Brief inactivation of c-Myc is not sufficient for sustained regression of c-Myc-induced tumours of pancreatic islets and skin epidermis
<p>Abstract</p> <p>Background</p> <p>Tumour regression observed in many conditional mouse models following oncogene inactivation provides the impetus to develop, and a platform to preclinically evaluate, novel therapeutics to inactivate specific oncogenes. Inactivating...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2004-12-01
|
| Series: | BMC Biology |
| Online Access: | http://www.biomedcentral.com/1741-7007/2/26 |
| _version_ | 1818353689707937792 |
|---|---|
| author | Zervou Sevasti Ifandi Vasiliki Cheung Linda Abouna Sylvie Pelengaris Stella Khan Michael |
| author_facet | Zervou Sevasti Ifandi Vasiliki Cheung Linda Abouna Sylvie Pelengaris Stella Khan Michael |
| author_sort | Zervou Sevasti |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Tumour regression observed in many conditional mouse models following oncogene inactivation provides the impetus to develop, and a platform to preclinically evaluate, novel therapeutics to inactivate specific oncogenes. Inactivating single oncogenes, such as c-Myc, can reverse even advanced tumours. Intriguingly, transient c-Myc inactivation proved sufficient for sustained osteosarcoma regression; the resulting osteocyte differentiation potentially explaining loss of c-Myc's oncogenic properties. But would this apply to other tumours?</p> <p>Results</p> <p>We show that brief inactivation of c-Myc does not sustain tumour regression in two distinct tissue types; tumour cells in pancreatic islets and skin epidermis continue to avoid apoptosis after c-Myc reactivation, by virtue of Bcl-x<sub>L </sub>over-expression or a favourable microenvironment, respectively. Moreover, tumours progress despite reacquiring a differentiated phenotype and partial loss of vasculature during c-Myc inactivation. Interestingly, reactivating c-Myc in β-cell tumours appears to result not only in further growth of the tumour, but also re-expansion of the accompanying angiogenesis and more pronounced β-cell invasion (adenocarcinoma).</p> <p>Conclusions</p> <p>Given that transient c-Myc inactivation could under some circumstances produce sustained tumour regression, the possible application of this potentially less toxic strategy in treating other tumours has been suggested. We show that brief inactivation of c-Myc fails to sustain tumour regression in two distinct models of tumourigenesis: pancreatic islets and skin epidermis. These findings challenge the potential for cancer therapies aimed at transient oncogene inactivation, at least under those circumstances where tumour cell differentiation and alteration of epigenetic context fail to reinstate apoptosis. Together, these results suggest that treatment schedules will need to be informed by knowledge of the molecular basis and environmental context of any given cancer.</p> |
| first_indexed | 2024-12-13T19:13:31Z |
| format | Article |
| id | doaj.art-540f2a6e83ba4d4683ec259b8ce04942 |
| institution | Directory Open Access Journal |
| issn | 1741-7007 |
| language | English |
| last_indexed | 2024-12-13T19:13:31Z |
| publishDate | 2004-12-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Biology |
| spelling | doaj.art-540f2a6e83ba4d4683ec259b8ce049422022-12-21T23:34:21ZengBMCBMC Biology1741-70072004-12-01212610.1186/1741-7007-2-26Brief inactivation of c-Myc is not sufficient for sustained regression of c-Myc-induced tumours of pancreatic islets and skin epidermisZervou SevastiIfandi VasilikiCheung LindaAbouna SylviePelengaris StellaKhan Michael<p>Abstract</p> <p>Background</p> <p>Tumour regression observed in many conditional mouse models following oncogene inactivation provides the impetus to develop, and a platform to preclinically evaluate, novel therapeutics to inactivate specific oncogenes. Inactivating single oncogenes, such as c-Myc, can reverse even advanced tumours. Intriguingly, transient c-Myc inactivation proved sufficient for sustained osteosarcoma regression; the resulting osteocyte differentiation potentially explaining loss of c-Myc's oncogenic properties. But would this apply to other tumours?</p> <p>Results</p> <p>We show that brief inactivation of c-Myc does not sustain tumour regression in two distinct tissue types; tumour cells in pancreatic islets and skin epidermis continue to avoid apoptosis after c-Myc reactivation, by virtue of Bcl-x<sub>L </sub>over-expression or a favourable microenvironment, respectively. Moreover, tumours progress despite reacquiring a differentiated phenotype and partial loss of vasculature during c-Myc inactivation. Interestingly, reactivating c-Myc in β-cell tumours appears to result not only in further growth of the tumour, but also re-expansion of the accompanying angiogenesis and more pronounced β-cell invasion (adenocarcinoma).</p> <p>Conclusions</p> <p>Given that transient c-Myc inactivation could under some circumstances produce sustained tumour regression, the possible application of this potentially less toxic strategy in treating other tumours has been suggested. We show that brief inactivation of c-Myc fails to sustain tumour regression in two distinct models of tumourigenesis: pancreatic islets and skin epidermis. These findings challenge the potential for cancer therapies aimed at transient oncogene inactivation, at least under those circumstances where tumour cell differentiation and alteration of epigenetic context fail to reinstate apoptosis. Together, these results suggest that treatment schedules will need to be informed by knowledge of the molecular basis and environmental context of any given cancer.</p>http://www.biomedcentral.com/1741-7007/2/26 |
| spellingShingle | Zervou Sevasti Ifandi Vasiliki Cheung Linda Abouna Sylvie Pelengaris Stella Khan Michael Brief inactivation of c-Myc is not sufficient for sustained regression of c-Myc-induced tumours of pancreatic islets and skin epidermis BMC Biology |
| title | Brief inactivation of c-Myc is not sufficient for sustained regression of c-Myc-induced tumours of pancreatic islets and skin epidermis |
| title_full | Brief inactivation of c-Myc is not sufficient for sustained regression of c-Myc-induced tumours of pancreatic islets and skin epidermis |
| title_fullStr | Brief inactivation of c-Myc is not sufficient for sustained regression of c-Myc-induced tumours of pancreatic islets and skin epidermis |
| title_full_unstemmed | Brief inactivation of c-Myc is not sufficient for sustained regression of c-Myc-induced tumours of pancreatic islets and skin epidermis |
| title_short | Brief inactivation of c-Myc is not sufficient for sustained regression of c-Myc-induced tumours of pancreatic islets and skin epidermis |
| title_sort | brief inactivation of c myc is not sufficient for sustained regression of c myc induced tumours of pancreatic islets and skin epidermis |
| url | http://www.biomedcentral.com/1741-7007/2/26 |
| work_keys_str_mv | AT zervousevasti briefinactivationofcmycisnotsufficientforsustainedregressionofcmycinducedtumoursofpancreaticisletsandskinepidermis AT ifandivasiliki briefinactivationofcmycisnotsufficientforsustainedregressionofcmycinducedtumoursofpancreaticisletsandskinepidermis AT cheunglinda briefinactivationofcmycisnotsufficientforsustainedregressionofcmycinducedtumoursofpancreaticisletsandskinepidermis AT abounasylvie briefinactivationofcmycisnotsufficientforsustainedregressionofcmycinducedtumoursofpancreaticisletsandskinepidermis AT pelengarisstella briefinactivationofcmycisnotsufficientforsustainedregressionofcmycinducedtumoursofpancreaticisletsandskinepidermis AT khanmichael briefinactivationofcmycisnotsufficientforsustainedregressionofcmycinducedtumoursofpancreaticisletsandskinepidermis |