Biomedical subjects

P Nettesheim

Publications and source records attributed to P Nettesheim.

At least 73 records · Page 4Linked to original sources

PubMed1991

Ultrastructural immunohistochemical localization of Clara cell secretory protein in pulmonary epithelium of rabbits.

Highly purified Clara cells (93 +/- 3%) isolated from the lungs of rabbits were used to produce an antiserum against Clara cell secretory proteins. This antiserum was used to identify and study the biosynthesis and secretion of [35S]methionine-labeled proteins from isolated Clara cells. The antiserum recognized one major secretory protein with apparent molecular weight of 6 kDa and reacted weakly with a higher molecular weight protein of about 180 kDa. Biosynthesis and secretion of these proteins was not detected in preparations of isolated alveolar type II cells or alveolar macrophages. Immunocytochemical localization of the antigen with colloidal gold indicated a dual localization in bronchiolar Clara cells. Gold labeling was found over the osmiophilic secretory granules of Clara cells and smooth endoplasmic reticulum. In tracheal Clara cells, labeling was found mostly in association with secretory granules and relatively little in association with the smooth endoplasmic reticulum. Labeling was also found over the lamellar bodies of type II cells, although the reaction was weak. Labeling of ciliated cells, alveolar type I cells, capillary endothelial cells, and alveolar macrophages was not distinguishable from background. These data indicate that Clara cells of both the bronchioles and trachea of rabbits synthesize and secrete the low molecular weight protein previously called Clara cell secretory protein (CCSP). This antigen does not belong to that group of surfactant proteins whose molecular weights range from 26 to 40 kDa.

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PubMed1991

Abnormalities of growth factor systems in transformed airway epithelial cells.

The role of the peptide growth factors transforming growth factor alpha (TGF alpha) and transforming growth factor beta (TGF beta) in the regulation of proliferation of normal and transformed airway epithelial cells was studied. Normal as well as transformed rat tracheal epithelial (RTE) cell cultures secrete similar amounts of TGF alpha during logarithmic growth. Once normal RTE cell cultures reach the plateau phase of growth, they down-regulate TGF alpha expression at the RNA and protein level; in contrast, transformed cells do not down-regulate TGF alpha. Using neutralizing TGF alpha antiserum and a tyrphostin TGF alpha/EGF receptor tyrosine kinase inhibitor, we show that the secreted TGF alpha is utilized by both normal and transformed cells as an autocrine mitogenic factor. Normal RTE cells are highly sensitive to the growth inhibitory effects of TGF beta, particularly during early phases of logarithmic growth. At late logarithmic and plateau phases of proliferation, cultures of normal RTE cells secrete large amounts of TGF beta. That the endogenous TGF beta is exerting growth inhibitory effects can be demonstrated by adding TGF beta antisera to the cultures which causes a burst of proliferation. Many transformed RTE cell lines exhibit a markedly reduced sensitivity to the growth inhibitory effects of TGF beta. However, the cells remain responsive to regulation of ECM genes by TGF beta. The transformed cell lines examined secrete less than one tenth the amount of TGF beta of normal cells. Our studies show that the autocrine TGF beta growth restraining mechanism is inoperative in many of the RTE cell transformants. We conclude, therefore, that alterations in TGF alpha and TGF beta regulation of cell proliferation are important factors contributing to the abnormal growth behavior of transformed RTE cells.

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PubMed1991

Stimulation of prostaglandin H synthase mRNA levels and prostaglandin biosynthesis by phorbol ester: mediation by protein kinase C.

We have investigated the mechanisms by which the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulates prostaglandin E2 (PGE2) formation in the rat tracheal epithelial cell line EGV-6aigT, which can be grown in serum-free medium. The addition of TPA to cells that were prelabeled with [3H]arachidonic acid did not enhance the release of [3H]arachidonic acid and/or [3H]PGE2, indicating that TPA does not stimulate phospholipase activity. The addition of exogenous arachidonic acid to cells pretreated with TPA resulted in increased PGE2 formation, compared with basal levels, indicating an elevation in prostaglandin H synthase (PHS) activity. PHS activity was maximal at 4 hr and was dependent upon the concentration of TPA. Actinomycin D and cycloheximide blocked the TPA response. The recovery of PHS activity of cells in which the existing PHS was inhibited by aspirin was enhanced by TPA treatment. TPA treatment enhanced the expression of PHS mRNA, as measured by Northern analysis. The addition of actinomycin D and cycloheximide reduced the TPA enhancement of PHS mRNA, indicating that the increase in PHS activity required de novo RNA and protein synthesis. Furthermore, pretreatment of the cells with protein kinase C inhibitors reduced the TPA-dependent stimulation of PHS activity and the expression of PHS mRNA. The data suggest that TPA-stimulated de novo synthesis of PHS is mediated by protein kinase C.

