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Conference Paper: p70 S6 kinase promotes a critical step in ovarian cancer metastasis by modulating tumor-mesothelial cell adhesion through a P-cadherin-beta1-integrin crosstalk

Titlep70 S6 kinase promotes a critical step in ovarian cancer metastasis by modulating tumor-mesothelial cell adhesion through a P-cadherin-beta1-integrin crosstalk
Authors
Keywordsovarian cancer
peritoneal adhesion
p70 S6 kinase
Issue Date2013
PublisherEuropean CanCer Organisation (ECCO).
Citation
European Cancer Congress 2013 (ECCO-ESMO-ESTRO): Reinforcing Multidisciplinarity, Amsterdam, The Netherlands, 27 September-1 October 2013, p. abstract no. 3015 How to Cite?
AbstractBackground: Ovarian cancer is the leading cause of death of all gynecologic tumors. These deaths are largely due to the fact that most patients are diagnosed at an advanced stage. Unlike most solid tumors, ovarian cancer rarely disseminates through the vasculature but metastasizes by the implantation of tumor spheroids onto the peritoneum, and successful adhesion is the first rate-limiting step in the metastasis formation of ovarian cancer cells. This unique metastatic mechanism poses distinct therapeutic challenges, in which current treatments are not effective. Unraveling the molecular mechanisms underlying this process may lead to new therapeutic targets. Material and Methods: We employed overexpression and knockdown approaches to investigate the molecular mechanisms of ovarian cancer spheroids which most closely mimic the in vivo ovarian carcinoma adhesion to human primary mesothelial cells in vitro and different extracellular matrix components, and utilized an intraperitoneal ovarian cancer model to test metastasis in vivo. Results: Here we report a novel function of p70S6K in the peritoneal adhesion of ovarian cancer cells, which is the first rate-limiting step in ovarian cancer metastasis. Ectopic expression of active p70S6K significantly enhanced, whereas depletion of p70S6K expression or inhibition of its activity resulted in diminished ovarian cancer spheroid adhesion to the mesothelium and specific extracellular matrix proteins. These effects were accompanied by an increase in the expression of P-cadherin and beta1 integrin. Furthermore, we provided evidence for the existence of a crosstalk between P-cadherin and beta1 integrin. In particular, we demonstrated that an upregulation of beta1 integrin occurred as a consequence of P-cadherin expression. In an attempt to establish the regulatory mechanism whereby P-cadherin exerted its transacting functions, we found that the upregulation of beta1 integrin mainly due to posttranslational events. Using an experimental metastatic mouse model, we showed that loss of p70S6K significantly attenuated the metastatic spread of ovarian cancer cells to the peritoneum. Targeting the P-cadherin/beta1-integrin interplay also abolished the metastatic dissemination of ovarian cancer cells in mice. Conclusions: These data strongly support a new function of p70S6K in ovarian cancer metastasis, and provide evidence that a novel interplay between P-cadherin and beta1-integrin is essential for this process.
Description17th ECCO - 38th ESMO - 32nd ESTRO European Cancer Congress (ECC 2013)
Session title: Gynaecological Cancer
Poster Session
Persistent Identifierhttp://hdl.handle.net/10722/198161

 

DC FieldValueLanguage
dc.contributor.authorIp, KMen_US
dc.contributor.authorYung, SSYen_US
dc.contributor.authorChan, DTMen_US
dc.contributor.authorTsao, GSWen_US
dc.contributor.authorWong, ASTen_US
dc.date.accessioned2014-06-25T02:49:56Z-
dc.date.available2014-06-25T02:49:56Z-
dc.date.issued2013en_US
dc.identifier.citationEuropean Cancer Congress 2013 (ECCO-ESMO-ESTRO): Reinforcing Multidisciplinarity, Amsterdam, The Netherlands, 27 September-1 October 2013, p. abstract no. 3015en_US
dc.identifier.urihttp://hdl.handle.net/10722/198161-
dc.description17th ECCO - 38th ESMO - 32nd ESTRO European Cancer Congress (ECC 2013)-
dc.descriptionSession title: Gynaecological Cancer-
dc.descriptionPoster Session-
dc.description.abstractBackground: Ovarian cancer is the leading cause of death of all gynecologic tumors. These deaths are largely due to the fact that most patients are diagnosed at an advanced stage. Unlike most solid tumors, ovarian cancer rarely disseminates through the vasculature but metastasizes by the implantation of tumor spheroids onto the peritoneum, and successful adhesion is the first rate-limiting step in the metastasis formation of ovarian cancer cells. This unique metastatic mechanism poses distinct therapeutic challenges, in which current treatments are not effective. Unraveling the molecular mechanisms underlying this process may lead to new therapeutic targets. Material and Methods: We employed overexpression and knockdown approaches to investigate the molecular mechanisms of ovarian cancer spheroids which most closely mimic the in vivo ovarian carcinoma adhesion to human primary mesothelial cells in vitro and different extracellular matrix components, and utilized an intraperitoneal ovarian cancer model to test metastasis in vivo. Results: Here we report a novel function of p70S6K in the peritoneal adhesion of ovarian cancer cells, which is the first rate-limiting step in ovarian cancer metastasis. Ectopic expression of active p70S6K significantly enhanced, whereas depletion of p70S6K expression or inhibition of its activity resulted in diminished ovarian cancer spheroid adhesion to the mesothelium and specific extracellular matrix proteins. These effects were accompanied by an increase in the expression of P-cadherin and beta1 integrin. Furthermore, we provided evidence for the existence of a crosstalk between P-cadherin and beta1 integrin. In particular, we demonstrated that an upregulation of beta1 integrin occurred as a consequence of P-cadherin expression. In an attempt to establish the regulatory mechanism whereby P-cadherin exerted its transacting functions, we found that the upregulation of beta1 integrin mainly due to posttranslational events. Using an experimental metastatic mouse model, we showed that loss of p70S6K significantly attenuated the metastatic spread of ovarian cancer cells to the peritoneum. Targeting the P-cadherin/beta1-integrin interplay also abolished the metastatic dissemination of ovarian cancer cells in mice. Conclusions: These data strongly support a new function of p70S6K in ovarian cancer metastasis, and provide evidence that a novel interplay between P-cadherin and beta1-integrin is essential for this process.-
dc.languageengen_US
dc.publisherEuropean CanCer Organisation (ECCO).-
dc.relation.ispartofEuropean Cancer Congressen_US
dc.subjectovarian cancer-
dc.subjectperitoneal adhesion-
dc.subjectp70 S6 kinase-
dc.titlep70 S6 kinase promotes a critical step in ovarian cancer metastasis by modulating tumor-mesothelial cell adhesion through a P-cadherin-beta1-integrin crosstalken_US
dc.typeConference_Paperen_US
dc.identifier.emailIp, KM: carmanip@hku.hken_US
dc.identifier.emailYung, SSY: ssyyung@hku.hken_US
dc.identifier.emailChan, DTM: dtmchan@hku.hken_US
dc.identifier.emailTsao, GSW: gswtsao@hku.hken_US
dc.identifier.emailWong, AST: awong1@hku.hken_US
dc.identifier.authorityYung, SSY=rp00455en_US
dc.identifier.authorityChan, DTM=rp00394en_US
dc.identifier.authorityTsao, GSW=rp00399en_US
dc.identifier.authorityWong, AST=rp00805en_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.hkuros229622en_US
dc.identifier.spageabstract no. 3015-
dc.identifier.epageabstract no. 3015-
dc.publisher.placeThe Netherlands-

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