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At least 127 records · Page 7Linked to original sources
PubMed1991

Synergistic inhibition of phorbol ester-induced transformation of JB6 cells by transforming growth factor-beta and retinoic acid.

Transforming growth factor-beta (TGF-beta) plays a complex role as a regulator of proliferation and differentiation of many cell types, including cells of epithelial origin. In this study, we examined whether TGF-beta, alone or in combination with retinoic acid, was able to inhibit the transformation of the murine epidermal cell line JB6. When treated with phorbol myristate acetate (PMA) and other tumor promoters, the nontumorigenic and anchorage-dependent JB6 cells acquired a tumor phenotype, as shown by the acquisition of tumorigenicity and anchorage independence. We found that TGB-beta inhibited the PMA-induced transformation of a subclone of JB6 cells. The effect of TGF-beta was due to an anti-transformation promoting activity, rather than to generalized growth inhibition, since TGF-beta neither inhibited the growth of monolayer cultures of JB6 cells, nor affected the colony-forming efficiency in agar of the JB6-derived permanently transformed RT101 cell line. TGF-beta was synergistic with retinoic acid, a known anti-tumor promoter, in inhibiting the PMA-induced transformation of JB6 cells. Examination of TGF-beta receptor expression on JB6 cells, by both binding and affinity labeling, showed that treatment with PMA significantly decreased TGF-beta receptor expression while retinoic acid counteracted this effect of PMA, thus suggesting that the synergy between retinoic acid and TGF-beta may be due, at least in part, to modulation of TGF-beta receptor expression. TGF-beta, therefore, appears to function as an incomplete antipromoter whose action can be permitted and/or complemented by retinoic acid. Our data demonstrating that TGF-beta has anti-transformation promoting activity suggest that TGF-beta plays a role in maintaining homeostasis of epithelial cells, not only by regulating cell proliferation and differentiation, but also by counteracting events that lead to malignant transformation.

Animals↗
PubMed1987

Production of transforming growth factors by simian sarcoma virus-transformed cells.

Cellular transformation of normal rat kidney (NRK) cells by simian sarcoma virus (SSV) results in a complete loss of the cellular requirement of externally added polypeptide growth factors for proliferation. Moreover, SSV-transformed NRK cells have a strongly reduced ability to bind both external platelet-derived growth factor and epidermal growth factor, when compared to nontransformed NRK cells. Analysis of serum-free medium conditioned by SSV-transformed NRK cells shows that this cell line secretes both types alpha and beta transforming growth factor (TGF). The level of TGF alpha production (300 ng/liter conditioned medium) by SSV-transformed NRK is among the highest described to date. Since addition of TGF alpha and beta in combination is sufficient to induce phenotypic transformation of NRK cells, it is concluded that although expression of the sis oncogene is essential for transformation, expression of additional genes may be required for the phenotypic alterations accompanying complete cellular transformation.

Animals↗
PubMed1961

Studies on transformations of Hemophilus influenzae. IV. Linked and unlinked transformations.

Unlinked transformations were demonstrated to occur by varying the multiplicity of DNA molecules taken up by competent cells. The number of doubles was directly proportional to the product of the frequency of singles for varying concentrations of cells. The kinetics of transformation to doubles and the effect of DNA concentration on double transformations were consistent with the concept that the cell must take up two molecules of DNA in order to be doubly transformed. Linked markers, on the other hand, were a constant fraction of the single transformation for variations in DNA or cell concentration, or time. The kinetics of transformation of linked markers was the same as for the kinetics of single transforming factors. It was, therefore, concluded that linked transformations involve interaction between the cell and a molecule of DNA carrying both markers. The frequency of transformation was found to be the same from resistance to sensitivity as from sensitivity to resistance for the markers streptomycin (S) and cathomycin (C). Purified DNAs, in general, show lower levels of linkage than crude DNA preparations, and for some crude preparations all the S markers were linked to C, suggesting that some dispersion, at least, was a result of DNA preparation. The inactivation of linked markers by heat, ultraviolet, and DNAase was studied.

DNA↗
PubMed1984

Reversibility of the transformed and neoplastic phenotype. IV. Effects of long-term interferon treatment of C3H/10T1/2 cells transformed by methylcholanthrene and SV40 virus.

