Regulation of growth of renal clear cell carcinoma by peroxisome proliferator-activated receptor gamma
Bibliographic record
Abstract
B67 Renal Clear Cell Carcinoma (RCC) is the tenth most prevalent cancer , accounting for 80% of all renal cancers. Recent results of a 15.3 year epidemiological study indicate that a diet of fatty fish offers significant protection against RCC, results which were attributed to omega-3 fatty acids. The question arises as to the molecular mechanisms by which such omega-3 fatty acids exert their protective effect. One possible mechanism is through the activation of Peroxisome Proliferator-Activated Receptors (PPARS) by omega-3 fatty acids, which presumably is altered during the process of tumorigenesis. In order to examine this hypothesis, normal renal proximal tubule cells have initially been examined with regards to their growth responses to PPAR agonists (the RCC is of renal proximal tubule origin). Towards these ends the effects of PPAR alpha and PPAR gamma agonists on the growth of a well-characterized primary renal proximal tubule cell culture system have been examined. The primary cultures were initiated from purified rabbit renal proximal tubules in serum free medium supplemented with 5 microgram/ ml bovine insulin, 5 microgram/ml human transferrin and 5 x 10-8 M hydrocortisone. Fibrate drugs and thiazolidinediones (TZDs) have been identified which have a high affinity for PPAR alpha and PPAR gamma, respectively. The effects of the TZD drug troglitazone on the growth of primary proximal tubule cells were examined over a concentration range between 10-7 and 10-4 M. After a 7 day incubation period, cells were removed from culture dishes by trypsinization, and counted in a Coulter Counter. The results of 3 independent studies indicated that troglitazone caused a 4-fold increase in cell number over a concentration range of 10-6 to 5 x 10-6 M. A physiologic PPAR gamma agonist, Prostaglandin J2 (PGJ2), was also growth stimulatory, albeit to a lesser extent than troglitazone. Both PPAR alpha and PPAR gamma are expressed in the renal proximal tubule. However, fenofibrate, a PPAR alpha agonist, had no significant affect on renal proximal tubule cell growth over a concentration range of 10-7 to10-4 M. Unlike the results that we have obtained with our normal renal proximal tubule cells, several recent studies have indicated that troglitazone, and other TZDs (PPAR gamma agonists) induce growth arrest and apoptosis in RCC, as well as other urological cancers. Presumably, PPAR gamma signaling is altered in RCC. Indeed PPAR gamma is included amongst the proteins that are up-regulated in RCCs as a consequence of mutations in the von Hippel-Lindau suppressor gene (VHL). Thus, omega-3 fatty acids may act to prevent the progression of the tumor stem cells which have arisen as a result of such mutations in the VHL gene. Alternatively, omega-3 fatty acids may act to prevent metabolic processes necessary for the emergence of RCC cells, with their distinctive lipid droplets.
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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) | 0.002 | 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".