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)

PC-SPES is a mixture of eight herbs with antiproliferative activity in prostate cancer cell lines and antitumor effects in animal models of prostate cancer. In addition, evidence of clinical efficacy in advanced prostate cancer has been reported. PC-SPES has also been shown to have antitumor activity against several other cancer cell lines including breast and neuroepithelial cancer, melanoma, and leukemia cell lines. Because of these findings, we investigated the effects of PC-SPES in vitro in colon cancer cell lines SW480, SW620, and DLD-1 and in vivo in the Apc(min) mouse, a murine model for intestinal carcinogenesis. For the in vitro studies, colon cancer cell lines were exposed to an ethanolic extract of PC-SPES compared with a diluent control [ethanol < or = 0.3% (v/v)]. PC-SPES resulted in a marked suppression of cell proliferation in all colon cancer cells studied. PC-SPES (3 micro l/ml) caused a 95% inhibition of cell proliferation of the DLD-1 colon cancer cell line, and similar results were observed in the SW480 and SW620 colon cancer cell lines. Cell cycle analysis demonstrated a drastic (> or =60%) accumulation of cells in the G(2)-M phase with a concomitant decrease of cells in the G(0)-G(1) phase in all colon cancer cell lines studied after treatment with PC-SPES (1.5 micro l/ml for 48 h). Western blot analysis demonstrated a decrease in protein levels of beta-tubulin in the SW620 cell line exposed to PC-SPES. Terminal deoxynucleotidyl transferase-mediated nick end labeling analysis revealed an increase in apoptotic colon cancer cells incubated with PC-SPES. For the in vivo studies, female 4-5-week-old Apc(min) mice were randomized to two groups: a PC-SPES-treated group (n = 11) received 250 mg/kg/day (0.2 ml) PC-SPES via gastrointestinal gavage; and a control group (n = 10) received 0.2 ml of the vehicle solution (1.5% carboxymethylcellulose with 0.2% Tween 20) via gastrointestinal gavage. Both groups were treated five times a week for 10 weeks. After treatment, the gastrointestinal tract was dissected for polyp scoring by two observers blinded to treatment. The Apc(min) mice given PC-SPES had a 58% reduction in tumor number and a 56% decrease in tumor load. No effect on either food intake or body weight was observed in the treated versus sham groups. The present study is the first to report the potent activity of PC-SPES against colon cancer. Both cell cycle arrest and apoptosis occurred after treatment with PC-SPES. This suggests that the components of this herbal mixture, either independently or in combination, acted in colon cancer, resulting in a drastic effect on tumor initiation and tumor progression.
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PMID:PC-SPES inhibits colon cancer growth in vitro and in vivo. 1223 85

Nitric oxide (NO) is a small gaseous molecule involved in many physiological and pathophysiological processes in the human organism. Reports published so far indicate its multiple and not fully understood role in tumor initiation and progression. The paper reviews basic mechanisms of protumorigenic effects of NO: genotoxicity and mutagenicity, the results of the studies on nitric oxide synthases activity and expression in human tumors of different origin, as well as the main mechanisms of NO-mediated processes responsible for tumor progression (tumor cell growth, angiogenesis, invasiveness and metastatic activity). Because the effects of NO in cancer development are not clearly defined after the review of protumorigenic effects, some data, which indicate the antitumorigenic effects of NO are also presented.
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PMID:Roles of nitric oxide in carcinogenesis. Protumorigenic effects. 1246 49

Tumor formation is a multi-step process that can be divided into the stages of tumor initiation, promotion and progression. Previously, we showed that overexpression in skin of mice of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) protects against N-methyl-N-nitrosourea (MNU)-induced tumor initiation without affecting tumor promotion. This indicated that O(6)-methylguanine, which is specifically repaired by MGMT, is a major tumor-initiating lesion. Here we extended this transgenic approach to the study of tumor progression. Benign papillomas that arose on the skin of CkMGMT transgenic mice upon initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) expressed higher levels of MGMT than papillomas that appeared on DMBA/TPA treated non-transgenic NMRI mice. Treatment of papillomas with MNU resulted in the formation of malignant carcinomas to a significantly lower frequency in CkMGMT mice as compared with the non-transgenic control. The data provide evidence that increased DNA repair protects against the conversion of benign into malignant tumors. They show at the same time that a particular type of damage induced in DNA, namely O(6)-methylguanine, is decisively involved in triggering tumor progression. This supports the concept that the major cause of both tumor initiation and tumor progression is mutation. Data also indicate that alkylating anti-neoplastic drugs may provoke tumor progression in case of failure of tumor therapy, which is attenuated by DNA repair.
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PMID:DNA repair protein MGMT protects against N-methyl-N-nitrosourea-induced conversion of benign into malignant tumors. 1266 16