The effects of long-term treatment with mouse interferon on the phenotype of untransformed C3H/10T1/2 cells and cloned derivatives transformed by methylcholanthrene (MCA) and Simian virus 40 (SV40) were investigated. Continuous presence of interferon induced morphologic reversion, with the development of thick, submembranous filaments in MCA-transformed cells, whereas no morphological effects were detected in SV40-transformed cells. Interferon inhibited the proliferation of all three cell lines and maintained low saturation densities. However, prolonged treatment of MCA-transformed cells with interferon rendered them tolerant toward the anti-proliferative and antiviral activities of interferon although 2-A synthetase activity was induced. Interferon treatment reduced the capacity of both MCA and SV40-transformed cells to form colonies in agar and decreased the tumorigenicity of MCA-transformed but not SV40-transformed cells in mice. These results indicate that the same cell type transformed by different means has different sensitivities to a number of interferon-induced changes in the cell phenotype.

Animals↗
PubMed1986

Monoclonal antibody detection of transformation associated protein (TAP) in ts110 Moloney murine sarcoma virus transformed 6M2 cells that are different from the mos gene product.

By the use of a highly specific monoclonal antibody (designated MC), we were able to detect three radiolabeled bands with molecular weights of 60,000, 63,000, and 66,000 daltons in the ts-110 Moloney murine sarcoma virus mutant-transformed rat kidney cells known as 6M2. Expression of transformation properties as well as these three bands in 6M2 cells was found to be temperature sensitive. Therefore, MC detected factors that are apparently associated with the transformation of 6M2 cells. These factors are tentatively referred to as transformation associated proteins. These transformation proteins were found in two other Moloney murine sarcoma virus-transformed rat cell lines. These proteins were found to differ from known gene products of the ts-110 Moloney murine sarcoma virus mutant and do not have kinase activity. The transformation associated proteins may represent rat cellular factors activated during the transformation of rat cells by Moloney murine sarcoma virus.

Animals↗
PubMed1978

Transformation of normal diploid cells by isolated metaphase chromosomes of virus-transformed or spontaneous tumor cells.

Normal diploid human cells with a limited life-span in culture, as well as primary or secondary cell cultures of mouse or rat embryos, can be transformed in vitro (i.e. grow in soft-agar or low-serum medium) after a single exposure to metaphase chromosomes from SV40-transformed human or rat cells, Ad5-transformed human cells and several spontaneous human or mouse tumor cells. Chromosomes from normal diploid cells do not show any such transforming activity. As judged from the number of colonies formed in selective medium, the efficiency of transformation is, with some exceptions, of the order of 10(-5)--10(-6) and is generally higher for homologous than for heterologous transfers. A fraction of the colonies demonstrate abortive transformation. Nevertheless, using chromosomes from all but one donor cell population, at least one transferent cell line expressing a stable transformed phenotype has been established. Our results demonstrate that transformation of normal diploid cells by a presumptive chromosome-mediated gene transfer can be obtained with a variety of donor and recipient cells.

Adenoviridae↗
PubMed2026

Genomic Profiling, Risk Stratification, and Post-Transformation Treatment Outcomes in Patients with Transformed Small-Cell Lung Cancer: A Multicenter Analysis.

BACKGROUND: Transformed small-cell lung cancer (T-SCLC) is an increasingly recognized resistance mechanism in EGFR-mutant lung adenocarcinoma. This study aimed to identify early predictors of histologic transformation and evaluate post-transformation treatment outcomes. METHODS: We retrospectively collected 163 T-SCLC patients from five Chinese centers. Next-generation sequencing was performed on 60 EGFR-mutant patients, including 47 paired primary-transformed samples. Integrated genomic and clinical analyses were conducted to delineate molecular features and survival outcomes. RESULTS: Among 150 EGFR-mutant patients, the median time to SCLC transformation was 25.8 months and median post-transformation overall survival (OS) was 14.2 months. Clinical and survival data for the 13 EGFR wild-type patients are reported descriptively given the limited sample size. Among 108 treatment-evaluable patients, first-line EGFR-TKI plus chemotherapy, chemotherapy alone, and immune checkpoint inhibitors (ICIs) plus chemotherapy yielded median progression-free survival (PFS) of 6.2, 5.30, and 4.07 months (P = 0.041) and median OS of 21.2, 27.6, and 13.6 months (P = 0.193). In later-line therapy, taxane-based regimens achieved a median PFS of 6.93 months, outperforming camptothecin-based (1.13 months) and other regimens (1.90 months; P = 0.049). High evolutionary diversity was associated with shorter post-transformation OS (6.77 vs. 11.10 months), with restricted cubic spline analysis showing a nonsignificant trend toward a nonlinear association (P = 0.055).Age, RB1/NTRK1 mutation, and secondary T790M mutation were identified as independent risk factors and integrated into a predictive model with high accuracy. CONCLUSIONS: This study establishes a clinically applicable model for early prediction and risk stratification of SCLC transformation. Taxane-based regimens emerge as a promising later-line therapeutic option for T-SCLC.

