%0 Generic
%A Khan, Mohammad Wasim Kayyum
%C Heidelberg
%D 2013
%F heidok:14917
%R 10.11588/heidok.00014917
%T PI3K/AKT signaling is essential for  communication between tissue infiltrating mast  cells, macrophages, and epithelial cells in colitis-induced  cancer
%U https://archiv.ub.uni-heidelberg.de/volltextserver/14917/
%X Colorectal cancer is one of the leading cause of mortality in USA and worldwide.  Colon cancer is a complex world of connective tissue epithelial, inflammatory and  endothelial cell interactions. It s long known that patients with persistent colitis  are at high risk of developing colon cancer, where the patients passes through a  phase from colitis to colitis induced dysplasia and finally invasive cancer. Though  a lot of efforts have been poured into understanding the mechanisms underlying  the etiology of colon cancer, less has been known with respect to the changes  happening at genomic and proteomic levels in the inflammatory compartment of  the colon cancer with respect to interaction with the tumor epithelium and  subsequent tumor progression.  It is well known that the levels of PI3K/AKT and inflammatory cells mainly mast  cells and macrophages are upregulated in the cancer. However, few efforts have  been done to understand the pathogenesis in this direction, but they lacked in the  correlative study of PI3K/AKT or immune infiltration in colon cancer or colitis and  their spatial distribution with respect to cancer prognosis. Hence for the first time  in this study a novel investigation was conducted where human patients were  studied in the various stages of inflammation associated colonic illness i.e. colitis  to dysplasia and invasive cancer and compared it to normal amongst  themselves. The human-patient colonic tissue specimens were investigated for  the spatial distribution of mast cells, macrophages and pAKT in the histological  areas of musoca and submucosa. It was observed that mast cells, macrophages  and pAKT levels incrementally rise from colitis to dysplasia to cancer in the  submucosal tissues. In mucosal tissue, pAKT levels were found atleast 10 fold  higher in the stromal cells in comparison with epithelial cells. The stromal and  submucosal pAKT+ cells were found to be the macrophages that progressively  infiltrate from colitis to dysplasia and invasive cancer, also mast cells were found  to be high in pAKT activity.  To investigate the role of PI3K/AKT in mast cells and macrophages biology and  4  their crosstalk with colonic epithelium a pan PI3K/AKT inhibitor used in clinical  trials “LY2949002” was used. PI3K/AKT in mast cells was found to be critical for  peripheral blood isolated human macrophage migration. LY294002 treatment of  human and gut-derived murine mast cells restricted their ability to degranulate in  dose-dependent manner. Moreover, inhibition of PI3K/AKT in human and mouse  mast cells blocked the release of growth factors from them, and attenuated tumor  proliferation and invasion promoting properties of mast cells. Also, PI3K/AKT  inhibition in tumor infiltrating leukocytes isolated from colitis-associated patients  lowered their soluble growth factor and cell-cell contact based tumor invasion  promoting properties.  Treatment of LY294002 using intra-peritoneal injections lowered the incidence of  colitis associated invasive cancer development by day 56 in the Piroxicam  treated IL-10-/- mice. LY294002 displayed a striking effect on the epithelial  proliferation, induced tumor apoptosis and attenuated the pAKT levels.  LY294002 showed special predilection for the pAKT+ stromal cells in comparison  with pAKT+ epithelial cells. Moreover, frequencies of mast cells and granulocytebased  inflammation were lowered after LY294002 treatment. Finally, the in situ  degraunulating potential of mast cells was attenuated by LY294002 treatment.  In conclusion, using in situ human patient specimen study, in vitro human and  murine assays and in vivo mouse model system this study confirms the role of  PI3K/AKT pathway in mast cells and tumor infiltrating leukocytes in crosstalk with  the colonic epithelium and progression of colonic tissue from colitis.