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Filename: drivers/Session_files_driver.php
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File: /var/www/html/index.php
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Function: require_once
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Message: session_start(): Failed to read session data: user (path: /var/lib/php/sessions)
Filename: Session/Session.php
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File: /var/www/html/index.php
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Function: require_once
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Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
Filename: helpers/my_audit_helper.php
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File: /var/www/html/application/helpers/my_audit_helper.php
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Function: file_get_contents
File: /var/www/html/application/helpers/my_audit_helper.php
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Function: simplexml_load_file_from_url
File: /var/www/html/application/helpers/my_audit_helper.php
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Function: getPubMedXML
File: /var/www/html/application/controllers/Detail.php
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Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
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Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
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Function: require_once
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Message: Attempt to read property "Count" on bool
Filename: helpers/my_audit_helper.php
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File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3100
Function: _error_handler
File: /var/www/html/application/controllers/Detail.php
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Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
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Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
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Function: require_once
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 tumor models is lacking. The effects of a 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 downregulates 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.
Download full-text PDF |
Source |
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10793420 | PMC |
http://dx.doi.org/10.1101/2023.12.29.573636 | DOI Listing |
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