St. Jude Children's Research Hospital

About: St. Jude Children's Research Hospital is a healthcare organization based out in Memphis, Tennessee, United States. It is known for research contribution in the topics: Population & Virus. The organization has 9344 authors who have published 19233 publications receiving 1233399 citations. The organization is also known as: St. Jude Children's Hospital & St. Jude Hospital.

mTOR and cancer therapy.

Abstract: Proteins regulating the mammalian target of rapamycin (mTOR), as well as some of the targets of the mTOR kinase, are overexpressed or mutated in cancer. Rapamycin, the naturally occurring inhibitor of mTOR, along with a number of recently developed rapamycin analogs (rapalogs) consisting of synthetically derived compounds containing minor chemical modifications to the parent structure, inhibit the growth of cell lines derived from multiple tumor types in vitro, and tumor models in vivo. Results from clinical trials indicate that the rapalogs may be useful for the treatment of subsets of certain types of cancer. The sporadic responses from the initial clinical trials, based on the hypothesis of general translation inhibition of cancer cells are now beginning to be understood owing to a more complete understanding of the dynamics of mTOR regulation and the function of mTOR in the tumor microenvironment. This review will summarize the preclinical and clinical data and recent discoveries of the function of mTOR in cancer and growth regulation.

c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression

Abstract: c-Myc functions are necessary and sufficient for the entry of most cells into the DNA synthetic (S) phase of the cell cycle (Eilers et al. 1989; de Alboran et al. 2001; Trumpp et al. 2001), and MYC family genes are commonly activated in cancer. However, the precise mechanisms by which c-Myc promotes cell growth and transformation have not been resolved. Under physiological conditions c-myc expression is dependent on mitogens. This control is lost in cancer cells, resulting in elevated levels of c-Myc oncoprotein. In normal cells c-Myc activation triggers the apoptotic program (Askew et al. 1991; Evan et al. 1992), and thus c-Myc-induced transformation generally does not occur until there is a loss of function of apoptotic regulators. In particular, c-Myc triggers the ARF–Mdm2–p53 tumor suppressor pathway, and this prevents c-Myc-induced lymphomagenesis (Zindy et al. 1998; Eischen et al. 1999). However, c-Myc is also continuously required to maintain the transformed state (Felsher and Bishop 1999; Jain et al. 2002; Pelengaris et al. 2002), and disabling apoptosis alone is generally considered insufficient to promote tumorigenesis. Thus, Myc oncoproteins must provide other functions that initiate and/or sustain malignancy. Tumor progression and maintenance requires the development of an ample blood supply, which ensures the delivery of oxygen, nutrients, and growth factors. This requires the development of both immature and mature blood vessels. First, vasculogenesis, which is regulated by vascular endothelial growth factor (VEGF) and its receptors Flk-1 and Flt-1, establishes a primitive vascular network from newly differentiated endothelial cells that assemble into vascular tubes. Second, angiogenesis promotes the sprouting and remodeling of capillaries from these preexisting vessels (Risau 1997). This process requires the dissociation of pericytes from endothelial cells, and is regulated by interplay between angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2) and signaling through their receptor Tie2 (Hanahan 1997). In the adult, angiogenesis is a tightly controlled process that regulates neovascularization during ovulation, placental development, and wound healing. Uncontrolled angiogenesis plays an important role during tumor growth (Hanahan and Folkman 1996), and the sprouting of new blood vessels into tumors suggests that angiogenesis is necessary for a successful malignancy. Angiogenesis is provoked early during tumor progression and occurs in part in response to environmental cues, in particular hypoxia, which regulates the expression of angiogenic factors critical for vasculogenesis and angiogenesis in tumors and during embryogenesis (Carmeliet et al. 1998; Iyer et al. 1998; Ryan et al. 1998). However, genetic changes in cancer may also flip the angiogenic switch. For example, in cell lines loss of p53 elevates VEGF levels (Volpert et al. 1997), whereas the oncogenes v-src, c-jun, and c-myc suppress the expression of the anti-angiogenic factor thrombospondin-1 (TSP-1; Mettouchi et al. 1994; Slack and Bornstein 1994; Tikhonenko et al. 1996). Furthermore, transgenic studies have shown that transformation induced by several oncoproteins, including c-Myc, is sufficient to induce an angiogenic response and the expression of VEGF (Kerbel et al. 1998; Pelengaris et al. 1999). However cause–effect relationships are difficult to establish, given that hypoxia accompanies tumor expansion in vivo. VEGF is a critical regulator of both vasculogenesis and angiogenesis (Hanahan 1997; Carmeliet and Collen 1999). Gene targeting in mice has shown that VEGF, Flk-1, and Flt-1 all have essential roles in early development, with lethality occurring between embryonic days 8.5 and 10.5 (E8.5 and E10.5; Fong et al. 1995; Shalaby et al. 1995; Carmeliet et al. 1996; Ferrara et al. 1996). Mouse embryos deficient in c-myc also die in utero at E10.5, and their lethality has been attributed to a delay in growth and cardiac and neural defects (Davis et al. 1993). Here we report that c-Myc deficiency results in profound defects in vasculogenesis, angiogenesis, and primitive erythropoiesis, and that these defects are associated with a failure in VEGF expression, and with improper expression of TSP-1, ANG-1, and ANG-2. The data support the model whereby c-Myc promotes tumorigenesis by functioning as a master regulator of cytokines necessary for growth, vasculogenesis, and angiogenesis.