There is evidence that transforming growth factor (TGF)beta acts as a suppressor of tumor initiation but also as a promoter of tumor progression when the antiproliferative effect of the TGFbeta signaling pathway has been overridden by other oncogenic mutations. Several somatic mutations that disrupt the TGFbeta-SMAD signaling pathway have been reported in human breast tumors. We have examined the association between single nucleotide polymorphisms (SNPs) in the TGFbeta1 gene and the incidence of invasive breast cancer in three case-control series, with a maximum of 3987 patients and 3867 controls, median age approximately 50 years, and range 22-92 years. The promoter SNP, C-509T, and the T +29C signal-peptide SNP (encoding Leu10Pro) are in strong linkage disequilibrium. They are both significantly associated with increased incidence of invasive breast cancer in a recessive manner [odds ratios: (TT versus C-carrier), 1.25; 95% confidence intervals 1.06-1.48; P = 0.009 and (ProPro versus Leu-carrier), 1.21; 95% confidence intervals 1.05-1.37; P = 0.01]. The G-800A SNP was not significantly associated with incidence of breast cancer. The C-509T SNP is not contained within a known consensus sequence for a promoter regulatory element and therefore unlikely to affect TGFbeta1 expression, whereas the Leu10Pro signal peptide substitution potentially affects TGFbeta1 secretion. Transfections of HeLa cells with constructs encoding either the Pro or Leu forms of TGFbeta1 and driven by the cytomegalovirus promoter indicate that the signal peptide with Pro at residue 10 causes a 2.8-fold increase in secretion compared with the Leu form. These data indicate that the allele encoding Pro10 is associated with increased rates of TGFbeta1 secretion and with increased incidence of invasive breast cancer for the population samples described. It is estimated that 3% of all breast cancer cases may be attributable to Pro10 homozygosity.
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PMID:A transforming growth factorbeta1 signal peptide variant increases secretion in vitro and is associated with increased incidence of invasive breast cancer. 1275 Feb 87

Mutation and deletion of the p53 tumor suppressor gene are arguably the most prevalent among the multiple genetic alterations found in human bladder cancer, but these p53 defects are primarily associated with the advanced diseases, and their roles in bladder tumor initiation and in synergizing with oncogenes in tumor progression have yet to be defined. Using the mouse uroplakin II gene promoter, we have targeted into urothelium of transgenic mice a dominant-negative mutant of p53 that lacks the DNA-binding domain but retains the tetramerization domain. Urothelium-expressed p53 mutant binds to and stabilizes the endogenous wild-type p53, induces nuclear abnormality, hyperplasia and occasionally dysplasia, without eliciting frank carcinomas. Concurrent expression of the p53 mutant with an activated Ha-ras, the latter of which alone induces urothelial hyperplasia, fails to accelerate tumor formation. In contrast, the expression of the activated Ha-ras in the absence of p53, as accomplished by crossing the activated Ha-ras transgenic mice with the p53 knockout mice, results in early-onset bladder tumors that are either low-grade superficial papillary or high grade in nature. These results provide the first in vivo experimental evidence that p53 deficiency predisposes the urothelium to hyperproliferation, but is insufficient for bladder tumorigenesis; that the mere reduction of p53 dosage, as produced in transgenic mice expressing the dominant-negative p53 or in heterozygous p53 knockouts, is incapable of synergizing with Ha-ras to induce bladder tumors; and that the complete loss of p53 is a prerequisite for collaborating with activated Ha-ras to promote bladder tumorigenesis.
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PMID:p53 deficiency provokes urothelial proliferation and synergizes with activated Ha-ras in promoting urothelial tumorigenesis. 1473 3

The processes by which cancer cells leave the tumor and enter adjacent tissue is known as invasion, whereas metastasis refers to secondary tumor colonization of tissue at a distance from the primary lesion. These two events are the most lethal of cancer phenomena and the signaling mechanisms that govern them are complex. The Ras signaling pathways are well represented in their involvement in tumor initiation, but considerably less is known about their contribution to invasion and metastasis. In this review, we discuss the current evidence for mutant Ras proteins as significant players in these aspects of cancer progression.
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PMID:Oncogenic Ras and its role in tumor cell invasion and metastasis. 1501 94

