Limits...
Molecular responses to hypoxia in tumor cells.

Kunz M, Ibrahim SM - Mol. Cancer (2003)

Bottom Line: Among these are activation of certain signal transduction pathways and gene regulatory mechanisms, induction of selection processes for gene mutations, tumor cell apoptosis and tumor angiogenesis.Most of these mechanisms contribute to tumor progression.Interfering with these pathways might open perspectives for future innovative treatment of highly aggressive metastasizing tumors.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Rostock, Department of Dermatology and Venereology, Augustenstr, 80-84, 18055 Rostock, Germany. manfred.kunz@med.uni-rostock.de

ABSTRACT
Highly aggressive, rapidly growing tumors are exposed to hypoxia or even anoxia which occurs as a consequence of inadequate blood supply. Both hypoxia and consecutive hypoxia/reoxygenation exert a variety of influences on tumor cell biology. Among these are activation of certain signal transduction pathways and gene regulatory mechanisms, induction of selection processes for gene mutations, tumor cell apoptosis and tumor angiogenesis. Most of these mechanisms contribute to tumor progression. Therefore, tissue hypoxia has been regarded as a central factor for tumor aggressiveness and metastasis. In this review, we summarize the current knowledge about the molecular mechanisms induced by tumor cell hypoxia with a special emphasis on intracellular signal transduction, gene regulation, angiogenesis and apoptosis. Interfering with these pathways might open perspectives for future innovative treatment of highly aggressive metastasizing tumors.

Show MeSH

Related in: MedlinePlus

MAP kinase signalling pathways. Major pathways that transfer extracellular signals to the nucleus are the MAP kinase signalling pathways. The extracellular stimuli may be heterogeneous, deriving from exposure of cells to growth factors, phorbol esters, cytokines, or cellular stresses, such as osmotic shock and γ-irradiation. In principal, the Ras-Raf-MEK-ERK pathway transduces mitogenic signals involved in cellular proliferation or differentiation. The JNK/SAPK and p38 pathways regulate the cellular inflammatory or stress response. There are interactions between both pathways on MAPK kinase kinase (MAPKKK) levels immediately upstream of MEK (not indicated in the presented scheme). The downstream targets of the MAP kinase signalling pathways are the MAP kinases, ERK, JNK/SAPK and p38, which directly or indirectly interfere with transcription factors, such as Elk-1, ATF2 or cJun for activation of gene transcription. Upstream signalling components include the family of Rho GTPases such as Rho, Rac and Cdc42 which interfere with MAPKKK. Cellular stresses such as hypoxia may activate JNK/SAPK and p38 pathways which exert influence on cJun and ATF-2 activation.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC155638&req=5

Figure 1: MAP kinase signalling pathways. Major pathways that transfer extracellular signals to the nucleus are the MAP kinase signalling pathways. The extracellular stimuli may be heterogeneous, deriving from exposure of cells to growth factors, phorbol esters, cytokines, or cellular stresses, such as osmotic shock and γ-irradiation. In principal, the Ras-Raf-MEK-ERK pathway transduces mitogenic signals involved in cellular proliferation or differentiation. The JNK/SAPK and p38 pathways regulate the cellular inflammatory or stress response. There are interactions between both pathways on MAPK kinase kinase (MAPKKK) levels immediately upstream of MEK (not indicated in the presented scheme). The downstream targets of the MAP kinase signalling pathways are the MAP kinases, ERK, JNK/SAPK and p38, which directly or indirectly interfere with transcription factors, such as Elk-1, ATF2 or cJun for activation of gene transcription. Upstream signalling components include the family of Rho GTPases such as Rho, Rac and Cdc42 which interfere with MAPKKK. Cellular stresses such as hypoxia may activate JNK/SAPK and p38 pathways which exert influence on cJun and ATF-2 activation.

Mentions: Extracellular stimuli that interfere with gene expression and gene regulation are mediated by different intracellular signalling cascades [for review, see [11,12]]. One of the most intensively studied signalling pathway is the mitogenic Ras/Raf/MEK/ERK cascade, which responds to growth factors and factors inducing cellular differentiation, such as epidermal growth factor (EGF) and platelet derived growth factor (PDGF) [13] (Fig. 1). Downstream targets of this cascade are well-known transcription factors such as AP-1, CREP and Elk. Parallel organized kinase cascades which particularly respond to cellular stresses, such as cellular injury by heat, UV and ionizing irradiation, and osmotic shock have been identified [for review, see [14,15]]. However, these cascades also respond to inflammatory cytokines, such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α. Members of these pathways are the stress-activated protein kinases (SAPK, also termed c-Jun N-terminal kinases, JNK) and the p38 kinase (Fig. 1).


Molecular responses to hypoxia in tumor cells.

Kunz M, Ibrahim SM - Mol. Cancer (2003)

MAP kinase signalling pathways. Major pathways that transfer extracellular signals to the nucleus are the MAP kinase signalling pathways. The extracellular stimuli may be heterogeneous, deriving from exposure of cells to growth factors, phorbol esters, cytokines, or cellular stresses, such as osmotic shock and γ-irradiation. In principal, the Ras-Raf-MEK-ERK pathway transduces mitogenic signals involved in cellular proliferation or differentiation. The JNK/SAPK and p38 pathways regulate the cellular inflammatory or stress response. There are interactions between both pathways on MAPK kinase kinase (MAPKKK) levels immediately upstream of MEK (not indicated in the presented scheme). The downstream targets of the MAP kinase signalling pathways are the MAP kinases, ERK, JNK/SAPK and p38, which directly or indirectly interfere with transcription factors, such as Elk-1, ATF2 or cJun for activation of gene transcription. Upstream signalling components include the family of Rho GTPases such as Rho, Rac and Cdc42 which interfere with MAPKKK. Cellular stresses such as hypoxia may activate JNK/SAPK and p38 pathways which exert influence on cJun and ATF-2 activation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC155638&req=5

Figure 1: MAP kinase signalling pathways. Major pathways that transfer extracellular signals to the nucleus are the MAP kinase signalling pathways. The extracellular stimuli may be heterogeneous, deriving from exposure of cells to growth factors, phorbol esters, cytokines, or cellular stresses, such as osmotic shock and γ-irradiation. In principal, the Ras-Raf-MEK-ERK pathway transduces mitogenic signals involved in cellular proliferation or differentiation. The JNK/SAPK and p38 pathways regulate the cellular inflammatory or stress response. There are interactions between both pathways on MAPK kinase kinase (MAPKKK) levels immediately upstream of MEK (not indicated in the presented scheme). The downstream targets of the MAP kinase signalling pathways are the MAP kinases, ERK, JNK/SAPK and p38, which directly or indirectly interfere with transcription factors, such as Elk-1, ATF2 or cJun for activation of gene transcription. Upstream signalling components include the family of Rho GTPases such as Rho, Rac and Cdc42 which interfere with MAPKKK. Cellular stresses such as hypoxia may activate JNK/SAPK and p38 pathways which exert influence on cJun and ATF-2 activation.
Mentions: Extracellular stimuli that interfere with gene expression and gene regulation are mediated by different intracellular signalling cascades [for review, see [11,12]]. One of the most intensively studied signalling pathway is the mitogenic Ras/Raf/MEK/ERK cascade, which responds to growth factors and factors inducing cellular differentiation, such as epidermal growth factor (EGF) and platelet derived growth factor (PDGF) [13] (Fig. 1). Downstream targets of this cascade are well-known transcription factors such as AP-1, CREP and Elk. Parallel organized kinase cascades which particularly respond to cellular stresses, such as cellular injury by heat, UV and ionizing irradiation, and osmotic shock have been identified [for review, see [14,15]]. However, these cascades also respond to inflammatory cytokines, such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α. Members of these pathways are the stress-activated protein kinases (SAPK, also termed c-Jun N-terminal kinases, JNK) and the p38 kinase (Fig. 1).

Bottom Line: Among these are activation of certain signal transduction pathways and gene regulatory mechanisms, induction of selection processes for gene mutations, tumor cell apoptosis and tumor angiogenesis.Most of these mechanisms contribute to tumor progression.Interfering with these pathways might open perspectives for future innovative treatment of highly aggressive metastasizing tumors.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Rostock, Department of Dermatology and Venereology, Augustenstr, 80-84, 18055 Rostock, Germany. manfred.kunz@med.uni-rostock.de

ABSTRACT
Highly aggressive, rapidly growing tumors are exposed to hypoxia or even anoxia which occurs as a consequence of inadequate blood supply. Both hypoxia and consecutive hypoxia/reoxygenation exert a variety of influences on tumor cell biology. Among these are activation of certain signal transduction pathways and gene regulatory mechanisms, induction of selection processes for gene mutations, tumor cell apoptosis and tumor angiogenesis. Most of these mechanisms contribute to tumor progression. Therefore, tissue hypoxia has been regarded as a central factor for tumor aggressiveness and metastasis. In this review, we summarize the current knowledge about the molecular mechanisms induced by tumor cell hypoxia with a special emphasis on intracellular signal transduction, gene regulation, angiogenesis and apoptosis. Interfering with these pathways might open perspectives for future innovative treatment of highly aggressive metastasizing tumors.

Show MeSH
Related in: MedlinePlus