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)

Papillomas induced by DMBA initiation-TPA promotion protocols are necessary precursor lesions of squamous cell carcinomas. The papillomas are heterogeneous in their potential for progression to carcinomas, a property apparently induced at the time of initiation. The probability of conversion to malignancy is highest for the papillomas most easily promoted, by either the first few TPA treatments or by "weak" promoters such as mezerein or chrysarobin. The conversion frequency is lowest for TPA-dependent papillomas and those papillomas which appear late in a TPA promotion protocol. The spontaneous rate of malignant conversion is not altered by continued TPA treatment; TPA promotion may simply expand clones of initiated cells which are already programmed with a given probability of conversion. Treatment of papilloma-bearing mice with a genotoxic agent, such as 4-NQO, urethane or cisplatin, increases the rate of malignant conversion. The properties of active converting agents differ markedly from those of the phorbol ester promoting agents, suggesting differences in the mechanisms of action of these two classes of compounds. A genetic mechanism appears likely to explain conversion. The differences between the two stages are further emphasized by the finding that inhibitors of tumor promotion are not inhibitory when given during malignant conversion. The converting agent urethane also affects the subsequent discrete stage in tumor progression, tumor metastasis. Differences in metastatic potential have been found between carcinomas which progress spontaneously after TPA promotion and carcinomas induced in TPA-promoted papillomas by urethane. The multistage nature of experimental epidermal carcinogenesis is well established. The mouse skin model will continue to be valuable for mechanistic studies since similar stages have been described in other tissues as well as in man.
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PMID:Malignant conversion, the first stage in progression, is distinct from phorbol ester promotion in mouse skin. 181 91

Sialyl Le(X)-i (Sialyl SSEA-1, SLX) is one of the type 2 chain carbohydrate antigens, which is defined by a monoclonal antibody FH-6. The clinical usefulness of the measurement of serum Sialyl LeX-i levels in the follow-up study of outpatient with ovarian cancer was examined for the early detection of recurrence as the serodiagnostic test. Elevated serum Sialy Le(X)-i levels (more than 38 unit/ml) were observed before treatment in 7 of 12 patients with a good prognosis (group A) and in 15 of 26 patients with a poor prognosis (group B). Six (85.7%) in 7 patients with elevated serum Sialyl Le(X)-i levels in group A decreased to the normal range after treatment, whereas 3 (20.0%) in 15 patients with positive serum Sialyl Le(X)-i levels in group B decreased below 38 unit/ml a after treatment. In 9 (34.6%) in group B, elevated serum Sialyl Le(X)-i levels were observed with an average 3.1 weeks before clinical evidence of recurrence. With tumor progression, serum Sialyl Le(X)-i levels also rose in 25 (96.2%) in group B. In 4 (15.4%) in group B, serum Sialyl Le(X)-i levels were a useful tumor marker compared with others including CA 125, TPA, and CEA. Consequently, the measurement of serum Sialyl Le(X)-i levels may be useful to monitor the condition of the disease, presume progression, and detect recurrence early in outpatients with ovarian cancer.
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PMID:[Clinical usefulness of serum sialyl Le(x)-i measurement in patients with ovarian cancer]. 256 10

We examined the effects of initiation with different doses of 7,12-dimethylbenz[a]anthracene (DMBA) on two-stage skin carcinogenesis in BALB/c mice. The induction of skin papillomas and their sequential tumor progression were followed by determination of locations of the tumors on the back of each mouse, by histological evaluation and by determining the phosphoglycerate kinase (PGK) phenotypes of neoplasms. Three doses of DMBA were tested, 20.0, 2.0 and 0.2 micrograms. Lowering the dose of DMBA initiation prolonged tumor latency and reduced tumor susceptibility and frequency. All of the papillomas that developed with the lowest dose of DMBA initiation were found to be clonal by PGK analysis and each of them was promoter dependent; termination of TPA promotion led to its regression. The 0.2-micrograms DMBA initiation dose also reduced to zero the delayed promoter-independent papillomas and the frequency of papillomas changing their PGK phenotype during tumor progression. Thus, these studies provide evidence that the carcinogen not only causes initiation in mouse skin epidermal cells but also that the dose of carcinogen strongly influences the mode of growth of the initiated cells to papillomas and the progression of these tumors.
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PMID:Influence of dose of initiator on two-stage skin carcinogenesis in BALB/c mice with cellular mosaicism. 313 Feb 3

