Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cellular growth interactions were studied between neonatal human lung fibroblasts (NLF-13) and human tumor lines derived from carcinomas of the prostate (PC-3, DU145), bladder (J82), and endometrium (HEC-1A) and from a glioma (Hs 683t). NLF-13 were interacted with tumor cells in soft agar or agarose media using two experimental protocols. In one system, NLF-13 cells were grown as anchored monolayers proliferating under the tumor cell layer. In the second, NLF-13 were embedded directly (nonanchored) into the agar or agarose layer with the tumor cells. The results from both interaction systems were similar for all five tumor lines. Anchored NLF-13 caused a dose-dependent inhibition of tumor growth, whereas nonanchored cells produced a dose-dependent growth stimulation. A time exposure experiment indicated that tumor stimulation and inhibition were biphasic responses to NLF-13. It was concluded that low concentrations of a diffusible NLF-13 product(s) accelerated tumor growth, whereas high concentrations were inhibitory. Further, the production of the active NLF-13 substance(s) was positively correlated with NLF-13 growth rate. Tumor cell inhibition was irreversible after a 5-day exposure to proliferating NLF-13 cells. Another line of normal neonatal human lung fibroblasts (NLF-147) showed inhibitory properties similar to those described for NLF-13. However, preliminary studies with fibroblasts from the skin of a Down's syndrome neonate (DS-172) and from a human kidney tumor (KTF-130) have shown both these fibroblast types to have a reduced ability to inhibit tumor cell cultures (J82) compared to the neonatal lung fibroblasts (NLF-13 and NLF-147).
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PMID:Comparable growth regulation of five human tumor cell lines by neonatal human lung fibroblasts in semisolid culture media. 668 26

Relapsed neuroblastomas are enriched with activating mutations of the RAS-MAPK signaling pathway. The MEK1/2 inhibitor trametinib delays tumor growth but does not sustain regression in neuroblastoma preclinical models. Recent studies have implicated the Hippo pathway transcriptional coactivator protein YAP1 as an additional driver of relapsed neuroblastomas, as well as a mediator of trametinib resistance in other cancers. Here, we used a highly annotated set of high-risk neuroblastoma cellular models to modulate YAP1 expression and RAS pathway activation to test whether increased YAP1 transcriptional activity is a mechanism of MEK1/2 inhibition resistance in RAS-driven neuroblastomas. In NLF (biallelic NF1 inactivation) and SK-N-AS (NRAS Q61K) cell lines, trametinib caused a near-complete translocation of YAP1 protein into the nucleus. YAP1 depletion sensitized neuroblastoma cells to trametinib, while overexpression of constitutively active YAP1 protein induced trametinib resistance. Mechanistically, significant enhancement of G1-S cell-cycle arrest, mediated by depletion of MYC/MYCN and E2F transcriptional output, sensitized RAS-driven neuroblastomas to trametinib following YAP1 deletion. These findings underscore the importance of YAP activity in response to trametinib in RAS-driven neuroblastomas, as well as the potential for targeting YAP in a trametinib combination. SIGNIFICANCE: High-risk neuroblastomas with hyperactivated RAS signaling escape the selective pressure of MEK inhibition via YAP1-mediated transcriptional reprogramming and may be sensitive to combination therapies targeting both YAP1 and MEK.
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PMID:YAP1 Mediates Resistance to MEK1/2 Inhibition in Neuroblastomas with Hyperactivated RAS Signaling. 3167 41