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PubMed1990

Nonrandom chromosome alterations that correlate with progression to immortality in rat tracheal epithelial cells transformed with N-methyl-N'-nitro-N-nitrosoguanidine.

Primary rat tracheal epithelial cells can be transformed in vitro by N-methyl-N'-nitro-N-nitrosoguanidine. The earliest recognizable morphological transformant is the enhanced growth variant (EGV), characterized by enhanced proliferative capacity. Transformed EGV colonies can progress to give rise to immortal cell lines. The purpose of this study was to determine if specific chromosome changes occur which correlate with immortalization. A total of 34 EGV colonies were isolated, of which five were able to progress in culture to become immortal (greater than or equal to 100 population doublings). Early passages of all five immortalized cultures exhibited additional copies of chromosomes 4, 7, and 11 as a common or recurrent abnormality. These numerical alterations were rarely observed in the primary EGV colonies from which the cell lines were derived, suggesting that these alterations occurred during progression. Structural alterations involving chromosome 1 (resulting in a net gain of 1q) and chromosome 3(3q) also occurred in four out of five immortalized cultures. In all cases, structural alterations involving 1q and/or 3q were detected in the primary EGV colonies from which the immortal cell lines arose. Comparison of the frequency of the structural and numerical alterations observed in the immortalized cultures with their frequency in the 29 EGV colonies which did not become immortal indicated that these changes correlated (P less than or equal to 0.005) with the ability to become immortal. These results suggest that structural alterations occur in primary EGV colonies which predispose cells to immortalization and that subsequent numerical changes occur during progression that correlate with acquisition of the immortal phenotype.

Aneuploidy↗

PubMed1990

Abnormalities in growth regulation of transformed rat tracheal epithelial cells.

We have examined the changes in growth regulation which take place during multistage transformation of rat tracheal epithelial (RTE) cells exposed to chemical carcinogens in vitro. Transformed RTE cells demonstrate: (1) altered negative growth factor sensitivity and (2) altered positive growth factor dependence and gene expression compared with primary RTE cells in culture. Primary RTE cells are sensitive to the growth inhibitory effects of retinoic acid and transforming growth factor beta (TGF beta). Enhanced growth variants of RTE cells, recognized 4-6 weeks after carcinogen treatment, lose sensitivity to the antiproliferative effects of retinoic acid. Likewise, many immortalized RTE cell lines lose responsiveness to growth inhibition by TGF beta. We also examined positive growth factor requirements and gene expression in primary and transformed RTE cells propagated in serum-free media. Many transformed cell lines lose dependence on epidermal growth factor in the media. These cell lines also overexpress TGF alpha mRNA and protein. Since TGF alpha acts at the epidermal growth factor receptor, these data suggest that TGF alpha plays an autocrine role in growth regulation of transformed RTE cells. Thus, alterations in both negative and positive growth factor regulation contribute to expression of the transformed phenotype in RTE cells.

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PubMed1990

Pathways of differentiation of airway epithelial cells.

The question being examined is whether one or more morphologically distinct cell types can be identified in the conducting airways of adult rabbits possessing stem cell functions. The term "stem cell" is used to denote cells with extensive self-replicating potential and the ability to produce differentiated progeny. According to various models of cell renewal in the conducting airways that have been proposed over the years, two different cell types have to be regarded as primary candidates for the stem cell: basal cells and some type of secretory cells. The question is complicated by the fact that significant differences exist between species in the distribution and morphological characteristics of airway cell types. In addition, different airway segments may or may not be occupied by different populations of stem cells. Previously, investigators have addressed the problem by studying normal cell regeneration or injury induced cell regeneration in vivo in the whole animal. We decided to attempt a different approach, namely, to separate specific cell types and to study the proliferation and differentiation capacity of such cell isolates using in vitro and in vivo cell culture techniques. Our studies lead us to conclude that the conducting airways of adult rabbits contain at least two distinct cell populations endowed with stem cell potential, namely basal cells and bronchiolar Clara cells. From that it follows that the trachea and bronchi, on one hand, and the bronchioles, on the other hand, are occupied by two different stem cell populations governing renewal of the epithelial lining.

