponding authors at: Extracellular Matrix Pathology Section, Laboratory of Pathology, National Cancer Institute, NIH, Building 10-CRC/6B05, 10 Center Drive, Bethesda, MD-20892. USA.Mounting evidence suggests that the tissue inhibitor of metalloproteinases-2 (TIMP2) can reduce tumor burden and metastasis. However, the demonstration of such anti-tumor activity and associated mechanisms using in vivo tumor models is lacking. The effects of a Timp2 functional mutation and administration of recombinant TIMP2 were examined in both orthotopic and heterotopic murine models of lung cancer using C57Bl/6 syngeneic Lewis Lung 2-luciferase 2 cells (LL2-Luc2) cells. Mice harboring a functional mutation of TIMP2 (mT2) display markedly increased primary lung tumor growth, increased mortality, enriched vasculature, and enhanced infiltration of pro-tumorigenic, immunosuppressive myeloid cells. Treatment with recombinant TIMP2 reduced primary tumor growth in both mutant and wild-type (wt) mice. Comparison of transcriptional profiles of lung tissues from tumor-free, wt versus mT2 mice reveals only minor changes. However, lung tumor-bearing mice of both genotypes demonstrate significant genotype-dependent changes in gene expression following treatment with TIMP. In tumor-bearing wt mice, TIMP2 treatment reduced the expression of upstream oncogenic mediators, whereas treatment of mT2 mice resulted in an immunomodulatory phenotype. A heterotopic subcutaneous model generating metastatic pulmonary tumors demonstrated that daily administration of recombinant TIMP2 significantly reduces the expression of heat shock proteins, suggesting a reduction of cell-stress responses. In summary, we describe how TIMP2 exerts novel, anti-tumor effects in a murine model of lung cancer and that rTIMP2 treatment supports a normalizing effect on the tumor microenvironment. Our findings show that TIMP2 treatment demonstrates significant potential as an adjuvant in the treatment of NSCLC.http://www.sciencedirect.com/science/article/pii/S1936523325000403TIMP2Lewis lung carcinomaLung cancerTherapy |
| spellingShingle | David Peeney Sarvesh Kumar Tej Pratap Singh Yueqin Liu Sandra M. Jensen Ananda Chowdhury Sasha Coates-Park Joshua Rich Sadeechya Gurung Yu Fan Daoud Meerzaman William G. Stetler-Stevenson Timp2 loss-of-function mutation and TIMP2 treatment in a murine model of NSCLC: Modulation of immunosuppression and oncogenic signaling Translational Oncology TIMP2 Lewis lung carcinoma Lung cancer Therapy |
| title | Timp2 loss-of-function mutation and TIMP2 treatment in a murine model of NSCLC: Modulation of immunosuppression and oncogenic signaling |
| title_full | Timp2 loss-of-function mutation and TIMP2 treatment in a murine model of NSCLC: Modulation of immunosuppression and oncogenic signaling |
| title_fullStr | Timp2 loss-of-function mutation and TIMP2 treatment in a murine model of NSCLC: Modulation of immunosuppression and oncogenic signaling |
| title_full_unstemmed | Timp2 loss-of-function mutation and TIMP2 treatment in a murine model of NSCLC: Modulation of immunosuppression and oncogenic signaling |
| title_short | Timp2 loss-of-function mutation and TIMP2 treatment in a murine model of NSCLC: Modulation of immunosuppression and oncogenic signaling |
| title_sort | timp2 loss of function mutation and timp2 treatment in a murine model of nsclc modulation of immunosuppression and oncogenic signaling |
| topic | TIMP2 Lewis lung carcinoma Lung cancer Therapy |
| url | http://www.sciencedirect.com/science/article/pii/S1936523325000403 |
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