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

Cellular senescence is a potent anti-cancer mechanism controlled by tumor suppressor genes, particularly p53 and pRb, which is characterized by the irreversible loss of proliferation. Senescence induced by DNA damage, oncogenic stimulation, or excessive mitogenic input, serves as a barrier that counteracts cancer progression. Emerging evidence in cellular and in in vivo models revealed the involvement of additional signaling players in senescence, including PML, CK2, Bcl-2, PI3K effectors such as Rheb, Rho small GTPases, and cytokines. Recent studies have also implicated protein kinase C (PKC) isozymes as modulators of senescence phenotypes and showed that phorbol esters, widely used PKC activators, can induce senescence in a number of cancer cells. These novel findings suggest a complex array of cross-talks between senescence pathways and may have significant implications in cancer therapy.
 ...
PMID:Hallmarks for senescence in carcinogenesis: novel signaling players. 1916 23

Cancer chemotherapy complexity ranges from the routes that the drug must follow before reaching the tumor site (pharmacokinetics), to the drug effects on tumor depletion (pharmacodynamics). Previous researchers, in their majority, have focused either on the pharmacokinetics (PK) or on the pharmacodynamics (PD) aspects of chemotherapy. Moreover, models that account for the molecular mechanisms of cancer development have limited scope in addressing the protein signals involved in tumor progression. For instance, the recently developed models for the p53 network, for which a number of mutations have been reported, must be integrated for further understanding of the disease. Here, we propose an integrated model that is composed of a compartmental PK/PD representation for drug therapy that incorporates p53 and cell cycle regulation. In particular, the dynamics of p53 and its network components, such as Mdm2, pRb, cyclin-cdk's, are modeled under drug administration. The results show that the proposed model is a realistic representation of the physiological expectations in a multi-scale, integrative approach.
 ...
PMID:An integrated network-based mechanistic model for tumor growth dynamics under drug administration. 1928 61

Galectin-3, a beta-galactoside-binding protein, has been implicated in a variety of biological functions including cell proliferation, apoptosis, angiogenesis, tumor progression, and metastasis. The present study was undertaken to understand the role of galectin-3 in the progression of prostate cancer. Immunohistochemical analysis of galectin-3 expression revealed that galectin-3 was cleaved during the progression of prostate cancer. Galectin-3 knockdown by small interfering RNA (siRNA) was associated with reduced cell migration, invasion, cell proliferation, anchorage-independent colony formation, and tumor growth in the prostates of nude mice. Galectin-3 knockdown in human prostate cancer PC3 cells led to cell-cycle arrest at G(1) phase, up-regulation of nuclear p21, and hypophosphorylation of the retinoblastoma tumor suppressor protein (pRb), with no effect on cyclin D1, cyclin E, cyclin-dependent kinases (CDK2 and CDK4), and p27 protein expression levels. The data obtained here implicate galectin-3 in prostate cancer progression and suggest that galectin-3 may serve as both a diagnostic marker and therapeutic target for future disease treatments.
 ...
PMID:Regulation of prostate cancer progression by galectin-3. 1928 70

Certain forms of hexavalent chromium [Cr(VI)] are human carcinogens. Our recent work has shown that a broad range protein tyrosine phosphatase (PTP) inhibitor, sodium orthovanadate (SOV), abrogated both Cr(VI)-induced growth arrest and clonogenic lethality. Notably, SOV enhanced Cr(VI) mutation frequency, ostensibly through forced survival of genetically damaged cells. In the present study, co-treatment with this PTP inhibitor bypassed the Cr(VI)-induced G(1)/S checkpoint arrest in diploid human lung fibroblasts (HLF). Moreover, the PTP inhibitor abrogated the Cr(VI)-induced decrease in the expression of key effectors of the G(1)/S checkpoint [Cyclin D1, phospho Ser 807/811 Rb (pRB), p27]. Cr(VI)-induced G(1) arrest was associated with the cytoplasmic appearance of pRb and the nuclear localization of p27, both of which were reversed by the PTP inhibitor. The PTP inhibitor's reversal of G(1)/S checkpoint effector localization after Cr exposure was found to be Akt1-dependent, as this was abrogated by transfection with either akt1 siRNA or an Akt1-kinase dead plasmid. Furthermore, Akt1 activation alone was sufficient to induce G(1)/S checkpoint bypass and to prevent Cr(VI)-induced changes in pRb and p27 localization. In conclusion, this work establishes Akt1 activation to be both sufficient to bypass the Cr(VI)-induced G(1)/S checkpoint, as well as necessary for the observed PTP inhibitor effects on key mediators of the G(1)/S transition. The potential for Akt to bypass G(1)/S checkpoint arrest in the face of genotoxic damage could increase genomic instability, which is a hallmark of neoplastic progression.
 ...
PMID:AKT1 mediates bypass of the G1/S checkpoint after genotoxic stress in normal human cells. 1937 90

