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Hyperglycemia as a risk factor for cancer progression.

Ryu TY, Park J, Scherer PE - Diabetes Metab J (2014)

Bottom Line: As the prevalence of diabetes mellitus is substantially increasing worldwide, associated diseases such as renal failure, cardiovascular diseases, fatty liver, and cancers have also increased.Recent studies have suggested that hyperinsulinemia, chronic inflammation and hyperglycemia, all frequently seen in diabetics, may lead to increased tumor growth; the underlying molecular mechanisms of this association are not fully understood.In particular, chronic hyperglycemic episodes could serve as a direct or indirect mediator of the increase in tumor cell growth.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology School of Life Sciences, Ulsan, Korea.

ABSTRACT
As the prevalence of diabetes mellitus is substantially increasing worldwide, associated diseases such as renal failure, cardiovascular diseases, fatty liver, and cancers have also increased. A number of cancers such as pancreatic, liver, breast, and female reproductive cancers have shown an increased prevalence and a higher mortality rate in diabetic patients compared to healthy subjects. Thus, this suggests an association between diabetes, especially type 2 diabetes and cancer incidence and progression. Recent studies have suggested that hyperinsulinemia, chronic inflammation and hyperglycemia, all frequently seen in diabetics, may lead to increased tumor growth; the underlying molecular mechanisms of this association are not fully understood. In particular, chronic hyperglycemic episodes could serve as a direct or indirect mediator of the increase in tumor cell growth. Here, we will discuss our current understanding how hyperglycemia and cancer risk may be linked, and what the implications are for the treatment of diabetic cancer patients.

No MeSH data available.


Related in: MedlinePlus

Impact of hyperglycemia on tumor progression. A hyperglycemic environment contributes to tumor progression through multiple pathways. Cancer cell proliferation is promoted by the up-regulation of glucose transporters (GLUT1 and GLUT3), epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR), and other growth promoting signals such as protein kinase C-α (PKC-α), peroxisome proliferator-activated receptor (PPAR)-α, PPAR-γ, glial cell line-derived neurotophic factor (GDNF), and its receptor, rearranged during transfection (RET) receptor. The levels of hypoxia inducible factor-1α (HIF1α), prolyl hydroxylase (PHD) enzyme and cytochrome c regulated by hyperglycemia are associated with antiapoptotic activity of cancer cells. Cancer cell migration and invasiveness is acquired by the up-regulation of superoxide dismutase (SOD), urokinase plasminogen activator (uPA), ZRT/IRT-like protein 6 (ZIP6), and ZRT/IRT-like protein 10 (ZIP10). Moreover, hyperglycemic memory, i.e., epigenetic regulation of cancer cells by hyperglylcemia, increases the expression of nuclear factor-κB (NF-κB) and neuregulin-1 (Nrg1), both are well-established oncogenic signals.
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Figure 1: Impact of hyperglycemia on tumor progression. A hyperglycemic environment contributes to tumor progression through multiple pathways. Cancer cell proliferation is promoted by the up-regulation of glucose transporters (GLUT1 and GLUT3), epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR), and other growth promoting signals such as protein kinase C-α (PKC-α), peroxisome proliferator-activated receptor (PPAR)-α, PPAR-γ, glial cell line-derived neurotophic factor (GDNF), and its receptor, rearranged during transfection (RET) receptor. The levels of hypoxia inducible factor-1α (HIF1α), prolyl hydroxylase (PHD) enzyme and cytochrome c regulated by hyperglycemia are associated with antiapoptotic activity of cancer cells. Cancer cell migration and invasiveness is acquired by the up-regulation of superoxide dismutase (SOD), urokinase plasminogen activator (uPA), ZRT/IRT-like protein 6 (ZIP6), and ZRT/IRT-like protein 10 (ZIP10). Moreover, hyperglycemic memory, i.e., epigenetic regulation of cancer cells by hyperglylcemia, increases the expression of nuclear factor-κB (NF-κB) and neuregulin-1 (Nrg1), both are well-established oncogenic signals.

