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)

We used an octapeptide analogue of somatostatin, SMS 201-995, in dosages ranging from 150 to 450 micrograms/d administered subcutaneously in three daily doses for 1 to 16 months, to treat 22 patients with advanced malignant islet cell carcinomas. Of the 22 patients, there were 9 with gastrinomas; 3 with glucagonomas; 4 with insulinomas; 1 with ectopic production of parathyroid hormone; and 3 with mixed syndromes. The only biochemical marker in 1 patient was pancreatic polypeptide, and 1 patient had no demonstrable peptide production from the tumor. In 14 patients, dramatic decreases in the levels of circulating peptides (insulin, vasoactive intestinal polypeptide, gastrin, and glucagon) have been accompanied by major alleviations of symptoms. Steatorrhea appears to be the most significant toxicity. This analogue of somatostatin may be appropriate for use as early therapy in patients who have symptoms from syndromes related to islet cell carcinomas but in whom there is no immediate threat from tumor progression.
 ...
PMID:Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201-995). 288 85

Because of the broad clinical interest which tissue polypeptide antigen (TPA) has attracted as a tumor marker, human cell lines and human tissues have been analyzed for TPA expression using immunofluorescence microscopy. Epithelial cell lines including HeLa, MCF-7, and A-431 are recognized by TPA antibodies whereas human lines of non-epithelial origin are not. The positive staining patterns coincide with keratin-type intermediate filaments of the cytoskeleton. On tissue sections a subset of epithelial cells including uterine epithelium, bile duct cells in liver and tumor cells in breast carcinoma are strongly positive; cells of the squamous epithelia of skin and tongue as well as cells of non-epithelial origin are negative. In immunoblots of human epidermis, human tongue mucosa, human hair follicles, Detroit 562 cells, HeLa cells, MCF-7 and RT-4 cells, only keratins 8, 18 and 19 show TPA antigenicity. Conversely a TPA preparation is recognized by various antibodies known to react with keratins, including alpha-IFA, KG 8.13.2 and two antibodies which recognize keratins 18 (CK2) and 19, respectively. Our results thus relate TPA to human keratins 8, 18 and 19 which are known cytoskeletal components in both normal and malignant epithelial cells of simple and non-squamous origin. We speculate that the elevated levels of circulating TPA antigenicity present in the sera of patients with carcinoma, which are often used to monitor tumor progression, correspond to soluble proteolytic fragments originating from this particular keratin subgroup.
 ...
PMID:Tissue polypeptide antigen (TPA) is related to the non-epidermal keratins 8, 18 and 19 typical of simple and non-squamous epithelia: re-evaluation of a human tumor marker. 621 Jan 99

Bone scans, serum tissue-specific polypeptide antigen (TPS), prostate specific antigen (PSA), and neuron-specific enolase (NSE) were assessed in a total of 80 hormonally treated prostate cancer patients. Thirty-nine patients were free of osseous lesions; in 8 subjects, 3 or fewer scintigraphic hot spots were found; in 29 patients, more than 3 bone lesions were recorded. In 3 patients, a partial contribution of endocrine cell cancer structures was found, while in one patient, a homogeneous small cell carcinoma was detected at autopsy. Measurement of the serum PSA test showed a clear-cut rise from stage D0 subjects to stage D2 patients, with a small number of bone lesions (> or = 3). However, a relative decrease in the mean PSA level was measured with further progression in a number of hot spots in bone (> 3). Androgen threshold that is critical for the induction of the PSA (and PAP) expression seems to differ markedly in various cell subpopulations that arise during adenocarcinoma dedifferentiation. This fact explains not only the rise in serum PSA in the majority of progressive and previously castrated subjects after an initial period of hormonal responsiveness, but also a relative decline of androgen-dependent PSA expression with further tumor progression. Localized disease was accompanied with normal or just slightly elevated TPS concentration. In metastatic tumors, serum TPS values revealed a steady increase with the progression in bone. These data seem to reflect not only an increase in tumor proliferation rate with progressively transformed genome, but also the rise in the number of proliferating cells. The presence of nonepithelial transformed tumor structures, such as small cell cancer within a bulk of adenocarcinoma, reduces or normalizes numerical serotests values of both TPS and PSA even during tumor progression. The extent of such decline depends upon the bulk of the endocrine component. The assessment of the above parameters, especially when associated with elevated plasma NSE concentrations, may help in distinguishing an advanced adenocarcinoma with and without elements of malignant neuroendocrine structures. The proposed approach, modified by applying corresponding organ-specific markers, may be checked for its possible general use in staging protocols of various heterogeneous tumors.
 ...
PMID:A more objective staging of advanced prostate cancer--routine recognition of malignant endocrine structures: the assessment of serum TPS, PSA, and NSE values. 750 85