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PubMed1989

In vitro neoplastic progression of rat tracheal epithelial cells transformed by diverse carcinogens.

Preneoplastic transformants were isolated from primary rat tracheal epithelial cells after treatment with (a) mutagenic concentrations of the alkylating agent N-methyl-N-nitro-N'-nitrosoguanidine, (b) nonmutagenic concentrations of the DNA hypomethylating agent 5-azacytidine, or (c) after arising spontaneously. We have addressed the question of whether preneoplastic transformants induced by different carcinogens differ in their ability to progress to the immortal stage and to become neoplastic. Spontaneous transformants occurred with a very low frequency, and 5-azacytidine induced preneoplastic transformants half as efficiently as N-methyl-N-nitro-N'-nitrosoguanidine. However, no phenotypic differences could be detected between the 70 preneoplastic colonies isolated from the 3 groups; colony size, cell density, and clonogenicity were not statistically different. Clones from all 3 groups became immortal and further progressed to become neoplastic with similar frequencies. The level of expression of the oncogenes H-ras, K-ras, and raf was also similar in all 3 groups. These experiments indicated that there was no difference in the ability of spontaneous transformants or those induced by N-methyl-N-nitro-N'-nitrosoguanidine or 5-azacytidine to progress to become immortal or neoplastic. This suggests that whereas the nature of the carcinogen influenced the frequency of the initial transforming event, progression to the neoplastic stage was independent of the nature of the transforming insult.

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PubMed1989

2,3,7,8-Tetrachlorodibenzo-p-dioxin enhancement of N-methyl-N'-nitro-N-nitrosoguanidine-induced transformation of rat tracheal epithelial cells in culture.

The abilities of various dioxins to induce toxicity or transformation of rat tracheal epithelial cells in culture were examined. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was not cytotoxic and did not induce transformation as measured by the induction of growth-altered, preneoplastic cells (termed enhanced growth variants). However, TCDD enhanced the transformation of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-initiated rat tracheal epithelial cells. Other dioxin congeners with 0 to 3 chloro substitutions were inactive in enhancing MNNG transformation. TCDD was most effective at a concentration of 0.3 nM and when treatment was administered immediately after MNNG exposure. The dose-response curves for enhancement of MNNG-induced transformation and induction of aryl hydrocarbon hydroxylase activity by TCDD were similar. These results are consistent with the hypothesis that the enhancement of cell transformation by TCDD is mediated through the TCDD receptor. TCDD also enhanced transformation when the cells were treated before MNNG treatment. The ability of 12-O-tetradecanoylphorbol-13-acetate (TPA) to enhance MNNG-induced rat tracheal epithelial transformation was also examined. In contrast to the findings with TCDD, the number of transformed colonies was increased only by pretreatment with TPA followed by MNNG. TPA-pretreatment enhanced equally the number of normal cells forming colonies and the total number of transformed colonies after selection; therefore, the transformation frequency (transformants per total surviving colonies) was unchanged by TPA. In contrast, TCDD treatment enhanced the transformation frequency in MNNG-exposed cultures since the number of transformed colonies increased while the number of total colonies remained constant. Thus, TCDD appears to act by a different mechanism than TPA. TCDD enhancement of MNNG-induced transformation may be attributed to a promotional effect, a comutagenic action, or a modulation of cell proliferation and/or differentiation mediated through the TCDD receptor.

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PubMed1989

Mouse retroviral sequences acquired by cell lines after passaging through nude mice detected by hybridization of the fms probe pSM3.

