Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of vasoactive intestinal peptide (VIP) on cyclooxygenase-2 (COX-2) expression was analyzed in human prostate non-neoplastic (RWPE-1) as well as cancer androgen-dependent (LNCaP) and independent (PC3) cells. The three cell lines expressed VIP mRNA and VIP peptide, as measured by RT-PCR and immunochemistry, which supports an autocrine/paracrine action of VIP in the prostate gland. VIP levels were progressively higher from non-neoplastic to androgen-dependent and independent cells. Real-time RT-PCR and Western-blotting showed that VIP stimulated both COX-2 mRNA and protein expression in a faster manner as prostate cancer stage progressed (i.e. RWPE1<LNCaP<PC3 cells). Furthermore, VIP induced higher levels of COX-2 protein expression in cancer cells as compared with non-neoplastic cells. The anti-inflammatory agent curcumin blocked VIP-induced COX-2 expression in all cell lines studied supporting the involvement of nuclear factor-kappaB (NFkappaB) in such a response. In fact, VIP increased the translocation of the NFkappaB p50 subunit to the nucleus and the binding of the active form to its target gene promoter, as measured by Western-blotting and ELISA, respectively. VIP provoked faster responses according to the most aggressive status in cancer progression (androgen-independent situation). These results together with the existence of two NFkappaB sites in the COX-2 gene promoter together suggest that COX-2 may be a target for VIP in prostate cancer progression. On the other hand, VIP could be a proinflammatory cytokine acting through the NFkappaB/COX-2 system.
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PMID:Vasoactive intestinal peptide induces cyclooxygenase-2 expression through nuclear factor-kappaB in human prostate cell lines Differential time-dependent responses in cancer progression. 1743 57

Transcriptional regulation plays a central role in the molecular pathways underlying preferential cancer growth and metastasis. In the present study, we investigated the regulation of human protease-activated receptor 1 (hPar1) gene overexpression in the malignant androgen hormone-resistant phase. We found increased hPar1 RNA chain elongation and no change in message stability in cells with high levels of PAR1 expression, indicating that increased transcription is largely responsible for the overexpression of hPar1 in prostate tumor progression. Enforced expression of early growth response-1 (Egr-1) plasmid markedly enhanced luciferase activity driven by the hPar1 promoter. The neuroendocrine peptide bombesin significantly induced hPar1 expression and increased the ability of the cells to invade Matrigel, an effect abolished by expression of hPar1 small interfering RNA, showing the importance of hPAR1 in invasion. Bombesin also markedly enhanced Egr-1 binding to the hPar1 promoter in vivo and in vitro. These data suggest that bombesin enhances Egr-1 expression leading to increased hPar1 transcription, thereby increasing PAR1 expression and function. Immunohistostaining of prostate tissue biopsy specimens revealed a direct correlation between the degree of prostate cancer malignancy, PAR1 expression, and EGR-1 expression. Altogether, we show that transcriptional regulation of hPar1 in the aggressive hormone-resistant prostate cancer stage is controlled in part by the transcription factor Egr-1 and may play a central role in invasiveness, an important indicator of malignancy.
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PMID:Transcriptional regulation of human protease-activated receptor 1: a role for the early growth response-1 protein in prostate cancer. 1794 14

Developing patient derived models from individual tumors that capture the biological heterogeneity and mutation landscape in advanced prostate cancer is challenging, but essential for understanding tumor progression and delivery of personalized therapy in metastatic castrate resistant prostate cancer stage. To demonstrate the feasibility of developing patient derived xenograft models in this stage, we present a case study wherein xenografts were derived from cancer metastases in a patient progressing on androgen deprivation therapy and prior to initiating pre-chemotherapy enzalutamide treatment. Tissue biopsies from a metastatic rib lesion were obtained for sequencing before and after initiating enzalutamide treatment over a twelve-week period and also implanted subcutaneously as well as under the renal capsule in immuno-deficient mice. The genome and transcriptome landscapes of xenografts and the original patient tumor tissues were compared by performing whole exome and transcriptome sequencing of the metastatic tumor tissues and the xenografts at both time points. After comparing the somatic mutations, copy number variations, gene fusions and gene expression we found that the patient's genomic and transcriptomic alterations were preserved in the patient derived xenografts with high fidelity. These xenograft models provide an opportunity for predicting efficacy of existing and potentially novel drugs that is based on individual metastatic tumor expression signature and molecular pharmacology for delivery of precision medicine.
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PMID:Mutational Landscapes of Sequential Prostate Metastases and Matched Patient Derived Xenografts during Enzalutamide Therapy. 2669 60