PMID- 23308058
OWN - NLM
STAT- MEDLINE
DCOM- 20130710
LR  - 20211203
IS  - 1476-5586 (Electronic)
IS  - 1522-8002 (Print)
IS  - 1476-5586 (Linking)
VI  - 14
IP  - 12
DP  - 2012 Dec
TI  - p16INK4A represses breast stromal fibroblasts migration/invasion and their 
      VEGF-A-dependent promotion of angiogenesis through Akt inhibition.
PG  - 1269-77
AB  - Stromal fibroblasts, the most abundant and probably the most active cellular 
      component of breast cancer-associated stroma, become active and promote 
      angiogenesis through paracrine effects. However, it still unclear how these 
      processes are regulated. Here, we have shown that down-regulation of the tumor 
      suppressor p16(INK4A) protein enhances the migration/invasion abilities of breast 
      stromal fibroblasts, which form dendritic network of extensions into matrigel. 
      Furthermore, we present clear evidence that p16(INK4A) represses the 
      expression/secretion of the proangiogenesis protein vascular endothelial growth 
      factor A (VEGF-A). Consequently, p16(INK4A)-deficient breast stromal fibroblasts 
      and mouse embryonic fibroblasts enhanced endothelial cell differentiation into 
      capillary-like structures in a paracrine manner. This effect was suppressed by 
      adding bevacizumab, a specific VEGF-A inhibitor. Additionally, 
      p16(INK4A)-defective mouse embryonic fibroblasts enhanced angiogenesis in breast 
      cancer xenografts in mice. Furthermore, we have shown that p16(INK4A) suppresses 
      the Akt/mammalian target of rapamycin (mTOR) signaling pathway and its downstream 
      effector hypoxia-inducible factor 1-alpha (HIF-1alpha), which transactivates VEGF-A. 
      Consequently, Akt inactivation suppressed both the p16(INK4A)-dependent autocrine 
      effect on fibroblast migration/invasion and the paracrine effect on angiogenesis, 
      showing the important role of this protein kinase in mediating the various 
      effects related to p16(INK4A) deficiency. These results indicate that p16(INK4A) 
      is an efficient inhibitor of the migration/invasion abilities of breast stromal 
      fibroblasts and also their paracrine proangiogenic effects, through inhibition of 
      Akt. Therefore, pharmacologic restoration of p16(INK4A) level in stromal 
      fibroblasts may be exploited as therapeutic strategy to help eradicate tumor 
      cells and/or prevent their recurrence, through suppressing cell non-autonomous 
      procarcinogenic mediators.
FAU - Al-Ansari, Mysoon M
AU  - Al-Ansari MM
AD  - Department of Molecular Oncology, King Faisal Specialist Hospital and Research 
      Center, Riyadh, Saudi Arabia.
FAU - Hendrayani, Siti-Fauziah
AU  - Hendrayani SF
FAU - Tulbah, Asma
AU  - Tulbah A
FAU - Al-Tweigeri, Taher
AU  - Al-Tweigeri T
FAU - Shehata, Afaf I
AU  - Shehata AI
FAU - Aboussekhra, Abdelilah
AU  - Aboussekhra A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Neoplasia
JT  - Neoplasia (New York, N.Y.)
JID - 100886622
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 2S9ZZM9Q9V (Bevacizumab)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Angiogenesis Inhibitors/pharmacology
MH  - Animals
MH  - Antibodies, Monoclonal, Humanized/pharmacology
MH  - Autocrine Communication
MH  - Bevacizumab
MH  - Breast Neoplasms/*blood supply/*metabolism
MH  - Cell Differentiation
MH  - *Cell Movement
MH  - Cyclin-Dependent Kinase Inhibitor p16/genetics/*metabolism
MH  - Down-Regulation
MH  - Fibroblasts/metabolism/pathology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - Mice
MH  - Neovascularization, Pathologic/*metabolism
MH  - Open Reading Frames
MH  - Paracrine Communication
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - RNA, Small Interfering
MH  - *Signal Transduction
MH  - Stromal Cells/metabolism/pathology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Tumor Cells, Cultured
MH  - Vascular Endothelial Growth Factor A/*metabolism
PMC - PMC3540951
EDAT- 2013/01/12 06:00
MHDA- 2013/07/11 06:00
PMCR- 2012/12/01
CRDT- 2013/01/12 06:00
PHST- 2012/09/29 00:00 [received]
PHST- 2012/10/24 00:00 [revised]
PHST- 2012/10/29 00:00 [accepted]
PHST- 2013/01/12 06:00 [entrez]
PHST- 2013/01/12 06:00 [pubmed]
PHST- 2013/07/11 06:00 [medline]
PHST- 2012/12/01 00:00 [pmc-release]
AID - 121632 [pii]
AID - 10.1593/neo.121632 [doi]
PST - ppublish
SO  - Neoplasia. 2012 Dec;14(12):1269-77. doi: 10.1593/neo.121632.