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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transformation of cloned rat embryo fibroblast (CREF) cells with the wild-type 5 adenovirus (wtAd5) transforming genes E1A and E1B (which extend from 0 to 11.2 map units) results in morphologically transformed cells that exhibit an increased saturation density in monolayer culture and display an anchorage-independent phenotype. WtAd5-transformed CREF (wtAd5 CREF) cells do not, however, induce tumors when injected subcutaneously into athymic nude mice or syngeneic Fischer rats. We have analyzed the effect of the ras oncogene and site-specific mutants in the ras oncogene that result in p21 proteins with altered biochemical properties on the oncogenic and metastatic properties of singly (ras) and doubly (ras + wtAd5) transformed CREF cells. Transformants expressing the wild-type ras p21 protein and ras mutants producing p21 proteins that retained GTP-binding properties grew in agar, induced tumors in nude mice and syngeneic rats, and metastasized to the lungs of rats when injected into their tail veins. In contrast, cells transformed with the ras mutant 116K (which contains a mutation at residue 116 that produces a Lys instead of an Asn and does not bind GTP or induce CREF cells to grow in agar) did not become morphologically transformed and were not oncogenic when injected subcutaneously into either nude mice or Fischer rats; further, such cells were not metastatic when injected into the tail veins of Fischer rats. When the wild-type ras or the ras mutants, including 116K, were expressed in nontumorigenic E1A-plus-E1B-expressing wtAd5 CREF cells, transformed cells induced tumors in both types of animals. The CREF cells doubly transformed with 116K + wtAd5, unlike transformants containing the wild-type ras and the other ras mutants that still retained GTP binding, were still unable to induce lung metastases. In addition, 116K + wtAd5-transformed CREF cells also did not display any alterations in morphology distinguishable from wtAd5 CREF cells and were not able to grow in agar with increased efficiency. These results indicate that the loss of GTP-binding ability by this mutant p21 ras protein eliminated the ability of these proteins to induce an oncogenic phenotype in an immortal but normal CREF cell line. However, the mutant ras could cooperate with wtAd5 transforming genes in transformed CREF cells to make these cells progress to an oncogenic (but not metastatic) phenotype.
Mol Carcinog 1992
PMID:Induction and progression of the transformed phenotype in cloned rat embryo fibroblast cells: studies employing type 5 adenovirus and wild-type and mutant Ha-ras oncogenes. 155 10

We found previously that transforming growth factor-beta 1 (TGF beta 1) mRNA levels are markedly elevated in rat prostate cancer (Dunning R3327 sublines) compared to levels in normal prostate. Our goal was to determine whether elevated expression of TGF beta 1 is biologically relevant to prostate cancer growth in vivo. We chose as our model the R3327-MATLyLu prostate cancer epithelial cell line, which produces metastatic anaplastic tumors when reinoculated in vivo. Our approach was to stably transfect MATLyLu cells with an expression vector that codes for latent TGF beta 1 and to isolate subclones of cells that over-expressed TGF beta 1 mRNA. We also isolated a subclone of MATLyLu cells transfected with a control vector lacking the TGF beta 1 cDNA insert. We then studied the growth of these cells in vivo and in vitro. Twenty days after sc inoculation of 10(6) cells in vivo, TGF beta 1-overproducing MATLyLu tumors were 50% larger, markedly less necrotic, and produced more extensive metastatic disease (lung metastases in 73% of all lobes and lymph node metastases in 88% of animals) compared to control MATLyLu tumors (lung metastases, 21%; lymph node metastases, 7%). Thus, TGF beta 1 produced in vivo is biologically active and can promote prostate cancer growth, viability, and aggressiveness, perhaps via effects on the host and/or on the tumor cells themselves. When followed in vitro, TGF beta 1-overproducing cells became growth inhibited, but this effect was transient as cells subsequently resumed proliferating. Growth inhibition was due to TGF beta, because it could be prevented by TGF beta-neutralizing antibody. Therefore, prostate cancer cells can activate and respond to secreted latent TGF beta 1, and although the cells are transiently inhibited in vitro, there is no net inhibition of growth. The ability of the cells to respond to endogenously produced TGF beta 1 suggests that TGF beta 1 overexpression enhances tumor growth in vivo at least in part via an effect of TGF beta 1 on the tumor cells themselves.
Mol Endocrinol 1992 Jan
PMID:Transforming growth factor-beta 1 overproduction in prostate cancer: effects on growth in vivo and in vitro. 173 67

