TGF-β Receptor Inactivation and Mutant Kras Induce Intestinal Neoplasms in Mice via a β-Catenin-Independent Pathway

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Gastroenterology (Impact Factor: 16.72). 02/2009; 136(5):1680-8.e7. DOI: 10.1053/j.gastro.2009.01.066
Source: PubMed


During colorectal cancer pathogenesis, mutations and epigenetic events cause neoplastic behavior in epithelial cells by deregulating the Wnt, Ras-Raf-extracellular signal-regulated kinase (ERK), and transforming growth factor (TGF)-beta-signaling pathways, among others. The TGF-beta-signaling pathway is often inactivated in colon cancer cells by mutations in the gene encoding the TGF-beta receptor TGFBR2. The RAS-RAF-ERK pathway is frequently up-regulated in colon cancer via mutational activation of KRAS or BRAF. We assessed how these pathways interact in vivo and affect formation of colorectal tumors.
We analyzed intestinal tumors that arose in mice that express an oncogenic (active) form of Kras and that have Tgfbr2 inactivations-2 common molecular events observed in human colorectal tumors. LSL-KrasG12D mice were crossed with Villin-Cre;Tgfbr2E2flx/E2flx mice, which do not express Tgfbr2 in the intestinal epithelium.
Neither inactivation of Tgfbr2 nor expression of oncogenic Kras alone was sufficient to induce formation of intestinal neoplasms. Histologic abnormalities arose in mice that expressed Kras, but only the combination of Tgfbr2 inactivation and Kras activation led to intestinal neoplasms and metastases. The cancers arose via a beta-catenin-independent mechanism; the epidermal growth factor-signaling pathway was also activated. Cells in the resulting tumors proliferated at higher rates, expressed decreased levels of p15, and expressed increased levels of cyclin D1 and cdk4, compared with control cells.
A combination of inactivation of the TGF-beta-signaling pathway and expression of oncogenic Kras leads to formation of invasive intestinal neoplasms through a beta-catenin-independent pathway; these adenocarcinomas have the capacity to metastasize.

  • Source
    • "The availability of TBRs dictates the relative levels of activated Erk1/2 and inactivated Smad2/3, thus determines the fate of the TGF-β paradox (25, 37, 38). It follows that any condition that results in downregulation of functional TBRs, such as inflammation (39, 40), Ras activation (41, 42), and loss-of-function mutations in TBRs (43–45), will be predisposed to development and progression of cancer. "
    [Show abstract] [Hide abstract]
    ABSTRACT: TGF-β regulates a wide range of biological functions including embryonic development, wound healing, organogenesis, immune modulation, and cancer progression. Interestingly, TGF-β is known to inhibit cell growth in benign cells but promote progression in cancer cells; this phenomenon is known as TGF-β paradox. To date, the mechanism of this paradox still remains a scientific mystery. In this review, we present our experience, along with the literature, in an attempt to answer this mystery. First, we observed that, on TGF-β engagement, there is a differential activation of Erk between benign and cancer cells. Since activated Erk is a major mediator in tumor progression and metastasis, a differentially activated Erk represents the answer to this mystery. Second, we identified a key player, PP2A-B56α, which is differentially recruited by the activated type I TGF-β receptor (TBRI) in benign and tumor cells, resulting in differential Erk activation. Finally, TGF-β stimulation leads to suppressed TBRs in tumor cells but not in benign cells. This differentially suppressed TBRs triggers differential recruitment of PP2A-B56α and, thus, differential activation of Erk. The above three events explain the mysteries of TGF-β paradox. Understanding the mechanism of TGF-β paradox will help us to predict indolent from aggressive cancers and develop novel anti-cancer strategies.
    Full-text · Article · May 2014 · Frontiers in Oncology
  • Source
    • "Moreover, the Lgr5+ cell population within existing intestinal adenomas maintain stem cell activity and fuels the growth of the tumor [13]. Although oncogenic mutated K-ras that is driven from the endogenous locus induces hyperplasia in a variety of tissues, including the colon, no morphologically detectable abnormalities are observed in the proximal small intestine [14, 15, 16, 17, 18] (supplementary information), despite its role in progressing intestinal adenomas towards a more aggressive adenomacarcinoma [16]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The concept of 'field cancerization' describes the clonal expansion of genetically altered, but morphologically normal cells that predisposes a tissue to cancer development. Here, we demonstrate that biased stem cell competition in the mouse small intestine can initiate the expansion of such clones. We quantitatively analyze how the activation of oncogenic K-ras in individual Lgr5(+) stem cells accelerates their cell division rate and creates a biased drift towards crypt clonality. K-ras mutant crypts then clonally expand within the epithelium through enhanced crypt fission, which distributes the existing Paneth cell niche over the two new crypts. Thus, an unequal competition between wild-type and mutant intestinal stem cells initiates a biased drift that leads to the clonal expansion of crypts carrying oncogenic mutations.
    Full-text · Article · Jan 2014 · EMBO Reports
  • Source
    • "Mutations in this gene have been associated with the development of various types of tumours [47]. Explicitly it has a defined role in colon cancer and a combination of inactivation of the TGF-3 signaling pathway and expression of oncogenic Kras leads to formation of invasive intestinal neoplasms through a beta-catenin-independent pathway [48]. Last, TNFSF15 encodes a cytokine, which belongs to the tumor necrosis factor (TNF) ligand family and its second common ID is VEGI, vascular endothelial cell growth inhibitor. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Octreotide is a widely used synthetic somatostatin analogue that significantly improves the management of neuroendocrine tumours (NETs). Octreotide acts through somatostatin receptors (SSTRs). However, the molecular mechanisms leading to successful disease control or symptom management, especially when SSTRs levels are low, are largely unknown. We provide novel insights into how octreotide controls NET cells. CNDT2.5 cells were treated from 1 day up to 16 months with octreotide and then were profiled using Affymetrix microarray analysis. Quantitative real-time PCR and western blot analyses were used to validate microarray profiling in silico data. WST-1 cell proliferation assay was applied to evaluate cell growth of CNDT2.5 cells in the presence or absence of 1 µM octreotide at different time points. Moreover, laser capture microdissected tumour cells and paraffin embedded tissue slides from SI-NETs at different stages of disease were used to identify transcriptional and translational expression. Microarrays analyses did not reveal relevant changes in SSTR expression levels. Unexpectedly, six novel genes were found to be upregulated by octreotide: annexin A1 (ANXA1), rho GTPase-activating protein 18 (ARHGAP18), epithelial membrane protein 1 (EMP1), growth/differentiation factor 15 (GDF15), TGF-beta type II receptor (TGFBR2) and tumour necrosis factor (ligand) superfamily member 15 (TNFSF15). Furthermore, these novel genes were expressed in tumour tissues at transcript and protein levels. We suggest that octreotide may use a potential novel framework to exert its beneficial effect as a drug and to convey its action on neuroendocrine cells. Thus, six novel genes may regulate cell growth and differentiation in normal and tumour neuroendocrine cells and have a role in a novel octreotide mechanism system.
    Full-text · Article · Oct 2012 · PLoS ONE
Show more