The expression of a large RNA transcript, 8.5 to 9.5 kilobases, possibly related to the fms oncogene in mouse, rat, and human tumor cells, has been described in the literature. However, the pSM3 fms probe used to detect this gene transcript contains a significant amount of the pol gene of the Susan McDonough strain of feline sarcoma virus from which it was derived. Using a fms probe which does not contain any viral pol sequences, no such "fms-related" transcripts were detected in cell lines previously reported to express the large transcripts. These cell lines did express a large 9.5-kilobase transcript which hybridized to a probe for murine leukemia virus. Partial sequence analysis of the 9.5-kilobase transcript detected with the pSM3 probe in transformed rat cells indicated sequence homology with AKV murine leukemia virus. Thus, the presence of large RNA transcripts, interpreted by us and others as being related to the oncogene fms, appears to be due to the expression of mouse retroviral sequences which hybridize to the viral pol region contained in the pSM3 fms probe. In the case of rat and human cells, such sequences appear to be acquired after the cells have been passaged in nude mice. These results should serve as a reminder of the important biohazard and data interpretation implications for investigations in which cells transfected with retroviral vector constructs are injected into nude mice, because rescue of the recombinant sequences in these cells could occur following infection by endogenous murine retroviral particles.

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PubMed1989

Cellular oncogene expression in cell lines derived from tumors produced by transformed rat tracheal epithelial cells.

Five tumor-derived cell lines established from transformed rat tracheal epithelial (RTE) cells were examined for activated oncogenes using the NIH 3T3 assay, and the expression of 11 cellular oncogenes in the transformed cells was quantitated and compared with expression in normal RTE cells. DNA from the tumor-derived cell lines lacked transforming activity, but expression of several oncogenes (fos, abl, Ki-ras, Ha-ras, and p53) was higher in the transformed cells than in normal RTE cells.

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PubMed1989

Altered growth factor dependence and transforming growth factor gene expression in transformed rat tracheal epithelial cells.

The role of peptide growth factors in neoplastic progression of transformed rat tracheal epithelial (RTE) cells was assessed by examining growth factor requirements and expression of growth factor and growth factor receptor genes in normal and transformed RTE cells. Neoplastically transformed cell lines showed decreased requirements for bovine pituitary extract, insulin, and epidermal growth factor compared to normal primary RTE cells. Neoplastic RTE cell lines expressed significantly increased levels of transforming growth factor alpha (TGF alpha) RNA and secreted TGF alpha into the media, suggesting an autocrine role for this growth factor. Increased levels of TGF alpha RNA were also observed in the preneoplastic stages of the same cell lines, indicating that increased TGF alpha expression is an early event in the multistage process of neoplastic transformation of RTE cells. TGF beta transcripts were also overexpressed in neoplastically transformed cell lines. Our studies suggest that aberrant expression of growth factors may play an important role in the development and/or maintenance of the transformed phenotype in RTE cells.

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PubMed1989

Squamous differentiation in normal and transformed rat tracheal epithelial cells.

Morphological observations suggest that rate tracheal epithelial (RTE) cells undergo squamous differentiation when maintained in cell culture. The purpose of the studies presented here was to examine and define differentiation of cultured RTE cells with the help of markers previously shown to be specific for squamous differentiation. Furthermore, we wanted to determine whether neoplastic transformation of these cells causes significant disruption of their differentiation program. Our experiments showed that squamous differentiation occurs in normal primary RTE cell cultures. Epidermal transglutaminase (transglutaminase type I) activity increased approximately 20-fold in RTE cultures as a function of time. Cholesterol sulfate, another marker of squamous differentiation, increased only modestly with time. A significant number of cells formed cross-linked envelopes in cultures growth-arrested at a cell density of approximately 250 cells/mm2. However, no significant changes in keratin expression were detected. Neoplastically transformed RTE cells which exhibit a greatly increased growth capacity expressed the same three markers of squamous differentiation as normal RTE cells. However, transglutaminase type I activity was relatively low. The cross-linked envelope formation was independent of cell density in the transformed cells. Like in normal RTE cultures, cholesterol sulfate accumulation only increased moderately with increasing cell density. The keratin pattern of transformed RTE cell lines was identical to that of normal primary RTE cells. A well-differentiated squamous cell carcinoma derived from one of the neoplastic cell lines expressed in vivo keratin markers typical of keratinization (56 kd acidic keratin and 65-67 kd basic keratins). We draw the following conclusions. (i) The biochemical studies confirm that normal RTE cells undergo squamous differentiation. The pathway of terminal squamous differentiation is cell density dependent. (ii) In transformed RTE cells, growth as well as differentiation are less subject to regulation by cell density than in normal cells. (iii) Transformed RTE cells are differentiation competent; the main abnormality appears to be that in transformed cell populations proliferation and differentiation occur concomitantly.

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PubMed1989

Arachidonic acid metabolism in normal and transformed rat tracheal epithelial cells and its possible role in the regulation of cell proliferation.

