Abstract P2-05-26: Focal adhesion kinase is required for efficient tumor-induced osteoclastogenesis via control of macrophage colony stimulating factor expression
Bibliographic record
Abstract
Abstract Breast cancer most commonly metastasizes to bone where metastases cause the potentiation of the vicious cycle. During this process, breast cancer bone metastases inhibit osteoblasts from forming new bone, while also activating osteoclasts to degrade bone. This in turn causes release of bone-matrix bound growth factors which propagate tumor growth. The overall net bone destruction can lead to significant adverse clinical consequences for patients including fractures or substantial pain. While agents such as bisphosphonates or the monoclonal antibody to RANKL denosumab, both of which inhibit the osteolytic activity of osteoclasts, are currently used in breast cancer bone metastatic patients to alleviate these adverse clinical outcomes, they have not been associated with increased patient survival. Given the lack of successful treatments for bone metastases providing survival advantages, we sought to evaluate the role of focal adhesion kinase (FAK), a novel therapeutic target, in breast cancer mediated osteolysis. FAK is a non-receptor tyrosine kinase that regulates many pathways that contribute to enhanced tumor progression and metastasis. FAK is also expressed in all the cell types involved in the vicious cycle. We thus hypothesized that FAK plays an important role in breast tumor-induced osteolysis and that its inhibition would lead to restoration of bone homeostasis, in addition to inhibition of tumor progression. Using in vitro siRNA-targeted depletion of FAK in breast cancer tumor cell lines, we found that production of numerous soluble growth factors, many of which are known contributors to osteoclastogenesis, was inhibited. We confirmed that FAK regulates the expression of the osteoclastogenic factor macrophage colony stimulating factor in breast cancer cell lines. Further, using conditioned media from FAK expressing versus depleted breast cancer tumor cells in osteoclastogenesis assays, we show that FAK-depletion results in impaired osteoclastogenesis. These data suggest that in addition to its proven direct anti-tumor effects, inhibition of FAK may also result in therapeutic blockade of bone degradation. Citation Format: Landon K, Howe GA, Zhao H, Addison CL. Focal adhesion kinase is required for efficient tumor-induced osteoclastogenesis via control of macrophage colony stimulating factor expression. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-26.
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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) | 0.001 | 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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
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".