The effects of the tumor promoter -12-O-tetradecanoyl phorbol-13-acetate, its analogues, and other tumor promoters, on the proliferation of human skin fibroblasts (SF) have been investigated. We have previously shown (Kopelovich and Bias, 1979), that TPA caused a biphasic (upward concave) dose effect in the cloning efficiency assay of normal and mutant human fibroblastic cell strains. Here we report that the biphasic dose response pattern, consisting of an inhibitory phase and a stimulatory phase, was shared by the active analogues of TPA, e.g., phorbol-12,13-dibutyrate and phorbol-12,13-dibenzoate. This biphasic dose effect relationship, however, was not seen with phorbol-12,13-diacetate or the inactive analogues of TPA such as phorbol and 4-O-methyl-12-O-tetradecanoyl phorbol-13-acetate, nor was it seen with mezerein, teleocidin, or bile-acid derivatives of humans. An analysis of the cloning efficiency data by the median-effect equation (Chou and Talalay, 1981) showed that in low-density cultures both the inhibitory phase and the stimulatory phase of the dose-effect relationships of TPA, its analogues, mezerein, and teleocidin exhibited a linear median-effect plot and thus closely followed the basic mass-action principle. The median-effect plot of these data allowed quantitative determination of growth curve characteristic such as regression coefficient, slope (a measure of sigmoidicity), median-effect concentrations such as I50 for the inhibitory effect, and A50 for the stimulatory effect (i.e., the relative potency of the analogues) and the transition point of the biphasic phenomenon in the case of the phorbol esters. In addition, we have demonstrated a relationship between the dose response effect of TPA on the proliferation of various human cells and tumor progression in vitro.
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PMID:The proliferative response of low-density human cell cultures to tumor promoters and its relevance to carcinogenic mechanisms in vitro. 643 50

Blood tissue polypeptide specific antigen (TPS) concentration was serially measured by IRMA radioimmunodetective procedure in hormonally treated prostate cancer patients with Stage Do-D1 tumor (20 subjects free of bone lesions) and Stage D2 disease (20 subjects with bone metastases). Monoclonal antibody against the principle M3-TPA epitope was used in this TPS assay. Serum TPS values were compared with respective blood prostate specific antigen (PSA), prostatic acid phosphatase (PAP), carcinoembryonic antigen (CEA) and testosterone levels in a retrospective manner. A control group included healthy men, patients with benign prostatic hypertrophy (BPH), subjects with inflammation of the prostate, and men with diabetes. PSA is reported to be a quantitative calibration for prostate cancer load in untreated patients, especially during early stages of the disease. In hormonally treated, advanced, and dedifferentiated prostatic carcinoma this serotest fails to reflect properly both tumor status and response to treatment. In Stage Do-D1 patients TPS concentrations remain normal or become slightly elevated even during local tumor progression. This finding is in accord with the slow proliferation of nonaggressive primary tumors. Circulating TPS concentrations are elevated in progressive metastatic patients, in the majority of Stage D2 subjects with stable disease and even in some of these patients during partial tumor remission. This latter result may be attributed not only to the heterogeneity of the advanced prostatic cancer but also to the actual tumor response to treatment, since serum PSA level fails to reflect properly the outcome of hormonal treatment. There is some evidence that an abrupt elevation in serum TPA level in such patients is a consequence of NK cell-mediated lysis of circulating tumor cells, thus giving rise to a simultaneous and rapid delivery of intracellular TPS into the bloodstream. Prostatic inflammation elevates TPS concentrations only slightly, while diabetes, even during a proper treatment, raises TPS concentration more intensely. In patients with BPH normal or slightly increased TPS values were measured. The results ot these preliminary investigations seem to open the way for further prospective studies.
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PMID:Serial measurements of tissue polypeptide specific antigen (TPS), PSA, PAP and CEA serotest values in treated patients with primary and metastatic prostate cancer. 768 62