The incidence and mortality rates of melanoma have increased at annual rates of 2%-3% for the last 30 years. Disseminated disease is largely refractory to cytotoxic chemotherapy and is almost universally fatal. Several recent advances in melanoma biology offer new strategies for potentially treating this aggressive malignancy. This review focuses on three significant advances involving tumor initiation, etiology, and progression. New experimental models reveal a direct role for UV-B light in initiating melanomas in human skin. Studies on E- and N-cadherin elucidate the importance of local homeostatic mechanisms in regulating tumor progression. Finally, several discoveries concerning apoptotic mechanisms in melanoma suggest strategies for future treatments.
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PMID:Recent advances in melanoma biology. 1504 22

A computational model of cancer progression is used to study how mutations in genes that control tumor initiation and progression accumulate in populations. The model assumes that cancer occurs only after a cell lineage has progressed through a series of stages. The greater the number of stages, the more strongly the individual is protected against cancer. It is shown that an extra stage initially improves the survival of individuals by decreasing mortality from cancer. However, the additional buffering by an extra stage reduces the impact of any single hereditary mutation and therefore allows the accumulation of more nonlethal mutations in the population. Extra stages thereby lead to the evolution of partially decreased cancer mortality and significantly increased genetic predisposition to disease in the population as a whole. In general, the model illustrates how all robust control networks allow the accumulation of deleterious mutations. An increase in the number of buffering components leads to significant mutational decay in the protection provided by each buffering component and increased genetic predisposition to disease. An extra buffering component's net contribution to survival and reproduction is often small.
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PMID:Genetic variation in cancer predisposition: mutational decay of a robust genetic control network. 1514 Oct 87

The development of noninvasive imaging technologies designed specifically for use with small animals has provided new paradigms for cancer research. Traditional molecular biology techniques are being melded with noninvasive imaging technologies to develop a new research domain, "molecular imaging." One of the most exciting advances in this research area is the adaptation and application of conventional reporter-gene imaging techniques, used extensively by cell and molecular biologists, to living animals. Using these new assays, investigators can image noninvasively, repeatedly, and quantitatively the location, magnitude, and duration of reporter-gene expression in living animals. This review will describe the instrumentation used for noninvasive imaging of reporter genes, the reporter genes developed for noninvasive imaging with radio-nuclide-based assays such as positron emission tomography, and the reporter genes used for optically based noninvasive assays using sensitive charged-coupled device cameras. Applications of noninvasive, whole-animal imaging to gene therapy for cancer, to cell-based therapy for cancer, to lymphocyte activation, to cancer progression and dissemination in engrafted models, to tumor initiation, promotion and metastasis in conditional murine models of cancer induction, and to the noninvasive monitoring of tumor responses to a variety of therapies are described. New developments in multimodality molecular imaging are discussed, and the potential utility of noninvasive reporter gene expression in the diagnosis and management of human cancer is presented.
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PMID:Noninvasive imaging of reporter gene expression in living subjects. 1553 May 56

Multiple experimental approaches have been employed to study exocrine pancreatic cancer, including the use of animals as surrogates for the human disease. Animals have the advantage that they can be manipulated to address specific hypotheses regarding mechanisms underlying this disease. Implicit in this opportunity is the necessity to match the question being asked with an appropriate animal model. Several approaches to modeling pancreatic cancer have been established that involve animals. First, xenogeneic cell transplantation, generally into immunocompromised rodent subcutis or pancreas, allows examination of (1) the effect of host environment on human or rodent pancreatic cancer cells, (2) whether specific genetic changes in donor cells correlate with certain cancer cell behaviors, and (3) novel approaches to cancer therapy or imaging of tumor growth. Second, carcinogen administration, typically to hamster or rat, allows examination of whether specific genetic, biochemical, cellular, and tissue phenotypic changes, including progression to neoplasia, accompany exposure to a particular chemical. Third, genetically engineered animals, usually transgenic or gene targeted mice, allow examination of (1) whether genetic changes, including oncogene overexpression/mutation or tumor suppressor gene loss, can increase the risk for neoplastic progression, (2) whether specific genetic changes can cooperate during pancreatic carcinogenesis, and (3) how the genetic signature of a neoplasm correlates with particular biological aspects of tumor initiation and progression. Collectively, these experimental approaches permit detailed exploration of pancreatic cancer genetics and biology in the whole animal context, thereby mimicking the environment in which human disease occurs.
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PMID:Modeling pancreatic cancer in animals to address specific hypotheses. 1554 10


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