Neoplastic transformation of normal and carcinogen-induced preneoplastic Syrian hamster embryo cells by the v-src oncogene.

Gilmer, Tona M.; Annab, Lois A.; Oshimura, Mitsuo; Barrett, J. Carl

doi:10.1128/mcb.5.7.1707

Cited by 13 publications

(9 citation statements)

References 29 publications

(33 reference statements)

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“…To our knowledge, no other studies have examined the direct role of cellular age in oncogene transformation of nonestablished cells. However, a number of papers have reported on the ability of various oncogenes (7,34,50,66), including v-src (15,23), to transform early-passage cells, findings which are consistent with the results obtained here. Furthermore, early work by Newbold and Overell (48) demonstrated that cellular senescence is a critical determinant of resistance of Syrian hamster fibroblasts to transformation by an activated ras gene, and more recent experiments by Newbold et al have provided further evidence for a role of cellular im-mortality in myc-ras transformation of these cells (47).…”

Section: Figsupporting

confidence: 91%

“…Transgenic mice bearing the activated c-neu oncogene develop mammary neoplasias in a single-step fashion (46), and retroviral delivery of v-Ha-ras to the rat mammary gland in vivo results in the emergence of multiple adenocarcinomas (75). Furthermore, a syndrome resembling chronic myelogenous leukemia is observed in mice after bone marrow infection with a retrovirus carrying the bcr-abl gene (8), and a number of studies have reported that primary cell cultures can be transformed by a single oncogene, like v-src (15,23), activated ras (10,26,34,50,52,66,68,78), EB2 of Epstein-Barr virus (7), eIF-4E (36), and simian virus 40 (SV40) large T (SV-LT). (6,72).…”

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Cellular aging is a critical determinant of primary cell resistance to v-src transformation

Tavoloni

Inoue

1997

J Virol

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Primary cell cultures are in general resistant to the transforming effect of a single oncogene, a finding considered consistent with the multistage theory of carcinogenesis. In the present studies, we examined whether cellular age, differentiation stage, and/or tissue origin of primary cells plays a role in determining their response to v-src transformation. To study the role of cellular age, rat mammary fibroblasts were isolated from a 50-day-old female rat and infected with a recombinant retrovirus carrying a v-src gene after 2, 7, 14, 21, and 28 days of continuous growth. To determine whether cellular differentiation is important, fibroblasts were isolated from embryos at 12 and 16 days of gestation, from newborns, and from a 30-day-old rat and similarly infected. Finally, the role of primary-cell histogenesis was assessed by infecting primary cultures of fibroblasts isolated from the mammary gland, dermis, and lungs of a mature rat. When compared to 3Y1 cells, all preparations of primary cultures exhibited considerable resistance to v-src transformation. However, whereas primary cells isolated from different tissues responded similarly to the transforming effect of the oncogene, major differences were observed when cells were transduced at different stages of their in vitro life span. v-src was capable of inducing formation of foci and growth in soft agar in early-passage cells but failed to do so in primary cultures infected after 14 days of continuous passaging. Similarly, both the number of foci and the number of colonies in soft agar decreased with tissue donor age. The differential response of young and senescing cells could not be explained by mutations in v-src provirus, by differences in functional v-src expression, or by growth stimulation or suppression via paracrine mechanisms. Furthermore, v-src cooperated with an immortalizing gene, like simian virus 40 large T, polyomavirus large T, E6 and E7 of human papillomavirus, or an activated p53 mutant, to induce anchorage-independent growth of primary cultures but failed to do so with cytoplasmic transforming genes, like v-abl, v-ras, or v-raf, which did not confer indefinite division potential. These studies indicate that cellular aging is a critical determinant of primary-cell resistance to v-src transformation. It is suggested that v-src requires a nuclear auxiliary function for transformation which is present in early-passage cells, particularly when these cells are derived from embryonic tissue, but is lost as cells approach replicative senescence. This auxiliary function is provided by nuclear oncogenes but not cytoplasmic transforming genes.

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confidence: 99%

Cellular aging is a critical determinant of primary cell resistance to v-src transformation

Tavoloni

Inoue

1997

J Virol

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“…Furthermore, carcinogen-induced immortality of these cells has been shown to be an important step in the tAg+ hybrid frequency was determined from the number of colonies growing in agar containing selective (HAT/ouabain) medium at 3 weeks after selection. neoplastic progression of these and other cells (1,6,17,29,30). However, several lines of evidence indicate that an additional change is required for neoplastic transformation.…”

Section: Resultsmentioning

confidence: 99%

Loss of tumor-suppressive function during chemically induced neoplastic progression of Syrian hamster embryo cells.

Koi¹,

Barrett²

1986

Proc. Natl. Acad. Sci. U.S.A.