Transforming growth factor (TGF)-beta 1, whose gene is located on mouse chromosome 7, has been proposed to be involved in skin carcinogenesis. In the study presented here, we demonstrated that single topical treatments with different types of tumor promoters, i.e., the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate (TPA, 2 micrograms); the non-protein kinase C activators anthralin (22.6 micrograms), benzoyl peroxide (20 mg), and cumene hydroperoxide (1.2 mg); the first-stage tumor promoters 4-O-methyl-TPA (500 micrograms) and A23187 (166 micrograms); and the second-stage tumor promoter mezerein (2 micrograms) produced transient induction of TGF-beta 1 mRNA in SSIN (inbred SENCAR) mouse skin. The time of maximum induction varied from 3 to 12 h; the relative extent of induction was ranked as cumene hydroperoxide > benzoyl peroxide > anthralin > TPA > 4-O-methyl-TPA > mezerein > A23187. These findings suggested that TGF-beta 1 mRNA induction is a common response of skin to several types of complete and stage-specific promoters; however, the extent of induction did not correlate with the reported hyperplastic activity of single applications of these promoters. We also demonstrated that TGF-beta 1 mRNA expression in papillomas of SENCAR mice generally correlated with expression levels of cyclin D1, another gene on chromosome 7, and with stage of tumor progression. TGF-beta 1 mRNA expression was constitutively elevated in most squamous cell carcinomas from either initiation-promotion or complete carcinogenesis protocols. Cell lines established from carcinomas also overexpressed TGF-beta 1 mRNA. Immunohistochemical staining of tissue sections of normal and TPA-treated skin revealed the presence of extracellular TGF-beta 1 protein in the dermis and intracellular TGF-beta 1 protein in the epidermis, especially in the suprabasal layers. The staining patterns of papillomas varied, with 62 +/- 13% of the tissue showing strong intracellular staining but only 25 +/- 8% of the connective tissue staining for extracellular TGF-beta 1. Variable staining patterns were also found in carcinomas; some areas stained heavily for both the intracellular and extracellular forms of TGF-beta 1. Overall, 28 +/- 6% of the tissue of the 12 analyzed carcinomas stained for the intracellular form and 18 +/- 5% for the extracellular form of TGF-beta 1.
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PMID:Altered expression of transforming growth factor-beta 1 mRNA and protein in mouse skin carcinogenesis. 814 55

Tissue polypeptide antigen is a differentiation and proliferation marker of non-squamous epithelium and derived neoplasms. No reliable tumor markers are available for bladder cancer. The value of tissue polypeptide antigen was therefore prospectively investigated. The serum tissue polypeptide antigen samples were obtained from 144 newly diagnosed transitional cell carcinoma patients and from 92 patients that were followed after treatment. The normal cut off value was defined at 95 units per liter. Nearly all TaT1 patients had normal TPA values, and 80% of the muscle invasive cancers had normal TPA levels. In those patients where TPA was elevated before treatment its monitoring proved to be a reliable predictor of tumor progression. Tissue polypeptide antigen is a useful marker not for the early detection of bladder cancer but for the monitoring of the efficacy of a treatment.
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PMID:Serum tissue polypeptide antigen (TPA) as tumor marker for bladder cancer. 869 44

A point mutation in PKCalpha was originally discovered in a subpopulation of human pituitary tumors characterized by their invasive phenotype, and the same mutation was also seen in some thyroid neoplasms. To investigate the role of this mutation in tumorigenesis, normal and mutant human PKCalpha cDNAs were overexpressed in Rat6 embryo fibroblasts (R6). When extracts of R6 cells that expressed either the normal or mutant PKCalpha were assayed in the presence of calcium, phosphatidylserine and the phorbol ester TPA, for phosphorylation of either histone IIIS or the EGF-receptor peptide, both extracts gave similar results. However, the subcellular localization of the two proteins differed. Immunohistochemistry studies indicated that after treatment with TPA normal PKCalpha mainly translocated to the plasma membrane, but mutant PKCalpha translocated mainly to the perinuclear region and slightly to the nucleus. Furthermore, the cells that expressed the mutant PKCalpha displayed a decreased requirement for serum when compared to the cells expressing the normal human PKCalpha, and they formed small colonies in soft agar. By contrast, the cells expressing the normal human PKCalpha failed to form colonies in soft-agar. Thus, ectopic expression in rat fibroblasts of this mutant human PKCalpha sequence alters the growth properties of these cells and, when activated, the mutant PKCalpha displays aberrant intracellular translocation. Therefore, this mutation in PKCalpha could contribute to the process of tumor progression in certain human tumors.
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PMID:Ectopic expression of a mutant form of PKCalpha originally found in human tumors: aberrant subcellular translocation and effects on growth control. 903 75

