Notch has been linked to beta-catenin-dependent tumorigenesis; however, the mechanisms leading to Notch activation and the contribution of the Notch pathway to colorectal cancer is not yet understood. By microarray analysis, we have identified a group of genes downstream of Wnt/beta-catenin (down-regulated when blocking Wnt/beta-catenin) that are directly regulated by Notch (repressed by gamma-secretase inhibitors and up-regulated by active Notch1 in the absence of beta-catenin signaling). We demonstrate that Notch is downstream of Wnt in colorectal cancer cells through beta-catenin-mediated transcriptional activation of the Notch-ligand Jagged1. Consistently, expression of activated Notch1 partially reverts the effects of blocking Wnt/beta-catenin pathway in tumors implanted s.c. in nude mice. Crossing APC(Min/+) with Jagged1(+/Delta) mice is sufficient to significantly reduce the size of the polyps arising in the APC mutant background indicating that Notch is an essential modulator of tumorigenesis induced by nuclear beta-catenin. We show that this mechanism is operating in human tumors from Familial Adenomatous Polyposis patients. We conclude that Notch activation, accomplished by beta-catenin-mediated up-regulation of Jagged1, is required for tumorigenesis in the intestine. The Notch-specific genetic signature is sufficient to block differentiation and promote vasculogenesis in tumors whereas proliferation depends on both pathways.
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"In mammalian skin, alterations in TH levels influence the Shh pathway, which in turn controls TH availability (Dentice et al., 2007). Notably, several components of the Notch pathway, including Hes1 and Jag1, have been described as targets of Wnt (Fre et al., 2009; Peignon et al., 2011; Rodilla et al., 2009; Estrach et al., 2006). Given that, in studies involving analysis of the whole mucosa, TRα1 activates the Wnt pathway in intestinal crypts (Plateroti et al., 2006; Kress et al., 2009), we cannot exclude the possibility that some of the responses observed for Notch also depend on Wnt activity. "
"Cell lines expressing dominant-negative TCF4 (Ls174T/dnTCF4) and ICN1 (Ls174T/dnTCF4/ICN1) have been previously described (Rodilla et al., 2009; van de Wetering et al., 2002) and were maintained in Dulbecco's media with 10% fetal bovine serum (FBS). Doxycycline (Sigma) was used at 1 µg/ml. "
"However, recent studies showed that Notch1 was correlated with poor survival in HCC as well  . Apart from the functions mentioned above, the Notch signaling pathway is also critical for endothelial progenitor cells to develop new blood vessels  . So far as VM is concerned, tumor cells with such capacity bear close resemblance to endothelial progenitor cells phenotypically and functionally. "
[Show abstract][Hide abstract] ABSTRACT: Background and aims:
According to recent findings, some tumor cells function as endothelial progenitor cells to initiate tumor vasculogenesis, known as "vasculogenic mimicry" (VM). Notch1, the key regulator of vasculogenesis and embryonic differentiation, has shown a correlation with a poor prognosis in hepatocellular carcinoma (HCC). We attempted to elucidate the relationship between Notch1 and the vascularization of HCC.
Materials and methods:
HCC cell lines were assayed for tube formation and low-density lipoprotein (LDL) absorption. The translation level of targets of interest was verified using western blot. Notch1 was silenced in HepG2, BEL-7402 and HCCLM6 using lentivirus shRNA. A hypoxic culture was conducted in an anaerobic culture chamber to induce VM in HepG2. Samples from 53 patients with HCC, i.e., 5 with metastasis and 48 without were tested for Notch1(+) cells and CD34 negative plus Periodic Acid-Schiff (PAS) positive structures, respectively.
BEL-7402 and HCCLM6 were capable of tube formation and LDL absorption in vitro, while HepG2 was negative for both. Notch1 down-regulation suppressed endothelial marker expression and greatly impaired tube formation. After hypoxic culture, the tube formation capacity of HepG2 was significantly enhanced, along with an increase in Notch1 expression. Notch1 was strongly and profusely expressed in all 5 cases of distant metastasis, while 19 of the 48 cases without metastasis were sparsely positive (P < 0.05). Notch1 positivity was mainly seen in the cytoplasm and nuclei. VM structures were only found in 2 cases from the metastasis group (P < 0.05).
HCC is capable of VM. Notch1 might serve as a potential target for VM development in HCC.
International journal of clinical and experimental pathology 10/2014; 7(9):5782-91. · 1.89 Impact Factor