Simultaneous Loss of Both Atypical Protein Kinase C Genes in the Intestinal Epithelium Drives Serrated Intestinal Cancer by Impairing Immunosurveillance.

ABSTRACT: Serrated adenocarcinoma, an alternative pathway for colorectal cancer (CRC) development, accounts for 15%-30% of all CRCs and is aggressive and treatment resistant. We show that the expression of atypical protein kinase C ζ (PKCζ) and PKCλ/ι was reduced in human serrated tumors. Simultaneous inactivation of the encoding genes in the mouse intestinal epithelium resulted in spontaneous serrated tumorigenesis that progressed to advanced cancer with a strongly reactive and immunosuppressive stroma. Whereas epithelial PKCλ/ι deficiency led to immunogenic cell death and the infiltration of CD8⁺ T cells, which repressed tumor initiation, PKCζ loss impaired interferon and CD8⁺ T cell responses, which resulted in tumorigenesis. Combined treatment with a TGF-β receptor inhibito

SUBMITTER: Nakanishi Y 

PROVIDER: S-EPMC6301096 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature