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

Autor: Troy A. Baudino, Kirsteen H. Maclean, James N. Ihle, John L. Cleveland, Elsie White, Helene Pendeville-Samain, Jonas Nilsson, Catriona McKay, Ann C. Davis
Rok vydání: 2002
Předmět:
Male
Vascular Endothelial Growth Factor A
medicine.medical_specialty
Angiogenesis
Cellular differentiation
Neovascularization
Physiologic
Endothelial Growth Factors
Mice
SCID
Biology
Cell Line
Neovascularization
Angiopoietin-2
Proto-Oncogene Proteins c-myc
Thrombospondin 1
chemistry.chemical_compound
Mice
Vasculogenesis
Internal medicine
Genetics
medicine
Angiopoietin-1
Animals
Erythropoiesis
Mice
Knockout
Lymphokines
Membrane Glycoproteins
Vascular Endothelial Growth Factors
Stem Cells
Cell Differentiation
Vascular endothelial growth factor
Platelet Endothelial Cell Adhesion Molecule-1
Vascular endothelial growth factor A
Endocrinology
chemistry
Tumor progression
Protein Biosynthesis
Cancer research
Intercellular Signaling Peptides and Proteins
Female
medicine.symptom
Developmental Biology
Research Paper
Zdroj: Genesdevelopment. 16(19)
ISSN: 0890-9369
Popis: 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.
Databáze: OpenAIRE
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