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Esophageal cancers comprise adenocarcinoma and squamous cell carcinoma, two distinct histologic subtypes. Both are difficult to treat and among the deadliest human malignancies. We describe protocols to initiate, grow, passage, and characterize patient-derived organoids (PDO) of esophageal cancers, as well as squamous cell carcinomas of oral/head-and-neck and anal origin. Formed rapidly (

Epidemiological and experimental evidence suggests that estrogen replacement therapy reduces the risk of colon cancer in postmenopausal women. Estrogen receptor beta (ERβ) is thought to be the principal mediator of the estrogen effect in the colon. Recent studies by our team suggested positive regulation of the transforming growth factor (TGF)β pathway by estrogen in mice colonocytes. We therefore wanted to investigate the effects of ERβ agonist treatment on intestinal tumorigenesis in ApcMin/+ mice. Weaned ApcMin/+ mice were injected subcutaneously three times a week for 12 wk with vehicle or ERβ-selective agonist, diarylpropionitrile (DPN, 5 mg/kg). DPN administration resulted in a significant reduction in small intestinal polyp multiplicity in both ApcMin/+ male and female mice. Furthermore, the mean diameter of small intestinal polyps was lower in DPN-treated than vehicle-treated males, along with lower BrdU incorporation indices in jejunal and colon epithelial cells of both sexes. DPN treatment also increased apoptosis in colon epithelium as measured by TUNEL assay and cleaved caspase 3 quantification. The effect of DPN on various components of the TGFβ pathway was also studied in colonocytes. DPN treatment increased expression of TGFβ1 and TGFβ3 transcripts, levels of nuclear and phosphorylated Smad2 as well as p27 cell-cycle inhibitor, a TGFβ pathway target gene. Our results demonstrate that DPN treatment reduces intestinal tumorigenesis in ApcMin/+ mice. Furthermore, we suggest that positive regulation of the TGFβ pathway by ERβ activation could contribute to the protective role of estrogen in intestinal tumor development. © 2010 Wiley-Liss, Inc.

Clinical evidence suggests that estradiol replacement therapy reduces colon cancer risk in ‘post’menopausal women. In colon epithelial cells, the estrogen receptor β (ERβ) is the predominant ER subtype and is thought to mediate the genomic effect of estrogens. The first aim of this study was to investigate the consequence of ERβ deficiency on intestinal tumorigenesis in the ApcMin/+ mouse model. Furthermore, to explore the biological mechanisms by which estrogens may influence the pathogenesis of colorectal cancer, we performed gene expression profiles in colonocytes from ovariectomized wild-type (WT) vs. ERβ−/− mice, treated with estradiol (E2) or vehicle. Specifically in female, ERβ deficiency was found to be associated with higher adenoma multiplicity in the small intestine, but not in the colon. Furthermore, tumors from ERβ−/−ApcMin/+ female mice were on average significantly larger than those from control ApcMin/+ mice. Higher steady-state proliferation in epithelial cells of the jejunum and colon from ERβ−/−ApcMin/+vs.ApcMin/+ female mice was confirmed by BrdU incorporation assay. Interestingly, functional categorization of microarray results revealed the TGFβ signaling pathway to be modulated in colonocytes, especially for the WT + E2vs. WT + Vehicle and the ERβ−/− + E2vs. WT + E2 comparisons. Using quantitative PCR analysis, we observed transcripts from ligands of the TGFβ pathway to be upregulated in colonocytes from E2-treated WT and ERβ−/− mice and downregulated in ERβ-deficient mice, mostly in an E2-independent manner. Therefore, our results demonstrate that ERβ deficiency enhances small intestinal tumorigenesis and suggest that modulation of the TGFβ signaling pathway could contribute to the protective role of estrogens on intestinal tumorigenesis. © 2008 Wiley-Liss, Inc.