Abstract 479: Targeting tumor initiating cells inhibits tumor growth and serial transplantation ability in soft-tissue sarcomas
Bibliographic record
Abstract
Abstract Tumors contain heterogeneous cell populations. There is a subpopulation of cells enriched for tumor initiating potential in sarcomas, which excludes Hoechst dye, and resides in the “side population” when subjected to flow cytometry (SP cells). These cells possess multi-potent differentiation potential, and as such they behave as “cancer stem cells” (CSCs), while the remainder of tumor cells act as “transient amplifying” cells. Because traditional cancer therapies may not target these tumor initiating cells, the persistence of SP cells could be responsible for relapse or a failed response to therapy. To detect signaling pathways that are differentially regulated in SP cells versus the remainder (non-SP) of the cells, we used gene profiling by microarray to compare their differences. RNA expressions were compared between these two cell populations from six malignant fibrous histiocytoma (MFH) samples using microarray. Differentially regulated genes were then analyzed by compiling a list of genes that showed a fold change greater than 1.25 in at least five of the six samples all in the same direction, and identifying if the list is enriched for genes involved in common molecular pathways, using Genespring® analysis tool. Two of the differentially regulated pathways detected were the Hedgehog signaling pathway and the Notch signaling pathway. Differential target gene expression for both pathways was verified using quantitative PCR. Triparanol (an agent that inhibits hedgehog signaling) and DAPT (an agent that inhibits Notch signaling) were used to treat eight primary MFH xenografts established in NOD-SCID mice. The xenografts produced visible tumors six weeks after subcutaneous transplantation, after which the mice were treated with one of the agents or a carrier as a control. At the end of the treatment, the tumors were harvested; their growth and SP% were assessed and compared; and the cells harvested from the treated xenografts were again implanted into mice to study the rate of re-growth upon secondary transplantation. Both triparanol and the Notch blocker DAPT treatment suppressed these pathways in tumor cells, depleted the abundance of SP cells, and reduced tumour growth. Intriguingly, treatment substantially inhibited the tumour-initiating potential of the treated sarcoma cells upon secondary transplantation. The data provides support that SP cells act as tumour initiating cells in sarcomas and shows that targeting the SP (in this case by targeting the Hh and Notch pathways) is an enticing approach for sarcoma therapy. 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 479. doi:10.1158/1538-7445.AM2011-479
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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) | 0.003 | 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".