Six3 repression of Wnt signaling in the anterior neuroectoderm is essential for vertebrate forebrain development

Abstract: Nieuwkoop's two-signal model proposed that induced neural tissue is inherently anterior (forebrain) in character and that a graded transforming (or posteriorizing) signal specifies posterior identity to the anterior neuroectoderm (Nieuwkoop 1952). It has been suggested that during vertebrate head development, the level of Wnt activity may specify posterior-to-anterior fates within the neural plate (Niehrs 1999; Heisenberg et al. 2001; Kiecker and Niehrs 2001). Wnt signaling must be inhibited to allow the development of the rostral telencephalon, or the prospective forebrain will acquire a caudal diencephalic identity (Niehrs 1999; Heisenberg et al. 2001; Kiecker and Niehrs 2001). This anterior Wnt-signaling-free zone is maintained by Wnt antagonists secreted by the anterior neuroectoderm and adjacent anterior mesendoderm (Niehrs 1999; Houart et al. 2002). Head truncations occur when genes that are required for the development of the anterior visceral endoderm (AVE; i.e., Hex, Lim1, and Otx2) are mutated (Thomas and Beddington 1996; Shawlot et al. 1999; Martinez-Barbera and Beddington 2001; Perea-Gomez et al. 2001). The lack of anterior head structures also occurs in mice that are double-homozygous for chordin and noggin, which encode secreted bone morphogenetic protein antagonists (Bachiller et al. 2000). In addition, mouse embryos lacking Dickkopf1 (Dkk1), a secreted protein that acts as an inhibitor of the Wnt coreceptor LRP-6, lack head structures anterior to the midbrain; Dkk1 activity is required in the axial mesendoderm (Mukhopadhyay et al. 2001). Variable forebrain truncations are also observed in mice with inactivating mutations in the homeobox gene Hesx1, whose activity is required in the anterior neural ectoderm (Martinez-Barbera and Beddington 2001). We have previously shown that in mice, Six3 is expressed in the most anterior part of the developing neural plate (Oliver et al. 1995). To determine the role of Six3 during vertebrate development, we inactivated the mouse Six3 locus. We find that Six3 is required for development of the mammalian rostral forebrain. The absence of Six3 results in forebrain truncations and posteriorization of the remaining mutant head. We demonstrate that Six3 binds to the Wnt1 promoter region in vivo and represses Wnt1 expression in the most anterior neuroectoderm. Work recently performed in zebrafish embryos has suggested that telencephalic induction, as well as the subsequent patterning of the forebrain into telencephalic, eye, and diencephalic regions, is the result of the graded expression of Wnt signaling in the anterior neural plate (Houart et al. 2002). Thus, during vertebrate head regional specification, the maintenance and refinement of anterior neural fates requires that Wnt signaling is transcriptionally repressed in the anterior neuroectoderm, and Six3 is a key player during this process. We also show that Six3 is sufficient to suppress the loss of forebrain resulting from excess Wnt1 signaling in headless (Tlc3) zebrafish mutants. Taken together, these results not only identified Six3 as a key player in vertebrate head development, but also demonstrated the existence of another regulatory step in the complex Wnt signaling pathway, the direct repression of Wnt1 expression by a transcription factor in the mammalian anterior neural plate at the late headfold–early somite stage, a step that is probably required for the maintenance of the anterior neural fates.

The plasticity and stability of regulatory T cells.

Abstract: Regulatory T (TReg) cells are crucial for the prevention of fatal autoimmunity in mice and humans. Forkhead box P3 (FOXP3)(+) TReg cells are produced in the thymus and are also generated from conventional CD4(+) T cells in peripheral sites. It has been suggested that FOXP3(+) TReg cells might become unstable under certain inflammatory conditions and might adopt a phenotype that is more characteristic of effector CD4(+) T cells. These suggestions have caused considerable debate in the field and have important implications for the therapeutic use of TReg cells. In this article, Nature Reviews Immunology asks several experts for their views on the plasticity and stability of TReg cells.