Tissue polypeptide specific antigen (TPS) is a new tumor proliferation serotest marker. The respective radioimmunodetective procedure is based on the application of monoclonal antibodies raised against one the principle epitopes of tissue polypeptide antigen (TPA). TPS is useful tool for the identification of proliferative epithelial cells and is negative in all non-epithelial tissues such as lymph nodes, bone marrow, carcino-sarcomic and neuroendocrine prostatic tumors. In previous studies we have shown the clinical usefulness of this serotest in serial measurements during prostate cancer monitoring. In this study serum prostatic specific antigen (PSA) concentrations and natural killer (NK) cell activity data were compared with serum TPS values in a wide spectrum of prostate cancer condition (99 patients), benign prostatic hypertrophy (BPH, 40 patients), atypical prostate (12 subjects) and in 8 healthy men. Measured parameters reflect different aspects of the disease. Blood PSA concentrations and TPS serotest values were found to denote the status of disseminated prostate cancer with nearly equal significance, while PSA appears to be a more appropriate tumor marker in early stages of the disease. In atypical prostate a nonsignificant elevation of both PSA and TPA values were recorded when compared with BPH. In parallel, a pronounced and sharp drop in NK activity data was assessed resembling closely respective data in progressive Stage D2 patients. TPS serotest clearly detects cancer progression in treated and untreated patients (P < 0.01) while being less efficient in distinguishing between tumor stabilization and partial remission (p > 0.05). In this respect NK activity data serve as a sensitive probe for the presence of epithelial tumor cells in the circulation even during stabilization of the disease. According to the reported results we advocate the application of the TPS serotest as a useful addition in monitoring progressive patients with advanced prostatic carcinoma.
 ...
PMID:Correlation of cell proliferation marker (TPS), natural killer (NK) activity and tumor load serotest (PSA) in untreated and treated prostatic tumors. 768

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.
 ...
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 beta 1 (TGF-beta 1) regulates a multitude of diverse biological functions in mammalian cells, and there is good evidence that aberrant expression of this growth factor can play an important role in mechanisms of malignant progression. We show that a TGF-beta 1-overexpressing mouse 10T1/2 cell line transfected with a TGF-beta 1 sequence that allows the synthesis of bioactive growth factor exhibits reduced sensitivity to the cytotoxic effects of the drug N-(phosphonacetyl)-L-aspartate (PALA) in colony-forming experiments. Furthermore, six independent 10T1/2 TGF-beta 1-transfected cell lines containing TGF-beta 1 gene expression under the control of a zinc sulfate-responsive metallothionein promoter were selected. In all cases, sensitivity to PALA cytotoxic effects was significantly reduced when cells were cultured under conditions that led to elevated levels of TGF-beta 1 gene expression when compared to cells containing basal levels of this growth factor. Fluctuation analysis to determine the rate of PALA resistance was performed with several TGF-beta 1-transfected cell lines in which growth factor expression was regulated by the metallothionein promoter. We observed significantly higher rates of PALA resistance/cell/generation in cell populations expressing high levels of TGF-beta 1 than in the same cells expressing relatively low levels of this growth factor. The only mechanism known for PALA resistance in mouse cells involves the amplification of the gene coding for the protein target of PALA, CAD, a multifunctional polypeptide containing carbamyl phosphate synthetase, aspartate transcarbamylase, and dihydroorotase. Southern blot analysis of colonies that survived normally cytotoxic concentrations of PALA exhibited CAD gene amplification. In total, these observations indicate that aberrant expression of TGF-beta 1 gene expression decreases the genetic stability of 10T1/2 cells, leading to increased rates of drug resistance and elevated gene amplification potential. The results of this study indicate a new malignancy related function for TGF-beta 1 alterations and suggest a novel role for aberrant expression of this growth factor in mechanisms of drug resistance and tumor progression.
 ...
PMID:Drug resistance and gene amplification potential regulated by transforming growth factor beta 1 gene expression. 771 85

The growth and metastasis of solid tumors rely on the activities of polypeptide growth factors. However, numerous growth factors are expressed in tumors, and it is difficult to decipher which are essential for tumor progression. We found the secreted growth factor pleiotrophin (PTN) expressed at high levels in a number of human tumor cell lines as well as in tumor samples. To assess the role of PTN in tumor growth, we inactivated the PTN gene with PTN-targeted hammerhead ribozyme constructs. Cotransfection of PTN and of the ribozymes inhibited PTN-induced colony formation of PTN-responsive cells whereas a point mutant, catalytically inactive ribozyme was ineffective. Colony formation induced by transfections with a closely related growth factor (midkine) was not affected by the ribozymes. In human melanoma cells that express high levels of PTN mRNA, stable transfection with PTN-targeted ribozymes quenched production of PTN, inhibited colony formation of the cells, and prevented their tumor growth in mice. This demonstrates that expression of a growth factor can be a rate-limiting step for malignant progression and suggests that ribozymes could be used therapeutically to target tumor growth factors.
 ...
PMID:Ribozyme-targeting elucidates a direct role of pleiotrophin in tumor growth. 806 62

