Academic Journal
Timp2 loss-of-function mutation and TIMP2 treatment in a murine model of NSCLC: Modulation of immunosuppression and oncogenic signaling
| Title: | Timp2 loss-of-function mutation and TIMP2 treatment in a murine model of NSCLC: Modulation of immunosuppression and oncogenic signaling |
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| Authors: | 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 |
| Source: | Translational Oncology, Vol 53, Iss , Pp 102309- (2025) |
| Publisher Information: | Elsevier, 2025. |
| Publication Year: | 2025 |
| Collection: | LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| Subject Terms: | TIMP2, Lewis lung carcinoma, Lung cancer, Therapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1936-5233 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S1936523325000403; https://doaj.org/toc/1936-5233 |
| DOI: | 10.1016/j.tranon.2025.102309 |
| Access URL: | https://doaj.org/article/459dae0592c5485d916d86497152124e |
| Accession Number: | edsdoj.459dae0592c5485d916d86497152124e |
| Database: | Directory of Open Access Journals |
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