Humans↗
PubMed2000

Na+/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes.

In this study we investigate the mechanism of intracellular pH change and its role in malignant transformation using the E7 oncogene of human papillomavirus type 16 (HPV16). Infecting NIH3T3 cells with recombinant retroviruses expressing the HPV16 E7 or a transformation deficient mutant we show that alkalinization is transformation specific. In NIH3T3 cells in which transformation can be turned on and followed by induction of the HPV16 E7 oncogene expression, we demonstrate that cytoplasmic alkalinization is an early event and was driven by stimulation of Na+/H+ exchanger activity via an increase in the affinity of the intracellular NHE-1 proton regulatory site. Annulment of the E7-induced cytoplasmic alkalinization by specific inhibition of the NHE-1, acidification of culture medium, or clamping the pHi to nontransformed levels prevented the development of later transformed phenotypes such as increased growth rate, serum-independent growth, anchorage-independent growth, and glycolytic metabolism. These findings were verified in human keratinocytes (HPKIA), the natural host of HPV. Results from both NIH3T3 and HPKIA cells show that alkalinization acts on pathways that are independent of the E2F-mediated transcriptional activation of cell cycle regulator genes. Moreover, we show that the transformation-dependent increase in proliferation is independent of the concomitant stimulation of glycolysis. Finally, treatment of nude mice with the specific inhibitor of NHE-1, DMA, delayed the development of HPV16-keratinocyte tumors. Our data confirm that activation of the NHE-1 and resulting cellular alkalinization is a key mechanism in oncogenic transformation and is necessary for the development and maintenance of the transformed phenotype.

3T3 Cells↗
PubMed2001

Captopril restores transforming growth factor-beta type II receptor and sensitivity to transforming growth factor-beta in murine renal cell cancer cells.

PURPOSE: Captopril is known to inhibit the growth of renal cancer but the mechanism involved has been unclear. The current study elucidates the mechanism of captopril induced inhibition of the growth of the Renca mouse renal cancer cell line involving transforming growth factor-beta, which is known to be a growth inhibitory cytokine in epithelial cells and tissues. MATERIALS AND METHODS: Transforming growth factor-beta in conditioned medium was measured by bioassay. Levels of transforming growth factor-beta and transforming growth factor-beta type II receptor expression messenger RNA were determined by reverse transcriptase-polymerase chain reaction and flow cytometry. Cell viability was determined by bromodeoxyuridine (BrdU) incorporation and tetrazolium bromide assay. RESULTS: Captopril (0.01 to 1 mM.) showed no significant effect on transforming growth factor-beta synthesis or transforming growth factor-beta messenger RNA in Renca cells. On the other hand, 1 mM. captopril significantly inhibited Renca cell growth. Reverse transcriptase-polymerase chain reaction and flow cytometry showed that 1 mM. captopril up-regulated type II receptor expression. CONCLUSIONS: These findings suggest that captopril restores transforming growth factor-beta type II receptor expression and inhibits the growth of Renca cells by increasing their sensitivity to transforming growth factor-beta.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Role of adenovirus E1B proteins in transformation: altered organization of intermediate filaments in transformed cells that express the 19-kilodalton protein.

Cooperation of the nuclear oncogene E1A with the E1B oncogene is required for transformation of primary cells. Expression vectors were constructed to produce the 19-kilodalton (19K) and 55K E1B proteins under the direction of heterologous promoters in order to investigate the role of individual E1B proteins in transformation. Coexpression of E1A and either the 19K or 55K E1B gene products was sufficient for the formation of transformed foci in primary rat cells at half the frequency of an intact E1B gene, suggesting that the 19K and 55K proteins function via independent pathways in transformation. Furthermore, the effects of Ha-ras and the E1B 19K gene product were additive when cotransfected with E1A, suggesting that the 19K protein functions in transformation by a mechanism independent from that of ras as well. Although expression of E1A and either E1B protein was sufficient for the subsequent growth of cells in long-term culture, the 19K protein was required to support growth in semisolid media. As the 19K protein has been shown to associate with and disrupt intermediate filaments (IFs) when transiently expressed with plasmid vectors (E. White and R. Cipriani, Proc. Natl. Acad. Sci. USA, 86:9886-9890, 1989), the organization of IFs in transformed cells was investigated. Primary rat cells transformed by plasmids encoding E1A plus the E1B 19K protein showed gross perturbations of IFs, whereas cell lines transformed by plasmids encoding E1A plus the E1B 55K protein or E1A plus Ha-ras did not. These results suggest that an intact IF cytoskeleton may inhibit anchorage-independent growth and that the E1B 19K protein can overcome this inhibition by disrupting the IF cytoskeleton.