Parathyroid hormone-related protein (PTHrP), a paraneoplastic protein expressed by two-thirds of human non-small cell lung cancers, has been reported to slow progression of lung carcinomas in mouse models and to lengthen survival of patients with lung cancer. This study investigated the effects of ectopic expression of PTHrP on proliferation and cell cycle progression of two human lung adenocarcinoma cell lines that are normally PTHrP negative. Stable transfection with PTHrP decreased H1944 cell DNA synthesis, measured by thymidine incorporation, bromodeoxyuridine uptake, and MTT proliferation assay. A substantial fraction of PTHrP-positive cells was arrested in or slowly progressing through G1. Cyclin D2 and cyclin A2 protein levels were 60-70% lower in PTHrP-expressing cells compared with control cells (P < 0.05, N = 3 independent clones per group), while expression of p27(Kip1), a cyclin-dependent kinase inhibitor, was increased by 35 +/- 9% (mean +/- SE, P < 0.05) in the presence of PTHrP. Expression of other cyclins, including cyclins D1 and D3, and cyclin-dependent kinases was unaffected by PTHrP. PTHrP did not alter the phosphorylation state of Rb, but decreased cyclin-dependent kinase (CDK) 2-cyclin A2 complex formation. Ectopic expression of PTHrP stimulated ERK phosphorylation. In MV522 cells, PTHrP had similar effects on DNA synthesis, cyclin A2 expression, pRb levels, CDK2-cyclin A2 association, and ERK activation. In summary, PTHrP appears to slow progression of lung cancer cells into S phase, possibly by decreasing activation of CDK2. Slower cancer cell proliferation could contribute to slower tumor progression and increased survival of patients with PTHrP-positive lung cancer.
 ...
PMID:Cell cycle actions of parathyroid hormone-related protein in non-small cell lung carcinoma. 1963 68

The immunohistochemical expression of cell cycle proteins p16, cyclin D1, and pRb was assessed in 112 benign and malignant melanocytic tumors and correlated with tumor progression, prognosis, and outcome. Comparing benign and malignant tumors, there were significant differences in the median score for all 3 proteins, with decreased p16 (P = .000001), increased cyclin D1 (P = .01), and increased pRb in melanomas (P = .01). There was a progressive loss of expression of p16 with progression from benign naevi to primary melanomas and to metastases. p16 was significantly decreased in primary tumors from melanoma patients who developed recurrent disease (P = .0000013). Cyclin D1 and pRb showed a progressive increase in expression from benign to malignant tumors but with relative decreases in the more advanced tumors (thick primaries and metastatic melanomas). Alterations in cell cycle proteins involved in G1/S transition are implicated in melanocytic tumor progression and have a potential role in diagnosis and prognostication.
 ...
PMID:Reduced p16 and increased cyclin D1 and pRb expression are correlated with progression in cutaneous melanocytic tumors. 1966 44

