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. 2018 Feb 21;37(7):e98311. doi: 10.15252/embj.201798311

Figure 3. mTORC1 activity correlates with stages of metaplasia during human gastric tumorigenesis.

Figure 3

  1. Immunofluorescent images of human gastric tissue from a patient with intestinal‐type gastric adenocarcinoma elsewhere. In this non‐carcinoma containing region of the gastric corpus, various states of metaplasia can be observed that reflect mouse injury models. Extensive previous work (Lennerz et al, 2010) of a dataset of such resection specimens and of biopsies showing SPEM in a non‐cancer setting has indicated likely stages of progression of SPEM from essentially normal wherein large, pyramidal‐columnar cells at the base express only chief cell markers like pepsinogen C (PGC, green) to “hybrid SPEM” (yellow arrowhead, inset) where smaller, cuboidal columnar cells label with varying degrees of PGC and the neck/SPEM cell marker GSII (purple) to “established SPEM” characterized by cells that label extensively with GSII and have scant PGC; established SPEM cells are mucus‐stuffed, with peripheral, basal, flattened nuclei (blue, DAPI). Higher magnification of each cellular phenotype is shown by color‐coded box on right. As parietal cells are lost in SPEM, the remnant one in the yellow boxed area (labeled “PC”) is consistent with the normal chief cell phenotype (representative individual cells outlined by white dashed lines). Note that there is consistently high expression of pS6 (red) throughout the cytoplasm of such normal chief cells but that this pS6 varies in the hybrid SPEM lesion and is largely scaled down in the established SPEM region (note pS6 only around the nuclei of these cells). Scale bar, 20 μm; pullouts 10 μm.
  2. Analysis of a human gastric tissue microarray with normal, metaplastic, and cancer tissue all represented from patients with resections for gastric cancer. Serial tissues sections of the array were stained by immunohistochemistry with pS6 or Ki67, counterstained with hematoxylin, and visually graded by blinded observers, supervised by a human pathologist, for staining intensity (from score 0 meaning undetectable to 3 most intense). Top—average histological score is plotted for each phenotype. Bottom—the relative fraction of tissue cores with each score is plotted (total scores of each type provided at the top of each column.
  3. Given the biphasic nature of the SPEM histological score and given that established SPEM, as observed in panel (A), shows decreased pS6, we separated all the SPEM lesions into Ki‐67+ (“proliferative”) and Ki‐67− (“quiescent”) and replotted as for panel (B).