Metastases from patients with solid tumors were harvested from 196 patients for the purpose of growing tumor-derived activated cells (TDAC). Cells were prepared from autologous tumor cultures by incubation with Interleukin-2 (IL-2) followed by repeated exposure to tumor antigen and/or anti-CD3 monoclonal antibody. Initial growth success was achieved in 66%; 45/56 (80%) of these early cultures were subsequently expanded for in vivo therapy. It took a mean of 69.4 +/- 24.0 days to grow TDAC for treatment. Thirty-eight patients were treated with cyclophosphamide (1 g/m2) on day one followed by a 96-hour continuous infusion of IL-2 (18 x 10(6) IU/m2/day) on days 2-5 and approximately 10(11) TDAC on day 2. Patients subsequently received monthly IL-2 as a 96-hour constant infusion if their cancers were stable or regressing. Median age was 51 yrs; 58% were male. Performance status was 0-1 in 64%, 29% had lung metastases; 34% had liver metastases. The usual IL-2 toxicities were seen. Responses were seen only in 1/38 patients (3%); a partial response in a patient with lymphoma. Forty-two percent were stable 90 days post-treatment, the rest were progressive or inevaluable. We conclude that a treatment plan for IL-2/TDAC is technically difficult, costly, and not practical under these conditions. Clinical results to date are not clearly different than those obtained with other IL-2 regimens.
Mol Biother 1991 Jun
PMID:Continuous infusion interleukin-2 and tumor-derived activated cells as treatment of advanced solid tumors: a National Biotherapy Study Group Trial. 191 Jun 22

Recombinant interleukin-2 (rIL-2; EuroCetus, Amsterdam, Netherlands) was studied in an outpatient phase II trial in 14 patients with progressive metastatic renal carcinoma, malignant melanoma, and colorectal cancer. Escalating doses of rIL-2 were administered as subcutaneous bolus every 12 hours, starting at 0.3 million U/m2/d. A 100% dose increase occurred at weekly intervals, up to a maximum of 2.4 million U/m2/d. Responding patients or patients with stable disease after 4 weeks of rIL-2 (n = 9) were continued on maintenance therapy at 1.8 million U/m2 of rIL-2 administered once weekly. After 12 weeks of therapy, one renal cell cancer patient had a partial regression in lung metastases. Bolus injection of rIL-2 (1.2 million U/m2) resulted in peak serum levels of 25 to 30 U/ml. Toxicity of this regimen was moderate, with local inflammation at the injection sites, grade I-II (World Health Organization) malaise, nausea and/or vomiting, and fevers in 70% to 100% of patients treated. Thyroid dysfunction was observed in 10 patients receiving subcutaneous rIL-2; four of these patients had laboratory evidence of hyperthyroidism, and one had hypothyroidism. rIL-2-induced toxicity reversed spontaneously after cessation of treatment. In all patients receiving rIL-2, a dose-dependent increase in peripheral blood lymphocyte and eosinophil counts was noted, with a mean of 2.6 and 3.8 x 1,000/microliters after 4 weeks of therapy; mean lymphocyte and eosinophil counts were measured at 2.0 and 2.4 x 1,000/microliters in patients who received prior high-dose chemotherapy, compared with 3.2 and 5.1 x 1,000/microliters in those who did not.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Biother 1990 Mar
PMID:Low-dose subcutaneous recombinant interleukin-2 in advanced human malignancy: a phase II outpatient study. 233 34

