Abstract 5255: The role of IGF1 signaling in site specific tumor metastasis: Regulating matrix metalloproteinase (MMP) expression
Bibliographic record
Abstract
Abstract The phenomenon of site-specific metastasis has been recognized for decades but the underlying molecular mechanisms have only recently become better understood, mainly due to insight from gene and protein profiling strategies. One family of proteins that emerged as a determinant of the organ-specificity of metastasis is that of the matrix metalloproteinases (MMPs). We recently reported that Lewis lung carcinoma cells that are highly metastatic to the lung (M-27) changed their preferred site of metastasis from the lung to the liver upon ectopic expression of the human insulin like growth factor-I receptor (M27IGF-IR). This change was associated with an altered MMP profile as MMP-2 and MMP-14 were upregulated while MMP-3, MMP-9 and MMP-13 expression markedly decreased in these cells (1, 2). The objective of the present study was to investigate the molecular basis for the loss of MMP-3, -9, and -13 expression in these cells. These proteinases are regulated by inflammatory mediators and we indeed found that following treatment with TNF-α, the expression of MMP-3 and MMP-13 in M-27, but not in M27IGF-IR cells was significantly increased, suggesting that the NFκB pathway was altered by IGF-IR overexpression. When expression levels for mediators of the TNFR/IKK/IκBα/NFκB signaling pathway in these cells were analyzed using qRT-PCR and Western blotting, we found that in M27IGF-IR cells, the expression of IKKε but not of IKKα or IKKβ was also downregulated. Moreover when IKKε was ectopically expressed in these cells, basal proteinase levels increased and could be further induced by TNF-α treatment, suggesting that the responsiveness to TNF-α in these cells was restored and was IKKε – dependent. Finally, using RT-PCR and Western blotting, we also observed that in cells with increased IKKε levels, MMP-3 mRNA and protein levels could also be stimulated by phorbol 12-myristate 13-acetate (PMA) treatment, suggesting that PKC signaling in these cells was potentiated. Taken together, our results indicate that the altered MMP profile in M27IGF-IR was due, at least in part, to the downregulation of IKKε- a mediator of inflammation-induced signaling that was recently identified as a potential oncogene in breast cancer (3). They suggest that the MMP profile of the tumor cells is regulated through crosstalk between inflammatory signals, the IGF axis and the PKC system. Moreover, they imply that in addition to intrinsic tumor cell properties, the type of stimuli predominating in the microenvironment will ultimately determine the MMP expression profile and thereby control tumor expansion and metastasis in specific sites. Supported by Canadian Institute for Health Research grant MOP-81201 (to PB). References 1. Brodt, P. et al (2001) J. Biol. Chem. 276:33608-33615. 2. Li, S. et al (2009) Mol. Endocrinology 23:2013-25. 3. Boehm, J.S. et al (2007). Cell 129:1065-79. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5255. doi:10.1158/1538-7445.AM2011-5255
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".