The objectives of our investigations were to characterize the profile of arachidonic acid metabolites produced by cultured rat tracheal epithelial cells, and to determine whether or not transformation of these cells causes major qualitative or quantitative changes in arachidonic acid metabolism and whether arachidonic acid metabolites play an important role in the regulation of proliferation of rat tracheal cells. Our studies showed that prostaglandin E2 was the only major prostanoid produced by normal and transformed rat tracheal epithelial cells. When stimulated with calcium ionophore A23187, 12-O-tetradecanoylphorbol 13-acetate, arachidonic acid, or serum, the cultures produced small amounts of thromboxane B2, prostaglandin F2 alpha, and hydroxyeicosatetraenoic acid(s) in addition to prostaglandin E2. Mitogenesis studies showed that none of the peptide growth factors tested stimulated either prostaglandin E2 production or DNA synthesis. Fetal bovine serum, on the other hand, stimulated both. 12-O-Tetradecanoylphorbol 13-acetate and arachidonic acid stimulated prostaglandin E2 production but caused no increase in DNA synthesis. Dexamethasone and indomethacin, inhibitors of phospholipase A2 and cyclooxygenase, respectively, significantly inhibited prostaglandin E2 production at concentrations as low as 10(-8) and 10(-9) M but did not inhibit DNA synthesis. It is concluded (1) that prostaglandin E2 is the major arachidonic acid metabolite of rat tracheal epithelial cells, (2) that transformation does not significantly alter arachidonic acid metabolism in these cells, and (3) that neither prostaglandin E2 nor other arachidonic acid metabolites play a significant role in mitogenic stimulation of rat tracheal epithelial cells.

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PubMed1989

In vitro and in vivo growth and differentiation of clones of tracheal basal cells.

Studies were performed to examine the hypothesis that the basal cells in the large conducting airways function as stem cells. Basal cells were isolated from the tracheas of adult rabbits using centrifugal elutriation procedures. Such cell isolates that contained greater than 90% basal cells were plated in culture at low cell density to produce individual basal cell clones. Clones were similarly obtained from unfractionated tracheal cells (mixed tracheal cells). Basal cell and mixed cell clones were tested to compare their in vitro growth capacity and their ability to reepithelialize denuded tracheal grafts with a mucociliary epithelium. Both basal cell and mixed cell clones underwent 15 to 20 population doublings in culture. The sizes of their clonogenic cell compartments were roughly similar. When inoculated into denuded tracheal grafts, both types of clones were equally efficient in establishing a mucociliary epithelium. The major secretory cell types observed in tracheas repopulated with the two types of cell clones were cells containing small secretory granules and either rough or smooth endoplasmic reticulum. Goblet cells were seen in approximately 40% of tracheas repopulated with either of the two types of cell clones. It is concluded that in rabbits tracheal basal cells can generate secretory cells with varying morphologic characteristics as well as ciliated cells and may be regarded as epithelial stem cells.

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PubMed1988

Cytogenetic changes in rat tracheal epithelial cells during early stages of carcinogen-induced neoplastic progression.

The cytogenetic changes in enhanced growth (EG) variants of rat tracheal epithelial cells in culture were examined. These variants which are detectable at 35 days after carcinogen exposure are the first phenotypic alteration in the multistep neoplastic process studied in this model system. Karyotypic analysis of N-methyl-N'-nitro-N-nitrosoguanidine-induced EG variants at Day 35 was made possible by the development of an in situ method of cytogenetic analysis on intact colonies containing too few cells for conventional chromosome preparation methods. Of the transformed EG variant colonies in both control and N-methyl-N'-nitro-N-nitrosoguanidine-treated groups, 62-78% had abnormal karyotypes which included numerical and structural changes. There were no specific chromosome changes, although aberrations of chromosomes 3 and 4 were recurrently observed. However, some colonies of even the most morphologically transformed EG variants were composed of only diploid cells. To confirm this finding 10 EG variant colonies were bisected and half of the clone was prepared for chromosome analysis and the other half was subcultured to measure the clonogenicity and karyotypes of the cells. Cells from 3 colonies plated very poorly on 3T3 feeders and therefore no karyotypic analysis of the colony-forming cells was possible; the cells of the 3 parental colonies were diploid. Three other parental colonies were predominantly diploid (80-90%) but upon replating the resultant daughter colonies had progressively smaller fractions of diploid cells indicating a selection for cells with abnormal karyotypes. When more selective conditions were used (i.e., growth after removal of the feeder cells), the percentage of abnormal cells increased even further. In one case the parental cells had a karyotypic alteration in the long arm of chromosome 4 and this karyotypic alteration was accentuated in the daughter colonies. Thus, selection of cells with increased growth ability upon subculturing or growth in the absence of feeder cells (properties associated with the acquisition of immortality) resulted in concomitant selection for cells with abnormal karyotypes. Since some of the carcinogen-induced rat tracheal epithelial cells expressing the EG variant phenotype were diploid, it is possible that the first step in this transformation process is an epigenetic change. However, most of the diploid cells became terminal. The aneuploid subpopulations present in these colonies have a selective growth advantage and comprise the cell compartment that expresses continued growth, immortality, and ultimately tumorigenicity.

