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Carcinoembryonic antigen, a human tumor marker, cooperates with Myc and Bcl-2 in cellular transformation.

Screaton RA, Penn LZ, Stanners CP - J. Cell Biol. (1997)

Bottom Line: The further expression of CEA has a dominant effect in blocking differentiation, regardless of the presence of the other activated oncogenes, generating cells that enter a reversible quiescent G0-like state in medium promoting differentiation.Transfectants expressing CEA with or without v-myc and bcl-2 allow the emergence of cells with the property of heritable, efficient, anchorage-independent growth in soft agar and the ability to markedly reduce the latency for tumor formation in nude mice.We propose that by prolonging cell survival in the presence of differentiation signals, CEA represents a novel class of dominant differentiation-blocking oncogene.

View Article: PubMed Central - PubMed

Affiliation: McGill Cancer Centre and Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6.

ABSTRACT
Carcinoembryonic antigen (CEA) is a tumor marker that is overexpressed in many human cancers and functions in vitro as a homotypic intercellular adhesion molecule. We have investigated the possibility of synergy between CEA, v-Myc, and Bcl-2 in the transformation of cells with differentiation capacity. We find that v-Myc increases the cell division rate and maximum density of rat L6 myoblasts but also markedly stimulates both apoptosis and surprisingly, differentiation, thus preventing transformation. The superposition of Bcl-2 blocks the apoptotic stimulation of v-Myc and independently promotes further cell division at confluence, but still allows differentiation. The further expression of CEA has a dominant effect in blocking differentiation, regardless of the presence of the other activated oncogenes, generating cells that enter a reversible quiescent G0-like state in medium promoting differentiation. Transfectants expressing CEA with or without v-myc and bcl-2 allow the emergence of cells with the property of heritable, efficient, anchorage-independent growth in soft agar and the ability to markedly reduce the latency for tumor formation in nude mice. We propose that by prolonging cell survival in the presence of differentiation signals, CEA represents a novel class of dominant differentiation-blocking oncogene.

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Model showing  integrated effects of Myc,  Bcl-2, and CEA. Postmitotic  cells in the presence of serum  growth factors (GF) pass  through G1 and reenter S  phase; at high GF levels, Myc  drives cells into S, reducing  the length of the G1 period.  At low GF levels, Myc will  activate both myogenic differentiation from G1/G0 and  apoptosis (not restricted to  G1); under these conditions  Bcl-2 may promote further  cycling. Coexpression of Bcl-2  with Myc blocks apoptosis.  CEA prevents normal and  Myc-induced differentiation  and directs cells into a viable,  reversible quiescent state  that prolongs survival. Stimulation with growth factors or  activation of an additional  oncogene(s) thus can drive  CEA-expressing cells back  into cycle.
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Figure 10: Model showing integrated effects of Myc, Bcl-2, and CEA. Postmitotic cells in the presence of serum growth factors (GF) pass through G1 and reenter S phase; at high GF levels, Myc drives cells into S, reducing the length of the G1 period. At low GF levels, Myc will activate both myogenic differentiation from G1/G0 and apoptosis (not restricted to G1); under these conditions Bcl-2 may promote further cycling. Coexpression of Bcl-2 with Myc blocks apoptosis. CEA prevents normal and Myc-induced differentiation and directs cells into a viable, reversible quiescent state that prolongs survival. Stimulation with growth factors or activation of an additional oncogene(s) thus can drive CEA-expressing cells back into cycle.

Mentions: From these results, we suggest that CEA expression accelerates progression towards transformation and increased tumorigenicity by blocking terminal differentiation, thus providing a “fertile soil” for the emergence of cellular variants with increased proliferative potential. Indeed, after reaching an initial stationary phase, all cell lines expressing CEA tend to increase slowly in cell number (Fig. 2), indicating an increased sensitivity to proliferative stimuli. CEA-expressing cell lines also accumulate tumorigenic macrocolony-producing cells, as noted above. The nature of the heritable changes giving rise to macrocolonies is presently unknown. Bcl-2 has also been suggested to provide a cellular state conducive to the emergence of more autonomous variants, yet accomplishes this by a fundamentally different mechanism, i.e., by the suppression of apoptosis. In transgenic mice, ectopic bcl-2 expression alone does not directly result in tumors (McDonnell et al., 1989) yet generates a population of quiescent cells that possesses oncogenic potential, perhaps as a consequence of extended survival (McDonnell and Korsmeyer, 1991). In the L6 system, however, Bcl-2 was relatively ineffective in promoting the emergence of variants or decreasing tumor latency. Thus CEA seems to posess a novel oncogenic activity, with a distinct mechanism from Bcl-2 for the induction of a long term viable quiescence (Fig. 10).