Mentions: Multiple proteins have been implicated as mediators of hyperglycemia and cancer cell proliferation (Fig. 1). Recent in vitro studies suggest that the expression of glucose transporters, such as the GLUT1 and GLUT3 isoforms, is regulated under hyperglycemic conditions in JAR cells, a choriocarcinoma cell line [20]. Hyperglycemic conditions in vitro (such as 25 mM D-glucose) trigger increased glucose uptake in JAR cells due to a transcriptional increase and enhanced protein levels for GLUT1 and GLUT3 [20]. Growth factors, such as epidermal growth factor (EGF) levels are augmented by high glucose treatment in pancreatic cancer cell lines, such as BxPC-3 and Panc-1, and subsequently activate its receptor, the epidermal growth factor receptor (EGFR), a well-known oncogenic pathway [21]. In addition, the levels of protein kinase C (PKC) and peroxisome proliferator-activated receptors (PPARs) are stimulated under hyperglycemic conditions in MCF-7 human breast cancer cells [22]. Overexpression of PKC-α in MCF-7 induces a more aggressive phenotype [23]. PPAR-α and PPAR-γ are influencing lipid metabolic pathways. High levels of PPAR-α and PPAR-γ can accelerate cell proliferation [24]. High glucose accelerates the cell cycle through regulating the levels of key proteins, such as cyclin-dependent kinase 2, E2F, cyclinA, and cyclinE, resulting in increased proliferation [16]. Furthermore, hyperglycemic conditions augment the levels of glial cell line derived neurotophic factor (GDNF) and its tyrosine kinase receptor gene, the rearranged during transfection (RET) gene, in human pancreatic cancer cells, such as BxPC-3 and MIA PaCa-2 cells [25]. GDNF is a cytokine related to the transforming growth factor-β family, enhancing the survival and differentiation of midbrain dopaminergic neurons [26] as well as promoting pancreatic cancer cell proliferation and invasion mediated through a protein complex of RET/GDNF-family receptor α-1 (GFR α-1) [27]. Taken together, these data strongly implicate hyperglycemia as a contributing factor leading to enhanced cell proliferation.


Hyperglycemia as a risk factor for cancer progression.

Ryu TY, Park J, Scherer PE - Diabetes Metab J (2014)

Impact of hyperglycemia on tumor progression. A hyperglycemic environment contributes to tumor progression through multiple pathways. Cancer cell proliferation is promoted by the up-regulation of glucose transporters (GLUT1 and GLUT3), epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR), and other growth promoting signals such as protein kinase C-α (PKC-α), peroxisome proliferator-activated receptor (PPAR)-α, PPAR-γ, glial cell line-derived neurotophic factor (GDNF), and its receptor, rearranged during transfection (RET) receptor. The levels of hypoxia inducible factor-1α (HIF1α), prolyl hydroxylase (PHD) enzyme and cytochrome c regulated by hyperglycemia are associated with antiapoptotic activity of cancer cells. Cancer cell migration and invasiveness is acquired by the up-regulation of superoxide dismutase (SOD), urokinase plasminogen activator (uPA), ZRT/IRT-like protein 6 (ZIP6), and ZRT/IRT-like protein 10 (ZIP10). Moreover, hyperglycemic memory, i.e., epigenetic regulation of cancer cells by hyperglylcemia, increases the expression of nuclear factor-κB (NF-κB) and neuregulin-1 (Nrg1), both are well-established oncogenic signals.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4209346&req=5

