Affo, Silvia

Chen, Xin

Schwabe, Robert F

Yu, Le-Xing

English

VCU Scholars Compass

Virginia Commonwealth UniversityVCU Scholars CompassHepatobiliary Cancers: Pathobiology andTranslational Advances Dept. of Pathology2017Hepatic Stellate Cell-Derived Cancer AssociatedFibroblasts Sustain Tumor Growth in IntrahepaticCholangiocarcinomaSilvia AffoColumbia University, sa2957@cumc.columbia.eduLe-Xing YuColumbia University, ly2379@cumc.columbia.eduXin ChenUniversity of California, San Francisco, xin.chen@ucsf.eduRobert F. SchwabeColumbia University, rfs2102@cumc.columbia.eduFollow this and additional works at: http://scholarscompass.vcu.edu/hepa_cancersPart of the Medicine and Health Sciences Commons© The Author(s)This Abstract Accepted for Presentation is brought to you for free and open access by the Dept. of Pathology at VCU Scholars Compass. It has beenaccepted for inclusion in Hepatobiliary Cancers: Pathobiology and Translational Advances by an authorized administrator of VCU Scholars Compass.For more information, please contact libcompass@vcu.edu.Downloaded fromhttp://scholarscompass.vcu.edu/hepa_cancers/31Hepatic  Stellate  Cell-­Derived  Cancer  Associated  Fibroblasts  Sustain  Tumor  Growth  in  Intrahepatic  Cholangiocarcinoma        Silvia  Affo1,  Le-­Xing  Yu1,  Xin  Chen2,  Robert  F.  Schwabe1    1  Department  of  Medicine,  Columbia  University,  New  York,  NY  10032,  USA.    2  Department  of  Bioengineering  and  Therapeutic  Sciences  and  Liver  Center,  University  of  California,  San  Francisco,  CA,  USA      Background:   Cholangiocarcinoma   (CCA)   is  characterized  by  abundant  cancer-­associated  fibroblasts  (CAF).  Clinical  data  suggest  an  inverse  correlation  between  αSMA-­positive  CAF  and  survival  in  CCA.  However,  functional  in  vivo  studies  that  determine   whether   CAF   promote   or   restrict   CCA   are   lacking.  Objectives:   To  determine  the  cellular  source  and  functions  of  CAF  in  intrahepatic  CCA  (ICC)   in  vivo.  Methods   and  Results:   Sleeping   beauty-­mediated   overexpression   of  HA-­tagged   pT3-­myr-­AKT   and   pT3-­EF1aH-­YapS127A   in   the   liver   resulted   in  desmoplastic  ICC  with  abundant  αSMA-­positive  CAF  and  significant  upregulation  of  fibrogenic  genes  Acta2  (34-­fold)  and  Col1a1  (125-­fold).  Expression  of  hepatic  stellate  cell  (HSC)  markers  Des  and  Lrat  mRNA  was  significantly  increased  in  ICC  (11-­  and  3-­fold,  respectively).  HSC  origin  of  CAF  was  further  supported  by  tracing  studies   in   triple   transgenic   mice   expressing   LratCre   and   Cre   reporter   TdTom,  which   label  >99%  of  HSCs   in   the   liver,   in  combination  with  Col1a1-­GFP,  which  labels  collagen-­producing  fibroblasts.  92.95±  5.27%  (n=10)  of  CAF  were  TdTom-­positive,  i.e.  derived  from  LratCre+  HSC.  To  functionally  manipulate  HSC-­derived  CAF   in   vivo,   we   employed   triple   transgenic   mice   expressing   LratCre,   Cre-­inducible  iDTR   and  Cre   reporter   TdTom.   By   this   approach,   we   depleted   >90%  CAF,  as  determined  by  TdTom  fluorescence,  qPCR  for  HSC  markers  Lrat,  Lhx2  and  Des,  as  well  as  Col1a1,  but  not  portal  fibroblast  marker  Msln.  Short-­term  CAF  depletion  reduced  fibrosis,  tumor  proliferation,  as  determined  by  Ki67  staining  and  qPCR  for  mKi67  and  Ccnb1,  and  increased  cell  death  in  ICC.  Conclusion:  Our  study  suggest  that  the  majority  of  CAF  are  HSC-­derived,  and  HSC-­derived  CAF  support  the  development  of  ICC  by  promoting  tumor  cell  proliferation  and  survival.  

Hepatic Stellate Cell-Derived Cancer Associated Fibroblasts Sustain Tumor Growth in Intrahepatic Cholangiocarcinoma

https://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=1003&amp;context=hepa_cancers

Hepatic Stellate Cell-Derived Cancer Associated Fibroblasts Sustain Tumor Growth in Intrahepatic Cholangiocarcinoma

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