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  • br The current work supports the finding that cancer organoi

    2020-08-12


    The current work supports the finding that cancer organoids derived from resected gastric cancer tumors may 
    capture the response to standard-of-care chemotherapeutics of the patient’s native tumor. Our data showed that each huTGO line exhibited a unique response to epirubicin, oxaliplatin, and 5-FU, when compared with the non-divergent responses of huFGOs to the same drugs. These results may be attributed to the heterogeneity in each cancer organoid line exhibiting various mutations that do not exist in organoids derived from normal tissue. A recent study also reporting the development of gastric cancer organoids supports our findings.23 Seidlitz et al23 report
    174 Steele et al Cellular and Molecular Gastroenterology and Hepatology Vol. 7, No. 1
    that human-derived cancer organoids represent typical characteristics and altered pathways of gastric cancer. Although the report also documents that gastric cancer organoids derived from individual patients exhibit divergent drug responses, this 138908-40-4 study fails to address the original patient’s tumor responses to treatment. Although a limita-tion of our current study is the small sample size, we report a potential correlation between organoid responses to chemotherapy with the patient’s own tumor response from which the cultures were derived. In support of this, huTGO7 
    Figure 10. IC50 values for huTGO6 dose-response curves. IC50 values for
    tumor-derived gastric organoids (huTGO) treated with (A) epirubicin with or without HER2I, (B) oxali-platin with or without HER2I, or (C) 5-FU with or without HER2I. CI, confi-dence interval.
    organoid line was highly chemosensitive to the combination treatment of epirubicin, oxaliplatin, and 5-FU (Figure 5A). Importantly, huTGO7 was derived from a patient who was diagnosed with a complete response to chemotherapy (Table 1). In contrast, huTGO4 responded partially to the combination in vitro treatment of the organoids (Figure 5A); however, this patient did not respond to chemotherapy treatment (Table 1). One potential explanation for these data is the absence of the patient’s immune component in the culture system. Immune dysregulation may contribute
    2019 Human-Derived Gastric Cancer Organoids 175
    176 Steele et al Cellular and Molecular Gastroenterology and Hepatology Vol. 7, No. 1
    Figure 12. Engraftment and immunostaining of adenocarcinoma arising from orthotopically transplanted patient-derived gastric cancer organoids. Immunohisto-chemical evaluation of CK7 in orthotopic (A) huTGO1 or (B) huTGO2 trans-planted mouse stomachs. Immunohistochemical analysis of CK20 in ortho-topic (C) huTGO1 or (D)
    huTGO2 transplanted mouse stomachs. Immu-nohistochemistry of Ki67 expression in orthotopic (E) huTGO1 or (F) huTGO2 transplanted mouse stom-achs. Immunofluorescence of E-cadherin expression (E cad, green) in orthotopic (G) huTGO1 or (H) huTGO2
    transplanted mouse stomachs.
    to tumor progression in gastric cancer. For example, it has been shown that the infiltration of myeloid-derived sup-pressor cells contributes not only to the suppression of
    T-cell activation but also the impairment of the efficacy of cancer immunotherapy.24,25 Thus, we may speculate that if the patient from whom huTGO4 was derived exhibited high
    Figure 11. (See previous page). Analysis of patient-derived gastric cancer organoid xenografts and orthotopic trans-plants. (A) Tumor volume measured over time of patient-derived xenografts (PDX). H&E staining of patient tumor tissue and patient-derived xenografts from (B) P1; PDX-huTGO1 and (C) P2; PDX-huTGO2. (D) Gross morphology of gastric tumor 30 days after orthotopic transplantation of patient-derived gastric cancer organoids in NSG mice. H&E staining of NSG mouse stomachs orthotopically transplanted with (E) huTGO1 and (F) huTGO2 30 days after injection. High-power magnification of human adenocarcinoma within submucosa of mice transplanted with (G) huTGO1 and (I) huTGO2. Immunofluorescence staining of human histone (red) and nuclear staining (Hoescht, blue) in NSG mouse stomachs orthotopically transplanted with (H) huTGO1 or (J) huTGO2.
    2019 Human-Derived Gastric Cancer Organoids 177
    Figure 13. Human histone immunofluorescence of nontransplanted mouse stomach. (A) Immunofluo- rescence of non- transplanted mouse stomach using an antibody specific for human histone (red) and Hoechst (blue). (B) Higher magnification is shown.
    infiltrating myeloid-derived suppressor cells, then the patient’s tumor response would be poor. However, in vitro in the absence of these immunosuppressive myeloid-derived suppressor cells and cytotoxic T lymphocytes, it may be expected that the huTGO4 cultures would exhibit increased chemosensitivity. Thus, our future studies will include co-culturing patient-derived immune cells and tumor organoids to investigate the potential effect of immune-tumor cell cross talk on treatment response. Importantly, our plans also entail using a larger patient sample size to truly predict patient outcome based on an organoid-based response to chemotherapy.