Streptococcus gallolyticus subsp. gallolyticus promotes colorectal tumor development.

Streptococcus gallolyticus subsp. gallolyticus (Sg) has long been known to have a strong association with colorectal cancer (CRC). This knowledge has important clinical implications, and yet little is known about the role of Sg in the development of CRC. Here we demonstrate that Sg promotes human colon cancer cell proliferation in a manner that depends on cell context, bacterial growth phase and direct contact between bacteria and colon cancer cells. In addition, we observed increased level of ß-catenin, c-Myc and PCNA in colon cancer cells following incubation with Sg. Knockdown or inhibition of ß-catenin abolished the effect of Sg. Furthermore, mice administered with Sg had significantly more tumors, higher tumor burden and dysplasia grade, and increased cell proliferation and ß-catenin staining in colonic crypts compared to mice receiving control bacteria. Finally, we showed that Sg is present in the majority of CRC patients and is preferentially associated with tumor compared to normal tissues obtained from CRC patients. These results taken together establish for the first time a tumor-promoting role of Sg that involves specific bacterial and host factors and have important clinical implications.

Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis.

Environmental exposures during sensitive windows of development can reprogram normal physiologic responses and alter disease susceptibility later in life in a process known as developmental reprogramming. For example, exposure to the xenoestrogen diethylstilbestrol during reproductive tract development can reprogram estrogen-responsive gene expression in the myometrium, resulting in hyperresponsiveness to hormone in the adult uterus and promotion of hormone-dependent uterine leiomyoma. We show here that the environmental estrogens genistein, a soy phytoestrogen, and the plasticizer bisphenol A, differ in their pattern of developmental reprogramming and promotion of tumorigenesis (leiomyomas) in the uterus. Whereas both genistein and bisphenol A induce genomic estrogen receptor (ER) signaling in the developing uterus, only genistein induced phosphoinositide 3-kinase (PI3K)/AKT nongenomic ER signaling to the histone methyltransferase enhancer of zeste homolog 2 (EZH2). As a result, this pregenomic signaling phosphorylates and represses EZH2 and reduces levels of H3K27me3 repressive mark in chromatin. Furthermore, only genistein caused estrogen-responsive genes in the adult myometrium to become hyperresponsive to hormone; estrogen-responsive genes were repressed in bisphenol A-exposed uteri. Importantly, this pattern of EZH2 engagement to decrease versus increase H3K27 methylation correlated with the effect of these xenoestrogens on tumorigenesis. Developmental reprogramming by genistein promoted development of uterine leiomyomas, increasing tumor incidence and multiplicity, whereas bisphenol A did not. These data show that environmental estrogens have distinct nongenomic effects in the developing uterus that determines their ability to engage the epigenetic regulator EZH2, decrease levels of the repressive epigenetic histone H3K27 methyl mark in chromatin during developmental reprogramming, and promote uterine tumorigenesis.

Identification of a sensitive period for developmental programming that increases risk for uterine leiomyoma in Eker rats.

Epidemiological and experimental animal studies have shown that exposure to xenoestrogens during reproductive tract development reprograms target tissues, leading to increased disease risk later in adult life. To understand what defines the critical risk period for this effect, termed developmental programming, the authors assess the sensitivity of the female reproductive tract to developmental programming during various stages of neonatal development. Eker rats, which are predisposed to develop uterine leiomyoma because of a germ-line defect in the tuberous sclerosis complex 2 (Tsc-2) tumor suppressor gene, were exposed to the xenoestrogen diethylstilbestrol (DES) on either postnatal days 3 to 5, 10 to 12, or 17 to 19, 3 important periods of reproductive tract development and differentiation. Developmental programming was observed in both carrier (Tsc-2(Ek/+)) and wild-type (Tsc-2(+/+)) rats exposed to DES at days 3 to 5 and days 10 to 12 but not in rats exposed at days 17 to 19. Developmental programming resulted in increased tumor suppressor gene penetrance in Tsc-2(Ek/+) females relative to vehicle controls. In contrast, DES exposure at days 17 to 19 did not significantly increase the incidence of uterine leiomyoma in carrier females, indicating that the window of susceptibility had closed by this time. Gene expression analysis to determine what defined the susceptible (days 3-5 and days 10-12) versus resistant (days 17-19) periods revealed that in adult myometrium, expression of the estrogen-responsive genes calbindin D(9)K and progesterone receptor had been reprogrammed in females exposed to DES at days 3 to 5 and days 10 to 12 but not in those exposed at days 17 to 19. Reprogramming in response to DES exposure resulted in a hyperresponsiveness to ovarian hormones and could be prevented by ovariectomy prior to sexual maturity. Furthermore, in the neonatal uterus, DES was equally effective at inducing transcription of estrogen-responsive genes during both sensitive and resistant periods, indicating that resistance to developmental programming was not due to an inability of the estrogen receptor to transactivate gene expression. Interestingly, the resistant period coincided with the time at which reproductive tract tissues are exposed to endogenous estrogen, suggesting that target tissues are most vulnerable to developmental programming during the period in which they would normally be maintained in an estrogen-naïve state.