Ascites sublines of the highly metastatic 13762 rat mammary adenocarcinoma contain abundant amounts of a heterodimeric cell surface glycoprotein complex composed of a mucin subunit ASGP-1 (ascites sialoglycoprotein-1) and a transmembrane subunit (ASGP-2). Previous studies showed that the complex is synthesized from a single polypeptide encoded by a 9 kb transcript. The sequence of the transmembrane subunit was obtained from a 5-kilobase (kb) cDNA isolated from a plasmid library (Sheng, Z., Wu, K., Carraway, K. L., and Fregien, N. (1992) J. Biol. Chem. 267, 16341-16346). Completion of the sequence of this cDNA revealed the C-terminal domain of ASGP-1, which is rich in serine and threonine but contains no typical mucin-type repeats. The remainder of the sequence of ASGP-1 and the 9-kb transcript was obtained by two 5'-RACE (rapid amplification of cDNA ends) steps and primer extension analysis. These results revealed that the 5' half of the 9-kb transcript contains a short 5'-noncoding region and encodes a signal sequence, a short nonrepeat region, and a repeat domain containing 11 repeats. Nine of these repeats are found in tandem, but the two end repeats are separated from the others by short unique sequences. The repeats vary from 117-124 amino acids and are 70-90% identical to a consensus sequence. Overall, the sequence predicts that ASGP-1 contains 2172 amino acids (M(r) 224,190), 43% of which are serine and threonine. We propose that the complex of this mucin and its transmembrane subunit, which contains growth factor-modulating activity, may play an important role in tumor progression.
 ...
PMID:Molecular cloning and sequencing of the mucin subunit of a heterodimeric, bifunctional cell surface glycoprotein complex of ascites rat mammary adenocarcinoma cells. 816 96

The role of balance of negative and positive autocrine growth factors in malignant progression is reviewed with an emphasis on transforming growth factor alpha (TGF-alpha) as a stimulating factor and transforming growth factor beta (TGF-beta) as an inhibiting factor. Evidence suggests that in normal cells TGF-alpha is down regulated in non-dividing or quiescent states in vitro. Tumor cells which have early stage characteristics as represented by poor clonal growth and poor tumorigenicity in athymic mice also show repression of TGF-alpha in non-dividing states. Progression of this phenotype is induced by uncontrolled low level expression of TGF-alpha by transfection with a constitutive expression vector for the polypeptide. Transfection of the unprogressed phenotype with a constitutive anti-sense vector for TGF-beta, also leads to tumor progression by repressing the autocrine negative TGF-beta activity normally expressed by these cells. Both the upregulation of TGF-alpha and the repression of TGF-beta generated in vivo progression without changing growth rates in vitro. Instead, clonality and ability to reenter the cell cycle from quiescence were increased. Thus, it is concluded that an autocrine balance of positive and negative factors is important for maintaining controlled re-entry into dividing states from non-dividing states and that disruption of this balance leads to malignant progression characterized by greater independence of the malignant cells from the control of exogenous growth factors.
 ...
PMID:Growth factor balance and tumor progression. 820 95

Polypeptide growth factors are a diverse group of biological regulators. Because they are fundamentally involved in the cellular processes that are important for transformation and progression to malignancy, alterations in growth factor control and in their signal pathways are often observed in tumor cells. In this review, we consider the participation of growth factors and the mechanisms by which they effect tumor progression, using as examples members of the transforming growth factor beta (TGF-beta) and fibroblast growth factor (FGF) families. We explore the hypothesis that although abrogation of TGF-beta negative growth regulation is necessary for transformation, in the later stages of tumor progression, TGF-beta plays a direct role in the enhancement of invasion and metastasis as an autocrine stimulator of these processes. In addition, we present evidence that demonstrates both the potential and the importance of members of the FGF family in transformation and induction of metastasis. Several models of growth factor regulation of malignancy are presented in which we demonstrate (1) a link between TGF-beta 1 mitogenic stimulation of malignant cells and alterations in the expression of ribonucleotide reductase, a key rate-limiting step in the synthesis of DNA and in cell proliferation; (2) autocrine and/or intracrine FGF mitogenic stimulation of malignant cell proliferation and metastasis; and (3) autocrine TGF-beta regulation of malignant cell locomotion and invasion through elevated proteolytic activity and increased synthesis of hyaluronan and RHAMM, a novel hyaluronan cell surface receptor.
 ...
PMID:Transforming growth factor beta and fibroblast growth factor as promoters of tumor progression to malignancy. 824 21


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>