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Fig. 6 | Journal for ImmunoTherapy of Cancer

Fig. 6

From: Ovarian cancer stem cells and macrophages reciprocally interact through the WNT pathway to promote pro-tumoral and malignant phenotypes in 3D engineered microenvironments

Fig. 6

Changes in tumorigenicity of hetero-spheroids in vivo in NSG mice. Tumors were generated in NSG mice from CSC mono-spheroids, or CSCs isolated from hetero-spheroids in CSC/M2 or CSC/shWNT5b M2. a Tumor initiation and growth kinetics are shown for all three groups, where CSC(M2) tumors (red curve) demonstrates elevated tumorigenicity, with faster tumor initiation and tumor burden development (gray shaded area indicates the tumor burden window). Similarly, the blue trace indicates the tumor growth in CSC/shWNT5b M2 tumors, which is significantly (*p < 0.05, two-way ANOVA) lower and slower compared to CSC and CSC(M2) groups at the time points indicated. b Histological examination demonstrates that all groups establish similar structures of tumors sub-cutaneously, with CSC tumors and CSC (M2) tumors establishing dense epitheliod cells, with CSC (shWNT5b M2) tumors more loosely arranged. Scale bar = 100 μm. c Gene expression analysis of xenografted tumors indicated that an elevated ALDH1A1 expression was maintained in CSC(M2) tumors (**p < 0.001, two-way ANOVA). M2-like macrophage conditioning also helped CSCs retain elevated expression of WNT2, WNT3A and WNT6 (*p < 0.05, **p < 0.001, two-way ANOVA) compared to CSCs in mono-spheroids. All other genes and conditions were not significantly different (ns) compared to CSCs, specifically CSC/shWnt5B M2 tumors. d The human IL-6 inhibitor Tocilizumab was used intra-peritoneally on CSC and CSC(M2) tumors, once palpable tumors were observed (Day 25), indicated by the arrow. Tocilizumab treatment resulted in a significant decrease in tumor volume (**p < 0.001, two-way ANOVA) compared to control untreated tumors in CSC mono-spheroid tumors (compare purple trace to black trace; ~ 70% reduction in tumor burden). However, in CSC/M2 tumors, tocilizumab treatment did not significantly alter the growth kinetics of treated vs. untreated tumors (~ 24% reduction in tumor burden), indicating the detainment of a chemoresistant phenotype upon M2-like macrophage co-culture and conditioning. Furthermore, the treated CSC Tocilizumab condition also resembles the control CSC (shWNT5B M2) tumors (blue trace in A), indicating that partial loss or inhibition of IL-6 based CSC enrichment may be at play

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