Defects in pRb tumor suppressor pathway occur in approximately 50% of the deadly muscle-invasive urothelial carcinomas in humans and urothelial carcinoma is the most prevalent epithelial cancer in long-term survivors of hereditary retinoblastomas caused by loss-of-function RB1 mutations. Here, we show that conditional inactivation of both RB1 alleles in mouse urothelium failed to accelerate urothelial proliferation. Instead, it profoundly activated the p53 pathway, leading to extensive apoptosis, and selectively induced pRb family member p107. Thus, pRb loss triggered multiple fail-safe mechanisms whereby urothelial cells evade tumorigenesis. Additional loss of p53 in pRb-deficient urothelial cells removed these p53-dependent tumor barriers, resulting in late-onset hyperplasia, umbrella cell nuclear atypia, and rare-occurring low-grade, superficial papillary bladder tumors, without eliciting invasive carcinomas. Importantly, mice deficient in both pRb and p53, but not those deficient in either protein alone, were highly susceptible to subthreshold carcinogen exposure and developed invasive urothelial carcinomas that strongly resembled the human counterparts. The invasive lesions had a marked reduction of p107 but not p130 of the pRb family. Our data provide compelling evidence, indicating that urothelium, one of the slowest cycling epithelia, is remarkably resistant to transformation by pRb or p53 deficiency; that concurrent loss of these two tumor suppressors is necessary but insufficient to initiate urothelial tumorigenesis along the invasive pathway; that p107 may play a critical role in suppressing invasive urothelial tumor formation; and that replacing/restoring the function of pRb, p107, or p53 could be explored as a potential therapeutic strategy to block urothelial tumor progression.
 ...
PMID:Deficiency of pRb family proteins and p53 in invasive urothelial tumorigenesis. 1995 92

Tumor suppressors negatively regulate angiogenesis, an essential step in tumor progression. Together, HPV 16 E6 and E7 proteins, which target p53 and pRb family members, respectively, for degradation, increase the expression of two angiogenic inducers, VEGF and IL-8, in primary foreskin keratinocytes (HFKs). Conditioned media from such cells are sufficient to alter endothelial cell behavior. Here, the individual contribution of E6 and E7 to angiogenesis was investigated. E7 and, to a lesser extent E6, increased expression of VEGF and IL-8. Nevertheless, neither conditioned media from HPV 16 E6 nor E7-expressing HFKs were sufficient to induce migration of endothelial cells. Conditioned media from HFKs expressing the HPV 16 E6 and the E7 mutant E7C24G, which can target p107 and p130 but not pRb for degradation, contained increased levels of VEGF and IL-8. The results suggest that the mechanism of HPV 16 E7-mediated increased levels of VEGF is pRb-independent.
 ...
PMID:Expression of human papillomavirus type 16 E7 is sufficient to significantly increase expression of angiogenic factors but is not sufficient to induce endothelial cell migration. 2115 59

Mutational inactivation of the RB1 tumor suppressor gene initiates retinoblastoma and other human cancers. RB1 protein (pRb) restrains cell proliferation by binding E2f transcription factors and repressing the expression of cell cycle target genes. It is presumed that loss of pRb/E2f interaction accounts for tumor initiation, but this has not been directly tested. RB1 mutation is a late event in other human cancers, suggesting a role in tumor progression as well as initiation. It is currently unknown whether RB1 mutation drives tumor progression and, if so, whether loss of pRb/E2f interaction is responsible. We have characterized tumorigenesis in mice expressing a mutant pRb that is specifically deficient in binding E2f. In endocrine tissue, the mutant pRb has no detectable effect on tumorigenesis. In contrast, it significantly delays progression to invasive and lethal prostate cancer. Tumor delay is associated with induction of a senescence response. We conclude that the pRb/E2f interaction is critical for preventing tumor initiation, but that pRb can use additional context-dependent mechanisms to restrain tumor progression.
 ...
PMID:E2f binding-deficient Rb1 protein suppresses prostate tumor progression in vivo. 2118 95

Autophagy, an intracellular degradation pathway involved in cell survival or demise, is tightly controlled by complex regulatory mechanisms. A link between the Rb tumor suppressor and autophagy is now emerging. pRb plays a critical role in cell cycle progression and survival as well as the differentiation of certain cell types. Recently, we have reported that during skeletal myogenesis, Rb-deficient myoblasts fuse to form short myotubes that quickly degenerate. Myotube degeneration was associated with increased autophagic flux and inhibition of autophagy rescued the defect leading to long, twitching myotubes. We propose that Rb-loss sensitizes cells to autophagy via direct and indirect mechanisms and we discuss how these might affect cancer progression and response to chemotherapy.
 ...
PMID:Direct and indirect effects of the pRb tumor suppressor on autophagy. 2132 79


<< Previous 1 2 3 4 5 6 7 8 Next >>