Adenovirus Early Proteins↗
PubMed1992

Differential expression of hepatocyte growth factor, transforming growth factor-alpha and transforming growth factor-beta 1 messenger RNAs in two experimental models of liver cell proliferation.

Hepatocyte growth factor, a potent hepatocyte mitogen in vitro, appears to trigger hepatocyte regeneration after partial hepatectomy and after acute liver cell necrosis. Transforming growth factor-alpha and transforming growth factor-beta 1 may also be involved in the control of liver regeneration. In this study we assessed possible roles of hepatocyte growth factor, transforming growth factor-alpha and transforming growth factor-beta 1 on liver cell proliferation in vivo, using a model of choline deficiency that is associated with liver cell necrosis and a model of a hypolipidemic agent (4-chloro-6-(2,3 xylidino)-2-pyrimidinylthio (N-beta-hydroxyethyl) acetamide) without liver necrosis. Male F344 rats were fed a choline-deficient diet or 0.16% 4-chloro-6-(2,3 xylidino)-2-pyrimidinylthio (N-beta-hydroxyethyl) acetamide diet for 6 and 4 wk, respectively. Rats were killed periodically, and the expression of hepatocyte growth factor messenger RNA in the liver, lung and kidney was determined by Northern-blot analysis. The levels of transforming growth factor-alpha and transforming growth factor-beta 1 messenger RNAs in the liver were also determined. Feeding a choline-deficient diet for 1 to 6 wk led to gradual increases in the levels of hepatocyte growth factor, transforming growth factor-alpha and transforming growth factor-beta 1 messenger RNAs in the liver. Feeding a 4-chloro-6-(2,3 xylidino)-2-pyrimidinylthio (N-beta-hydroxyethyl) acetamide diet for 3 days and 2 wk induced marked enhancement of liver cell proliferation as judged by hepatocyte 5-bromo-2-deoxyuridine incorporation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Raf and RhoA cooperate to transform intestinal epithelial cells and induce growth resistance to transforming growth factor beta.

Although unregulated activation of the Ras/Raf/mitogen-activated protein kinase kinase/Erk signaling pathway is believed to be a central mechanism by which many cell types undergo oncogenic transformation, recent studies indicate that activation of Raf kinase by oncogenic Ras is not sufficient to cause tumorigenic transformation in intestinal epithelial cells. Thus, identification of signaling proteins and pathways that interact with Raf to transform intestinal epithelial cells may be critical for understanding aberrant growth control in the intestinal epithelium. Functional interactions between Raf and the small GTPase RhoA were studied in RIE-1 cells overexpressing both activated Raf(22W) and activated RhoA(63L). Double transfectants were morphologically transformed, formed colonies in soft agar, grew in nude mice, overexpressed cyclin D1 and cyclooxygenase-2 (COX-2), and were resistant to growth inhibition by transforming growth factor (TGF) beta. RIE-Raf and RIE-RhoA single transfectants showed none of these characteristics. Expression of a dominant-negative RhoA(N19) construct in RIE-Ras(12V) cells was associated with markedly reduced COX-2 mRNA, COX-2 protein, and prostaglandin E2 levels when compared with RIE-Ras(12V) cells transfected with vector alone. However, no change in transformed morphology, growth in soft agar, cyclin D1 expression, TGFalpha expression, or TGFbeta sensitivity was observed. In summary, coexpression of activated Raf and RhoA induces transformation and TGFbeta resistance in intestinal epithelial cells. Although blockade of RhoA signaling reverses certain well-described characteristics of RIE-Ras cells, it is insufficient to reverse the transformed phenotype and restore TGFbeta sensitivity. Blockade of additional Rho family members or alternate Ras effector pathways may be necessary to fully reverse the Ras phenotype.

Alkyl and Aryl Transferases↗