Increased protein kinase C (PKC) activity in malignant breast tissue and in most aggressive breast cancer cell lines has suggested a possible role of PKC in breast carcinogenesis and tumor progression. We have investigated here the involvement of PKC in the in vitro invasiveness and motility of several breast cancer cell lines. Modulation of PKC activity by treatment with a phorbol ester (TPA), drastically increased the invasiveness of 2 estrogen receptor-positive (ER+) lines (MCF7 and ZR 75.1), whereas it markedly decreased the invasiveness of 2 ER- cell lines (MDA-MB-231 and MDA-MB-435). A PKC inhibitor (H7) reversed the TPA effects in MCF7 cells, whereas it mimicked TPA action in MDA-MB-231 cells. All of these effects of TPA also were observed to a similar extent for cell chemotaxis, and they were not dependent on protein neo-synthesis. In parallel, short TPA treatment induced cell spreading and microtubule organization in MCF7 cells and inverse morphological changes in MDA-MB-231 cells. In ER+ cells, constitutive PKC activity and PKCalpha expression were very low as compared to ER- cells, and this correlated with the invasive potential of the cells. The opposed effects of TPA in ER+ and ER- cells could be due to the abnormal TPA regulation of PKCalpha observed in ER- cells.
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PMID:Breast cancer cell invasiveness: correlation with protein kinase C activity and differential regulation by phorbol ester in estrogen receptor-positive and -negative cells. 949 44

AP-1 transactivation appears to be required for mouse JB6 cell neoplastic transformation induced by the tumor promoter TPA or epidermal growth factor (EGF). Exposure to AP-1 transrepressing retinoids and glucocorticoids and expression of a dominant negative c-jun (TAM67) blocked tumor promoter-induced AP-1 transactivation and neoplastic transformation. The aim of the present study was to extend the inquiry of the role of AP-1 and other transcription factors to human neoplastic progression. Expression of human papillomavirus (HPV) 16 or 18 E6 and E7 immortalizes human keratinocytes and inhibits serum/calcium-stimulated differentiation. Further transformation by v-fos co-expression renders these keratinocytes tumorigenic in nude mice. We have analysed two series of E6/E7 immortalized human keratinocyte cell lines that show progressing phenotypes ranging from differentiation sensitive to anchorage-independent to tumorigenic in nude mice. We analysed the activities of AP-1 and NF-kappaB which may 'cross-talk'. Both DNA binding and transactivation of AP-1 and NF-kappaB transcription factors showed elevation in the anchorage-independent (16RH) and tumorigenic (18 v-fos) keratinocyte lines compared to the less progressed but immortalized cell lines. HPV E7 was expressed at a constant level shown by quantitative RT-PCR in both the more and the less progressed lines, indicating that E7 is not the factor limiting this progression. Blocked shift/supershift analysis indicates that Fos family member proteins especially Fra-1 and Fra-2 are related to progression and no changes found in the Jun family member proteins although they are present in the AP-1/DNA binding complex. When a dominant negative mutant c-jun driven by a human keratin 14 promoter was co-transfected with AP-1 or NF-kappaB reporters, both AP-1 and NF-kappaB activities were suppressed in the more progressed cell lines 16RH and 18 v-fos but not in the less progressed 16RL or 18 cell lines. Overexpression of the same dominant negative c-jun did not inhibit p53 dependent reporter transactivation, indicating the specificity of inhibition of AP-1 and NF-kappaB transactivation in the HPV-immortalized cells. Stable transfectants of this mutant c-jun in the two more progressed cell lines 16RH and 18 v-fos showed reduced AP-1 and NF-kappaB activation and reduced anchorage-independent growth. Together, these results indicate that activation of AP-1, NF-kappaB or both may contribute to neoplastic progression in HPV immortalized human keratinocytes and that specific targeting of the elevated levels seen in benign or malignant tumors might be effective for prevention or treatment of human cancer.
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PMID:Expression of dominant negative Jun inhibits elevated AP-1 and NF-kappaB transactivation and suppresses anchorage independent growth of HPV immortalized human keratinocytes. 965 37


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