Abstract 961: Pathways of tumorigenesis promoted by the growth factor progranulin in SW-13 adrenocortical carcinoma cells
Bibliographic record
Abstract
Abstract Adrenocortical carcinomas are highly malignant cancers, with a very low 5 year survival rate. The SW-13 cell line originated from a stage IV adrenocortical carcinoma, but is only poorly tumorigenic in mice. It can, however, be made highly tumorigenic in vivo if it is engineered to express a limited number of growth factors including progranulin (PGRN, also called PCDGF, granulin epithelin precursor, or proepithelin) and secreted FGFs. This provides a model system to study the transition of an adrenocortical carcinoma from low to a high malignant potential. PGRN is a secreted glycoprotein growth factor that is over produced by many cancers including those of the breast, ovary, endometrium, prostate, bladder, and liver. It acts on cancer growth by increasing mitosis, decreasing apoptosis and stimulating invasion. In addition, PGRN has been implicated as a stimulator of tumor stroma growth in breast cancer. We examined the expression of PGRN in SW-13 cells at different stages of the cell cycle. Cells were synchronized using two independent agents, L-Mimosine and aphidicolin to arrest cell division. Washout of the drugs released the SW-13 cells into the cell cycles with slow (L-Mimosine) or rapid (aphidicolin) kinetics, and PGRN expression increased in parallel with the increased proportion of cells in active cell division. Depleting PGRN mRNA levels slowed reentry into the cell cycle following drug removal. Inhibition of MEK1/2, phosphatidylinositol-3 kinase (PI3K), protein kinase C (PKC) and phospholipase-C-α (PLCγ) impairs proliferation of SW-13 cells carrying only empty vector (SW-13V) with differential effects on mitosis and apoptosis. In cells with elevated PGRN, (SW-13P), the anti-proliferative effects of inhibiting MEK1/2, PI3K and PKC, but not PLCγ, are attenuated. Inhibition of the stress kinase p38 increases proliferation of SW-13V, but not SW-13P cells, suggesting that PGRN and p38 have opposing effects on proliferation. Inhibition of p38 enhances the phosphorylation of MEK1/2 in SW-13V cells, while inhibiting PKC decreases it, suggesting that PKC and p38 pathways interact with the PGRN-regulated MEK1/2 signaling cascade. Transcriptional profiling indicated that expression of PGRN modulated levels of proteins in the Wnt and Notch-signaling pathways. These results suggest that PGRN expression may be coordinated with the cell cycle, and, may promote tumorigenesis by intervening in several signaling pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 961. doi:1538-7445.AM2012-961
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".