An autocrine inflammatory forward-feedback loop after chemotherapy withdrawal facilitates the repopulation of drug-resistant breast cancer cells
Why this work is in the frame
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Bibliographic record
Abstract
Stromal cells, infiltrating immune cells, paracrine factors and extracellular matrix have been extensively studied in cancers. However, autocrine factors produced by tumor cells and communications between autocrine factors and intracellular signaling pathways in the development of drug resistance, cancer stem-like cells (CSCs) and tumorigenesis have not been well investigated, and the precise mechanism and tangible approaches remain elusive. Here we reveal a new mechanism by which cytokines produced by breast cancer cells after chemotherapy withdrawal activate both Wnt/β-catenin and NF-κB pathways, which in turn further promote breast cancer cells to produce and secrete cytokines, forming an autocrine inflammatory forward-feedback loop to facilitate the enrichment of drug-resistant breast cancer cells and/or CSCs. Such an unexpected autocrine forward-feedback loop and CSC enrichment can be effectively blocked by inhibition of Wnt/β-catenin and NF-κB signaling. It can also be diminished by IL8-neutralizing antibody or blockade of IL8 receptors CXCR1/2 with reparixin. Administration of reparixin after chemotherapy withdrawal effectively attenuates tumor masses in a human xenograft model and abolishes paclitaxel-enriched CSCs in the secondary transplantation. These results are partially supported by the latest clinical data set. Breast cancer patients treated with chemotherapeutic drugs exhibited poor survival rate (66.7 vs 282.8 months, P=0.00071) and shorter disease-free survival time if their tumor samples expressed high level of IL8, CXCR1, CXCR2 genes and Wnt target genes. Taken together, this study provides new insights into the communication between autocrine niches and signaling pathways in the development of chemotherapy resistance and CSCs; it also offers a tangible approach in breast cancer treatment.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 0.000 |
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 it