Figure 1: Impact of hyperglycemia on tumor progression. A hyperglycemic environment contributes to tumor progression through multiple pathways. Cancer cell proliferation is promoted by the up-regulation of glucose transporters (GLUT1 and GLUT3), epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR), and other growth promoting signals such as protein kinase C-α (PKC-α), peroxisome proliferator-activated receptor (PPAR)-α, PPAR-γ, glial cell line-derived neurotophic factor (GDNF), and its receptor, rearranged during transfection (RET) receptor. The levels of hypoxia inducible factor-1α (HIF1α), prolyl hydroxylase (PHD) enzyme and cytochrome c regulated by hyperglycemia are associated with antiapoptotic activity of cancer cells. Cancer cell migration and invasiveness is acquired by the up-regulation of superoxide dismutase (SOD), urokinase plasminogen activator (uPA), ZRT/IRT-like protein 6 (ZIP6), and ZRT/IRT-like protein 10 (ZIP10). Moreover, hyperglycemic memory, i.e., epigenetic regulation of cancer cells by hyperglylcemia, increases the expression of nuclear factor-κB (NF-κB) and neuregulin-1 (Nrg1), both are well-established oncogenic signals.
Mentions: Multiple proteins have been implicated as mediators of hyperglycemia and cancer cell proliferation (Fig. 1). Recent in vitro studies suggest that the expression of glucose transporters, such as the GLUT1 and GLUT3 isoforms, is regulated under hyperglycemic conditions in JAR cells, a choriocarcinoma cell line [20]. Hyperglycemic conditions in vitro (such as 25 mM D-glucose) trigger increased glucose uptake in JAR cells due to a transcriptional increase and enhanced protein levels for GLUT1 and GLUT3 [20]. Growth factors, such as epidermal growth factor (EGF) levels are augmented by high glucose treatment in pancreatic cancer cell lines, such as BxPC-3 and Panc-1, and subsequently activate its receptor, the epidermal growth factor receptor (EGFR), a well-known oncogenic pathway [21]. In addition, the levels of protein kinase C (PKC) and peroxisome proliferator-activated receptors (PPARs) are stimulated under hyperglycemic conditions in MCF-7 human breast cancer cells [22]. Overexpression of PKC-α in MCF-7 induces a more aggressive phenotype [23]. PPAR-α and PPAR-γ are influencing lipid metabolic pathways. High levels of PPAR-α and PPAR-γ can accelerate cell proliferation [24]. High glucose accelerates the cell cycle through regulating the levels of key proteins, such as cyclin-dependent kinase 2, E2F, cyclinA, and cyclinE, resulting in increased proliferation [16]. Furthermore, hyperglycemic conditions augment the levels of glial cell line derived neurotophic factor (GDNF) and its tyrosine kinase receptor gene, the rearranged during transfection (RET) gene, in human pancreatic cancer cells, such as BxPC-3 and MIA PaCa-2 cells [25]. GDNF is a cytokine related to the transforming growth factor-β family, enhancing the survival and differentiation of midbrain dopaminergic neurons [26] as well as promoting pancreatic cancer cell proliferation and invasion mediated through a protein complex of RET/GDNF-family receptor α-1 (GFR α-1) [27]. Taken together, these data strongly implicate hyperglycemia as a contributing factor leading to enhanced cell proliferation.

Bottom Line: As the prevalence of diabetes mellitus is substantially increasing worldwide, associated diseases such as renal failure, cardiovascular diseases, fatty liver, and cancers have also increased.Recent studies have suggested that hyperinsulinemia, chronic inflammation and hyperglycemia, all frequently seen in diabetics, may lead to increased tumor growth; the underlying molecular mechanisms of this association are not fully understood.In particular, chronic hyperglycemic episodes could serve as a direct or indirect mediator of the increase in tumor cell growth.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology School of Life Sciences, Ulsan, Korea.

ABSTRACT
As the prevalence of diabetes mellitus is substantially increasing worldwide, associated diseases such as renal failure, cardiovascular diseases, fatty liver, and cancers have also increased. A number of cancers such as pancreatic, liver, breast, and female reproductive cancers have shown an increased prevalence and a higher mortality rate in diabetic patients compared to healthy subjects. Thus, this suggests an association between diabetes, especially type 2 diabetes and cancer incidence and progression. Recent studies have suggested that hyperinsulinemia, chronic inflammation and hyperglycemia, all frequently seen in diabetics, may lead to increased tumor growth; the underlying molecular mechanisms of this association are not fully understood. In particular, chronic hyperglycemic episodes could serve as a direct or indirect mediator of the increase in tumor cell growth. Here, we will discuss our current understanding how hyperglycemia and cancer risk may be linked, and what the implications are for the treatment of diabetic cancer patients.

No MeSH data available.


Related in: MedlinePlus