Aneuploidy↗

PubMed1988

The differentiation potential of tracheal basal cells.

The objective of this study was to examine the differentiation potential of basal cells purified from rabbit tracheas by means of centrifugal elutriation. Cell suspensions containing between 83 and 94% basal cells were inoculated into tracheal grafts denuded of their own epithelium and transplanted to the backs of nude mice. Within 1 week after inoculation, the basal cells reestablished a continuous poorly differentiated epithelial sheet which at 2 to 4 weeks showed typical mucociliary differentiation. Basal cells, ciliated cells, goblet cells, and secretory cells with small granules were present. Some of the latter contained abundant rough endoplasmic reticulum and others contained predominantly smooth endoplasmic reticulum. These data indicate that basal cells can give rise to all major tracheal cell types suggesting that they are the main stem cell in the large airways of rabbits.

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PubMed1987

Expression of a fms-related oncogene in carcinogen-induced neoplastic epithelial cells.

Following carcinogen exposure in vitro, normal rat tracheal epithelial cells are transformed in a multistage process in which the cultured cells become immortal and, ultimately, neoplastic. Five cell lines derived from tumors produced by neoplastically transformed rat tracheal epithelial cells were examined for the expression of 11 cellular oncogenes previously implicated in pulmonary or epithelial carcinogenesis. RNA homologous to fms was expressed at a level 5-19 times higher than normal tracheal epithelial cells in three of five of the tumor-derived lines. All three lines expressing high levels of fms-related RNA gave rise to invasive tumors of epithelial origin when injected into nude mice. Increased expression of the fms-related mRNA was not due to gene amplification, and no gene rearrangement was detected by Southern analyses. RNA blot analysis using a 3' v-fms probe detected a 9.5-kilobase message in the three tumor-derived lines, whereas both normal rat alveolar macrophages and the human choriocarcinoma line BeWo expressed a fms transcript of approximately 4 kilobases. We conclude from these data that the gene expressed as a 9.5-kilobase transcript in these neoplastic epithelial cells is a member of a fms-related gene family but may be distinct from the gene that encodes the macrophage colony-stimulating factor (CSF-1) receptor.

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PubMed1987

In vitro analysis of multistage carcinogenesis.

Several key events in the multistep process of neoplastic transformation of rat tracheal epithelium (RTE) are described. Whether tracheal epithelium is exposed in vivo to carcinogenic agents or whether primary tracheal epithelial cells are exposed in vitro to carcinogens, initiated stem cells can be detected soon after the exposure by their ability to grow under selective conditions in culture. These initiated stem cells differ fundamentally from normal stem cells in their response to factors normally constraining proliferation and self-renewal. Thus, disruption of inhibitory control mechanisms of stem cell replication appears to be the first event in RTE cell transformation. While the probability of self-renewal (PSR) is clearly increased in initiated stem cells, most of the descendants derived from such stem cells differentiate and become terminal and do not express transformed characteristics. Progression from the first to the second stage of RTE cell transformation, the stage of the immortal growth variant (IGV), is characterized by loss of responsiveness to the growth-restraining effects of retinoic acid. In the third stage of neoplastic transformation, the stage during which neoplastic growth variants (NGV) appear, a growth factor receptor gene is inappropriately expressed in some of the transformants. Thus, it appears that loss of growth-restraining mechanisms may be an early event, and activation of a growth stimulatory mechanism a late event, in neoplastic transformation of RTE cells.

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