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Cell hybrids between normal, early-passage Syrian hamster embryo cells and a highly tumorigenic, chemically transformed hamster cell line, BP6T, were formed, selected, and analyzed. Tumorigenicity andanchorage-independent growth were suppressed in the hybrid cells compared to the tumorigenic BP6T cells. These two phenotypes segregated coordinately in these cells. To determine at what stage in the neoplastic process this tumor-suppressive function was lost, two chemically induced immortal cell lines were examined at different passages for the ability to suppress the tumorigenic phenotype of BP6T cells following hybridization. Hybrids of BP6T cells with the immortal, nontumorigenic cell lines at early passages were suppressed for tumorigenicity and anchorageindependent growth. This tumor-suppressive ability was reduced in the same cells at later passages and in some cases nearly completely lost, prior to the neoplastic transformation of the immortal cell lines. Subclones of the cell lines were heterogeneous in their ability to suppress tumorigenicity in cell hybrids; some clones retained the tumor-suppressive ability and others lost this function. The susceptibility to neoplastic transformation of these cells following DNA transfection with the viral ras oncogene or BP6T DNA inversely correlated with the tumor-suppressive ability of the cells. These results suggest that chemically induced neoplastic progression of Syrian hamster embryo cells involves at least three steps: (i) induction of immortality, (ii) activation of a transforming oncogene, and (iii) loss of a tumor-suppressive function.The conversion of a normal cell into a malignant cell is recognized as a multistep process (1-3); however, the number of genetic changes involved is not known. A major advance in our understanding was the discovery of oncogenes that are capable of transforming immortal cells as well as normal, primary rodent cells when certain combinations of oncogenes are transfected into the cells (4-7).These experiments indicate that at least two cooperating, apparently dominantly acting, oncogenes are required for neoplastic transformation ofnormal, diploid cells. It has been proposed that one oncogene is involved in the immortalization process and the second in the expression of various transformed phenotypes, such as focus formation or anchorage-independent growth (3, 4, 7). However, certain observations suggest that changes in addition to these two steps are also needed. These seemingly disparate results were recently demonstrated in parallel with the same cells. Craig and Sager have shown that the ras oncogene can transform Chinese hamster CHEF-18 cells following transfection but hybrids between oncogene-transformed cells and the nontransformed CHEF-18 cells were nontransformed (13). These observations suggested to these authors that a suppressive function, possibly an anti-oncogene, is operative in the nontransformed cells and has to be lost for the expression of transformation (13). Other lines of evidence are also consistent ...

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“…p60 "-~ also transforms rodent cell lines (5,24,27), yet it is not clear whether it can efficiently convert primary cultures of mammalian cells. Gilmer et al (17) reported that v-src transforms Syrian hamster embryo cells, but considerable suppression was apparent when compared to the transforming effect in cells immortalized by carcinogens. MacAuley and Pawson (35) have also demonstrated that v-src poorly converts early passage rat adrenocortical epithelial cells to anchorageindependent growth.…”

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v-src transformation of rat embryo fibroblasts. Inefficient conversion to anchorage-independent growth involves heterogeneity of primary cultures.

Tavoloni

Inoue

Sabe

et al. 1994

The Journal of Cell Biology

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Abstract. To clarify whether a single oncogene can transform primary cells in culture, we compared the transforming effect of a recombinant retrovirus (ZSV) containing the v-src gene in rat embryo fibroblasts (REFs) to that in the rat cell line 3Y1. In the focus assay, REFs exhibited resistance to transformation as only six foci were observed in the primary cultures as opposed to 98 in 3Y1 cells. After (3418 selection, efficiency of transformation was again somewhat lower with REFs compared to that with 3Y1 cells, but the number of G418-resistant REF colonies was much greater than the number of foci in REF cultures. Furthermore, while 98% of G418-resistant colonies of ZSV-infected REFs were morphologically transformed, only 25 % were converted to anchorage-independent growth, as opposed to 100% conversion seen in ZSVinfected 3Y1 cells. The poor susceptibility of REFs to anchorage-independent transformation did not involve differences in expression and subcellular distribution of p60v"rL or its kinase activity in vitro and in vivo. It rather reflected a property of the primary cultures, as cloning of REFs before ZSV infection demonstrated that only 2 out of 6 REF clones tested were permissive for anchorage-independent growth. The nonpermissive phenotype was dominant over the permissive one in somatic hybrid cells, and associated with organized actin filament bundles and a lower growth rate, both before and after ZSV infection. These results indicate that the poor susceptibility of REFs to anchorage-independent transformation by p60 v-~ reflects the heterogeneity of the primary cultures. REFs can be morphologically transformed by p60 v-sr~ with high efficiency but only a small fraction is convertible to anchorage-independent growth. REF resistance seems to involve the presence of a suppressor factor which may emerge from REF differentiation during embryonic development.

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Neoplastic transformation of normal and carcinogen-induced preneoplastic Syrian hamster embryo cells by the v-src oncogene.

Cited by 13 publications

References 29 publications

Cellular aging is a critical determinant of primary cell resistance to v-src transformation

Cellular aging is a critical determinant of primary cell resistance to v-src transformation

Loss of tumor-suppressive function during chemically induced neoplastic progression of Syrian hamster embryo cells.

v-src transformation of rat embryo fibroblasts. Inefficient conversion to anchorage-independent growth involves heterogeneity of primary cultures.

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