Abstract 251: Stem cell altruism may serve as a novel drug resistance mechanism in oral cancer
Bibliographic record
Abstract
Abstract Background: The mechanism of oral squamous cell carcinoma resistance to platinum-based chemotherapy is not clearly known. Previous studies indicated that glutathione (GSH), a cellular antioxidant may detoxify cisplatinum (CDDP), a commonly used chemotherapy agent in oral cancer. Our previous research in human embryonic stem cells (hESCs) indicated the altruistic behavior of ABCG2+ hESCs that secrete high level of GSH to protect other hESCs exposed to oxidative stress (Das B et al. Stem Cells, 2012). Here we investigated if CDDP exposure lead to altruistic stem cell reprogramming of ABCG2+ oral squamous cell carcinoma cells and subsequent GSH-mediated resistance against CDDP. Methods: Two oral squamous cell cancer cell lines SCC-25 and SCC-15 were treated with 3-10 uM CDDP for three-days, and then subjected to flow cytometry and immunomagnetic sorting based evaluation of ABCG2+ cells. The conditioned media (CM) obtained from ABCG2+ cells were examined for GSH content. The CM treated cancer cell lines were examined for resistance against CDDP toxicity. Next, the post-CDDP treated ABCG2+ cells were examined for enhanced stemness phenotype that corresponds to altruistic stem cell phenotype (Das B et al, Stem Cells 2012). Results: We found that CDDP treatment increases the ABCG2+ self-renewal capacity of SCC-25 and SCC-15 cells as measured by serial transplantation assay. The CM of the post-CDDP treated cells exhibited high level of GSH. When the SCC-15 and SCC-25 cells were treated with CM plus CDDP, the cancer cells exhibited 10-15-fold increase in resistance against CDDP toxicity. Next, the post-CDDP treated SCC-25 and SCC-15 cells exhibited enhanced stemness reprogramming phenotype characterized by very high HIF-2alpha, Sox-2 and Nanog transcriptional activity. Furthemore, we found increased expression of EMT (epithelial mesenchymal transition) marker expression including Snail, Twist and vimentin as evaluated by flow cytometry. siRNA HIF-2alpha treatment led to marked loss in the in vivo self-renewal capacity of ABCG2+ SCC-25 and SCC-15 cells. We then noted that post-CDDP ABCG2+ cells exhibited reversible state, as after two weeks of culture, most of the cells either differentiated or underwent apoptosis. Conclusions: These results indicate that oral cancer cells exhibit altruistic defense mechanism to resist the toxicity of CDDP. The altruistic defense mechanism involved high secretion of GSH. Thus, we suggest that similar to bacterial altruism as a mechanism of drug resistance, stem cell altruism may also serve as a novel mechanism of drug resistance in cancer. Citation Format: Bidisha Pal, Reza Bayat-Mokhtari, Hong Li, Rashmi Bhuyan, Joyeeta Talukdar, Sora Sandhya, Anupam Sarma, Wael Tasabehji, Seema Bhuyan, Sukanya Gayan, Amal Ch Kataki, Debabrata Baishya, Herman Yeger, Dean W. Felsher, Bikul Das. Stem cell altruism may serve as a novel drug resistance mechanism in oral cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 251.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".