Search results for "FIBROBLASTS"
showing 10 items of 445 documents
Topotecan-triggered degradation of topoisomerase I is p53-dependent and impacts cell survival.
2005
Abstract The anticancer drug topotecan belongs to the group of topoisomerase I (topo I) inhibitors. In the presence of topotecan, topo I cleaves the DNA but is unable to religate the single-strand break. This leads to stabilization of topo I-DNA–bound complexes and the accumulation of DNA strand breaks that may interfere with DNA replication. The molecular mechanism of controlling the repair of topo I-DNA covalent complexes and its impact on sensitivity of cells to topotecan is largely unknown. Here, we used mouse embryonic fibroblasts expressing wild-type p53 and deficient in p53, in order to elucidate the role of p53 in topotecan-induced cell death. We show that p53-deficient mouse embryo…
Identification and validation of novel ERBB2 (HER2, NEU) targets including genes involved in angiogenesis.
2005
V-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2; synonyms HER2, NEU) encodes a transmembrane glycoprotein with tyrosine kinase-specific activity that acts as a major switch in different signal-transduction processes. ERBB2 amplification and overexpression have been found in a number of human cancers, including breast, ovary and kidney carcinoma. Our aim was to detect ERBB2-regulated target genes that contribute to its tumorigenic effect on a genomewide scale. The differential gene expression profile of ERBB2-transfected and wild-type mouse fibroblasts was monitored employing DNA microarrays. Regulated expression of selected genes was verified by RT-PCR and validated by West…
Interleukin-6 and the soluble interleukin-6 receptor induce stem cell factor and Flt-3L expression in vivo and in vitro.
2001
Abstract Objective We recently established transgenic animals expressing either interleukin-6 (IL-6) or the soluble IL-6 receptor (sIL-6R) alone, or both components, IL-6 and the sIL-6R, in the liver. This animal model demonstrated that the expression of IL-6 in combination with its sIL-6R led to extramedullary expansion of hematopoietic progenitor cells in the spleen and liver. Materials and Methods We studied other relevant hematopoietic cytokines involved in the IL-6/sIL-6R–induced stimulation of hematopoiesis. Results Using immunohistochemistry, we showed that cell-associated stem cell factor (SCF) and Flt-3L expression were upregulated in liver and spleen only in double transgenic mice…
Tumor and its microenvironment: a synergistic interplay.
2013
The mutual and interdependent interaction between tumor and its microenvironment is a crucial topic in cancer research. Recently, it was reported that targeting stromal events could improve efficacies of current therapeutics and prevent metastatic spreading. Tumor microenvironment is a "complex network" of different cell types, soluble factors, signaling molecules and extracellular matrix components, which orchestrate the fate of tumor progression. As by definition, cancer stem cells (CSCs) are proposed to be the unique cell type able to maintain tumor mass and survive outside the primary tumor at metastatic sites. Being exposed to environmental stressors, including reactive oxygen species …
Preclinical and Clinical Characterization of Fibroblast-derived Neuregulin-1 on Trastuzumab and Pertuzumab Activity in HER2-positive Breast Cancer.
2021
[Purpose]: To characterize expression of neuregulin-1 (NRG1), an HER3 ligand, in HER2-positive breast cancer and its relation with the efficacy of trastuzumab with or without pertuzumab.
MYCN and survivin cooperatively contribute to malignant transformation of fibroblasts
2013
The oncogenes MYCN and survivin (BIRC5) maintain aggressiveness of diverse cancers including sarcomas. To investigate whether these oncogenes cooperate in initial malignant transformation, we transduced them into Rat-1 fibroblasts. Indeed, survivin enhanced MYCN-driven contact-uninhibited and anchorage-independent growth in vitro. Importantly, upon subcutaneous transplantation into mice, cells overexpressing both instead of either one of the oncogenes generated tumors with shortened latency, marked anaplasia and an increased proliferation-to-apoptosis ratio resulting in accelerated growth. Mechanistically, the increased tumorigenicity was associated with an enhanced Warburg effect and a hyp…
Involvement of protein kinase Cdelta in contact-dependent inhibition of growth in human and murine fibroblasts.
2001
There is evidence that protein kinase C delta (PKCdelta) is a tumor suppressor, although its physiological role has not been elucidated so far. Since important anti-proliferative signals are mediated by cell-cell contacts we studied whether PKCdelta is involved in contact-dependent inhibition of growth in human (FH109) and murine (NIH3T3) fibroblasts. Cell-cell contacts were imitated by the addition of glutardialdehyde-fixed cells to sparsely seeded fibroblasts. Downregulation of the PKC isoforms alpha, delta, epsilon, and mu after prolonged treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA, 0.1 microM) resulted in a significant release from contact-inhibition in FH109 cells. Bryosta…
Reduction of glutathione content by 12-O-tetradecanoylphorbol-13-acetate in confluent, but not in sparse cultures of human diploid fibroblasts.
1990
Treatment of confluent cultures of human diploid fibroblasts with 12-O-tetradecanoylphorbol-13-acetate (TPA) (10(-7) M) resulted in a 70% reduction of the glutathione (GSH) content, compared with untreated controls. The effect, which was dose-dependent, was observed 8 h after the beginning of the treatment could be followed for up to 72 h. On the other hand, GSH reduction was specific for confluent cultures, as the level of glutathione remained unchanged by TPA treatment of sparse cultures. The addition of immobilized plasma membrane proteins to sparsely seeded cells has been shown previously to induce cellular reactions which are characteristic for confluent cultures. It was shown that TPA…
RB acute loss induces centrosome amplification and aneuploidy in murine primary fibroblasts
2006
AbstractBackgroundIncorrect segregation of whole chromosomes or parts of chromosome leads to aneuploidy commonly observed in cancer. The correct centrosome duplication, assuring assembly of a bipolar mitotic spindle, is essential for chromosome segregation fidelity and preventing aneuploidy. Alteration of p53 and pRb functions by expression of HPV16-E6 and E7 oncoproteins has been associated with centrosome amplification. However, these last findings could be the result of targeting cellular proteins in addition to pRb by HPV16-E7 oncoprotein. To get a more detailed picture on the role of pRb in chromosomal instability and centrosome amplification, we analyzed the effects of the acute loss …
Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription
2003
AbstractRecent efforts to develop pharmacologic agents that restore function to mutant forms of p53 hold significant promise in cancer therapy. Here, we examine the effects of such pharmacologic activation of p53 function using a small molecule, PRIMA-1, and a model system employing a p53 protein fused to a mutant steroid binding domain of the murine estrogen receptor (p53ERtam) that renders it responsive only in the presence of 4-hydroxytamoxifen. In either case, p53 activation triggered apoptosis that was not inhibited by the presence of macromolecular synthesis inhibitors. This p53-induced, transcription-independent apoptosis is Bax dependent, proceeds in the absence of a nucleus, and in…