Hepatocellular carcinoma cells (Line-10), obtained from ascitic fluid after diethylnitrosamine treatment of Sewall Wright strain-2 guinea pigs, produce solid (primary) tumours, lymph-node and lung metastases and malignant ascites when reinjected into animals of the same strain. Monoclonal antibodies were raised against the tumour cells by immunizing BALB/c mice with viable ascitic hepatocellular Line-10 tumour cells. Three hybridomas producing anti-Line-10 monoclonal antibodies were selected for further studies (10TL1, 10TL40 and 10TL43) and compared with monoclonal antibodies against intermediate filament keratins. The anti-Line-10 monoclonal antibodies did not cross react with Line-1 hepatocellular carcinoma cells, nor with normal guinea pig hepatocytes. When ascitic Line-10 cells form high papillary projections on the peritoneal surface, they significantly reduced their antigen expression of 10TL40 and of 10TL43 defined antigens, while the expression of 10TL1 defined antigens remained unaltered. Invading Line-10 cells in the deep submesothelial stromal tissue, however, lost reactivity with MoAb 10TL43 but not with the MoAb's 10TL40 and 10TL1. The antigens on lung- and lymphnode metastases remained largely unaffected. The reactivity with MoAb's 10TL40 and with 10TL43 was also lost upon prolonged culturing of Line-10 cells. The reactivity of Line-10 and Line-1 cells with all monoclonal antibodies against keratin filaments remained unaltered. Line-1 cells could be distinguished from Line-10 cells by the absence of any reactivity with the MoAb's 10TL1, -40, -43, but also by the fact that 100% of the Line-1 cells were positive with antibodies against keratins 5/8, 18, and 7.(ABSTRACT TRUNCATED AT 250 WORDS)
Virchows Arch B Cell Pathol Incl Mol Pathol 1989
PMID:Changing tumour antigen expression in metastatic hepatocellular carcinoma cells of the guinea pig. 246 49

The purpose of this study was to examine the effective anti-metastatic activity by multiple i.v. administrations of mouse recombinant interferon-gamma (IFN-gamma) against pulmonary metastases of 3LL or B16-BL6 melanoma cells after surgical excision of primary tumors. Multiple treatments with IFN-gamma reduced effectively the incidence of pulmonary tumor metastases. Repeated 4 consecutive treatment modalities with IFN-gamma showed remarkable reduction of lung tumor colonies, and also rendered alveolar macrophages (AM) cytotoxic against B16-BL6 cells. In contrast, 14 consecutive administrations of IFN-gamma at any doses (10(2) and 10(3) U/mouse) could not activate macrophages to become cytotoxic, but were effective in regressing metastases. Thus, antimetastatic activity of IFN-gamma may be due to the stimulation of host immune defense systems such as induction of tumoricidal macrophages, presumably the direct antiproliferative action to tumor cells, or both actions under the appropriate administration conditions. We found that the systemic administration of IFN-gamma under appropriate multiple treatment modalities results in the reduction of the lung metastases and can activate AM to become tumor cytotoxic at relatively low doses (10(2) U). High-dose IFN-gamma in the multiple administration schedule was also effective for the reduction of lung tumor colonies, but strongly suppressed the nonspecific immune function and could not activate tumoricidal properties of AM.
Mol Biother 1989
PMID:Effect of systemic administration of mouse recombinant interferon-gamma on the lung tumor metastases in mice. 251 71

We examined the activities of activated lymphocytes, interferon-gamma (IFN-gamma), and interleukin 2 (IL-2) in adoptive immunotherapy of pulmonary metastases. Pulmonary metastases produced in Balb/c mice by a single tail-vein injection of 5 X 10(5) murine sarcoma (MCB8) tumor cells on day 0 were treated with combinations of Con A-activated lymphocytes (CAL) (3 X 10(7) cells on days 3 and 7), IL-2 (5 X 10(4) U three times a day on days 3 to 8), and IFN-gamma (5 X 10(4) U/mouse on days 1 to 8). Treated tumors contained increased numbers of infiltrating Thy-1.2+ lymphocytes and a predominance of L3T4+(CD4+) lymphocytes. The level of expression of class I and class II MHC antigens by tumor cells in the lung was increased after treatment. Mice that received CAL + IL-2 + IFN-gamma showed approximately 80% reduction in tumor burden as compared to controls (P = 0.001). Mice treated with IL-2 + CAL, or IL-2 + IFN-gamma, displayed approximately 50% reduction (both P less than 0.02 as compared to triple therapy), whereas IL-2, IFN-gamma, or CAL administered as single agents had little effect on pulmonary metastases. We conclude that adoptive immunotherapy with activated lymphocytes and IL-2 is enhanced by IFN-gamma.
Am J Respir Cell Mol Biol 1989 Nov
PMID:Adoptive immunotherapy of murine pulmonary metastases with interleukin 2 and interferon-gamma. 251 74

Syngeneic colon carcinoma cells and glioma cells were injected into the portal vein of BD IX rats. After various time periods the animals were sacrificed and the livers and lungs were fixed and prepared for histology. Atypical cells were observed in the liver 4 and 7 days after the injection of tumor cells, whereas distinct colonies of both colon carcinoma and glioma cells were demonstrated after 14 days. Lung metastases of both tumor cell types were seen after 14 and 30 days. Furthermore, injection of glioma and carcinoma cells into the tail vein gave detectable lung metastases after 7 and 4 days respectively. Intraperitoneal injection of tumor cells resulted in the accumulation of large tumor masses, particularly in the mesentery. By in situ perfusions of the liver with tumor cells included in the perfusion medium it was possible to establish that all the tumor cells were arrested in the course of 4 min. In contrast, normal rat leukocytes were not trapped in the liver, whereas trypsin-treated leukocytes were, suggesting the importance of trypsin-sensitive structures for binding to hepatic tissue. The binding of both glioma and carcinoma cells to the liver and the ensuing growth of tumor nodules in this organ indicate a lack of specificity on part of the malignant cell types for metastasis to the liver in the rat. Both tumor cell types colonized the first organ encountered after injection.
Virchows Arch B Cell Pathol Incl Mol Pathol 1988
PMID:Colonization of the rat liver by syngeneic tumor cells. An experimental approach by in vivo and in situ studies. 290 Nov 59

Retrovirus vector infection was used to introduce large numbers of unique genetic markers into tumor cell populations for the purpose of analyzing comparative changes in the clonal composition of metastatic versus that of nonmetastatic tumors during their progressive growth in vivo. The cell lines used were SP1, a nonmetastatic, aneuploid mouse mammary adenocarcinoma, and SP1HU9L, a metastatic variant of SP1. Cells were infected with delta e delta pMoTN, a replication-defective retrovirus vector which possesses the dominant selectable neo gene and crippled long terminal repeats. G418r colonies were obtained at a frequency of 4 x 10(-3). Southern blot analysis of a number of clones provided evidence of random and heritable integration of one or two copies of the proviral DNA. Clonal evolution of primary tumor growth and the nature of lineage relationships among spontaneous metastases and primary tumors were analyzed by subcutaneously injecting 10(5) cells from a pooled mixture of 3.6 x 10(2) G418r SP1HU9L or 10(4) G418r SP1 colonies into syngeneic CBA/J mice. The most striking finding was the relative clonal homogeneity of advanced primary tumors; they invariably consisted of a small number (less than 10) of distinct clones despite the fact that hundreds or thousands of uniquely marked clones had been injected. In the case of the metastatic SP1HU9L cells, the nature of these "dominant" clones varied from one tumor to another. Analysis of a number of lung metastases revealed that a proportion of them were derived from dominant primary tumor clones and were composed of one, and sometimes two, distinct progenitors. In some animals, all the lung metastases were derived from a common progenitor clone, whereas in others, each metastatic nodule had a different progenitor. The results show the following. (i) Retrovirus vector infection can be used to introduce large numbers of unique and stable clonal markers into tumor cell populations. (ii) The progeny of a very limited number of clones dominate in advanced primary tumors. (iii) Mammary carcinoma metastases are of mono- or biclonal origin. The significance of the results is discussed.
Mol Cell Biol 1988 Aug
PMID:Genetic tagging of tumor cells with retrovirus vectors: clonal analysis of tumor growth and metastasis in vivo. 321 Nov 40

NIH/3T3 cells transfected with DNA from malignant human tumors produced experimental and spontaneous metastases in nude mice. In contrast, parent or spontaneously transformed NIH/3T3 cells failed to metastasize. The transfected clones contained either activated c-Harvey-ras or N-ras oncogenes. A representative clone (T71-17SA2) which was used to assess selected cellular and host factors relevant to the metastatic process produced lung metastases in 100% of the NIH nude mice recipients, secreted augmented levels of type IV collagenase, and invaded human amnion basement membrane in vitro. Expression of the metastatic phenotype was not related to decreased sensitivity to natural killer cells or macrophage-mediated cytotoxicity. Analysis of the cellular DNA from the T71-17SA2 transfectant and its corresponding metastases, both of which contained activated N-ras oncogenes, revealed a twofold increase in the N-ras-specific DNA sequences in the metastatic cells. Thus, transfection with human tumor DNA containing activated ras oncogenes can induce the complete metastatic phenotype in NIH/3T3 cells by a mechanism apparently unrelated to immune cell killing.
Mol Cell Biol 1985 Jan
PMID:NIH/3T3 cells transfected with human tumor DNA containing activated ras oncogenes express the metastatic phenotype in nude mice. 398 18


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