Carcinoembryonic antigen, a human tumor marker, cooperates with Myc and Bcl-2 in cellular transformation.

Screaton RA, Penn LZ, Stanners CP - J. Cell Biol. (1997)

Model showing  integrated effects of Myc,  Bcl-2, and CEA. Postmitotic  cells in the presence of serum  growth factors (GF) pass  through G1 and reenter S  phase; at high GF levels, Myc  drives cells into S, reducing  the length of the G1 period.  At low GF levels, Myc will  activate both myogenic differentiation from G1/G0 and  apoptosis (not restricted to  G1); under these conditions  Bcl-2 may promote further  cycling. Coexpression of Bcl-2  with Myc blocks apoptosis.  CEA prevents normal and  Myc-induced differentiation  and directs cells into a viable,  reversible quiescent state  that prolongs survival. Stimulation with growth factors or  activation of an additional  oncogene(s) thus can drive  CEA-expressing cells back  into cycle.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2139844&req=5

Figure 10: Model showing integrated effects of Myc, Bcl-2, and CEA. Postmitotic cells in the presence of serum growth factors (GF) pass through G1 and reenter S phase; at high GF levels, Myc drives cells into S, reducing the length of the G1 period. At low GF levels, Myc will activate both myogenic differentiation from G1/G0 and apoptosis (not restricted to G1); under these conditions Bcl-2 may promote further cycling. Coexpression of Bcl-2 with Myc blocks apoptosis. CEA prevents normal and Myc-induced differentiation and directs cells into a viable, reversible quiescent state that prolongs survival. Stimulation with growth factors or activation of an additional oncogene(s) thus can drive CEA-expressing cells back into cycle.
Mentions: From these results, we suggest that CEA expression accelerates progression towards transformation and increased tumorigenicity by blocking terminal differentiation, thus providing a “fertile soil” for the emergence of cellular variants with increased proliferative potential. Indeed, after reaching an initial stationary phase, all cell lines expressing CEA tend to increase slowly in cell number (Fig. 2), indicating an increased sensitivity to proliferative stimuli. CEA-expressing cell lines also accumulate tumorigenic macrocolony-producing cells, as noted above. The nature of the heritable changes giving rise to macrocolonies is presently unknown. Bcl-2 has also been suggested to provide a cellular state conducive to the emergence of more autonomous variants, yet accomplishes this by a fundamentally different mechanism, i.e., by the suppression of apoptosis. In transgenic mice, ectopic bcl-2 expression alone does not directly result in tumors (McDonnell et al., 1989) yet generates a population of quiescent cells that possesses oncogenic potential, perhaps as a consequence of extended survival (McDonnell and Korsmeyer, 1991). In the L6 system, however, Bcl-2 was relatively ineffective in promoting the emergence of variants or decreasing tumor latency. Thus CEA seems to posess a novel oncogenic activity, with a distinct mechanism from Bcl-2 for the induction of a long term viable quiescence (Fig. 10).

Bottom Line: The further expression of CEA has a dominant effect in blocking differentiation, regardless of the presence of the other activated oncogenes, generating cells that enter a reversible quiescent G0-like state in medium promoting differentiation.Transfectants expressing CEA with or without v-myc and bcl-2 allow the emergence of cells with the property of heritable, efficient, anchorage-independent growth in soft agar and the ability to markedly reduce the latency for tumor formation in nude mice.We propose that by prolonging cell survival in the presence of differentiation signals, CEA represents a novel class of dominant differentiation-blocking oncogene.

View Article: PubMed Central - PubMed

Affiliation: McGill Cancer Centre and Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6.

ABSTRACT
Carcinoembryonic antigen (CEA) is a tumor marker that is overexpressed in many human cancers and functions in vitro as a homotypic intercellular adhesion molecule. We have investigated the possibility of synergy between CEA, v-Myc, and Bcl-2 in the transformation of cells with differentiation capacity. We find that v-Myc increases the cell division rate and maximum density of rat L6 myoblasts but also markedly stimulates both apoptosis and surprisingly, differentiation, thus preventing transformation. The superposition of Bcl-2 blocks the apoptotic stimulation of v-Myc and independently promotes further cell division at confluence, but still allows differentiation. The further expression of CEA has a dominant effect in blocking differentiation, regardless of the presence of the other activated oncogenes, generating cells that enter a reversible quiescent G0-like state in medium promoting differentiation. Transfectants expressing CEA with or without v-myc and bcl-2 allow the emergence of cells with the property of heritable, efficient, anchorage-independent growth in soft agar and the ability to markedly reduce the latency for tumor formation in nude mice. We propose that by prolonging cell survival in the presence of differentiation signals, CEA represents a novel class of dominant differentiation-blocking oncogene.

Show MeSH
Related in: MedlinePlus