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Tissue Transglutaminase (TG2)-Induced Inflammation in Initiation, Progression, and Pathogenesis of Pancreatic Cancer.

Mehta K, Han A - Cancers (Basel) (2011)

Bottom Line: According to this model, oncogenic K-ras induces PanIN formation but fails to promote the invasive stage.These results are consistent with epidemiologic studies showing that patients with chronic pancreatitis have a much higher risk of developing PC.In line with these observations, recent studies have revealed elevated expression of the pro-inflammatory protein tissue transglutaminase (TG2) in early PanINs, and its expression increases even more as the disease progresses.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. kmehta@mdanderson.org.

ABSTRACT
Pancreatic cancer (PC) is among the deadliest cancers, with a median survival of six months. It is generally believed that infiltrating PC arises through the progression of early grade pancreatic intraepithelial lesions (PanINs). In one model of the disease, the K-ras mutation is an early molecular event during progression of pancreatic cancer; it is followed by the accumulation of additional genetic abnormalities. This model has been supported by animal studies in which activated K-ras and p53 mutations produced metastatic pancreatic ductal adenocarcinoma in mice. According to this model, oncogenic K-ras induces PanIN formation but fails to promote the invasive stage. However, when these mice are subjected to caerulein treatment, which induces a chronic pancreatitis-like state and inflammatory response, PanINs rapidly progress to invasive carcinoma. These results are consistent with epidemiologic studies showing that patients with chronic pancreatitis have a much higher risk of developing PC. In line with these observations, recent studies have revealed elevated expression of the pro-inflammatory protein tissue transglutaminase (TG2) in early PanINs, and its expression increases even more as the disease progresses. In this review we discuss the implications of increased TG2 expression in initiation, progression, and pathogenesis of pancreatic cancer.

No MeSH data available.


Related in: MedlinePlus

Epithelial-to-mesenchymal transition (EMT) causes functional phenotypic transition of polarized epithelial cells into migratory mesenchymal cells. Stable expression of TG2 induces EMT in epithelial cells (shown here are mammary epithelial MCF10A cells) as revealed by the loss of E-cadherin, upregulation of N-cadherin, fibronectin, and vimentin, anchorage-independent growth, increased invasion, and resistance to doxorubicin [48].
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f3-cancers-03-00897: Epithelial-to-mesenchymal transition (EMT) causes functional phenotypic transition of polarized epithelial cells into migratory mesenchymal cells. Stable expression of TG2 induces EMT in epithelial cells (shown here are mammary epithelial MCF10A cells) as revealed by the loss of E-cadherin, upregulation of N-cadherin, fibronectin, and vimentin, anchorage-independent growth, increased invasion, and resistance to doxorubicin [48].

Mentions: The molecular mechanisms that link inflammation and cancer have remained elusive until recently. Multiple studies of molecular pathways involved in inflammation and cancer have pointed to the EMT as a common link between inflammation, organ fibrosis, and cancer [43,44]. The EMT marks the conversion of polarized epithelial cells into highly motile fibroblastoid-like cells and involves the loss of epithelial cell-cell junctions and modification of the cytoskeleton (Figure 3). The reduction in intracellular cohesion is mainly the result of alterations in the intracellular junctions composed of desmosomes, adherens junctions, and tight junctions. Epithelial cells use E-cadherin as a major protein in adherens junctions and promote its interaction with the extracellular domain of another E-cadherin molecule from a neighboring cell. During EMT, the activity of the adherens junctions is substantially modified, predominantly owing to the replacement of E-cadherin by N-cadherin, a process called “cadherin switching”.


Tissue Transglutaminase (TG2)-Induced Inflammation in Initiation, Progression, and Pathogenesis of Pancreatic Cancer.

Mehta K, Han A - Cancers (Basel) (2011)

Epithelial-to-mesenchymal transition (EMT) causes functional phenotypic transition of polarized epithelial cells into migratory mesenchymal cells. Stable expression of TG2 induces EMT in epithelial cells (shown here are mammary epithelial MCF10A cells) as revealed by the loss of E-cadherin, upregulation of N-cadherin, fibronectin, and vimentin, anchorage-independent growth, increased invasion, and resistance to doxorubicin [48].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756395&req=5

f3-cancers-03-00897: Epithelial-to-mesenchymal transition (EMT) causes functional phenotypic transition of polarized epithelial cells into migratory mesenchymal cells. Stable expression of TG2 induces EMT in epithelial cells (shown here are mammary epithelial MCF10A cells) as revealed by the loss of E-cadherin, upregulation of N-cadherin, fibronectin, and vimentin, anchorage-independent growth, increased invasion, and resistance to doxorubicin [48].
Mentions: The molecular mechanisms that link inflammation and cancer have remained elusive until recently. Multiple studies of molecular pathways involved in inflammation and cancer have pointed to the EMT as a common link between inflammation, organ fibrosis, and cancer [43,44]. The EMT marks the conversion of polarized epithelial cells into highly motile fibroblastoid-like cells and involves the loss of epithelial cell-cell junctions and modification of the cytoskeleton (Figure 3). The reduction in intracellular cohesion is mainly the result of alterations in the intracellular junctions composed of desmosomes, adherens junctions, and tight junctions. Epithelial cells use E-cadherin as a major protein in adherens junctions and promote its interaction with the extracellular domain of another E-cadherin molecule from a neighboring cell. During EMT, the activity of the adherens junctions is substantially modified, predominantly owing to the replacement of E-cadherin by N-cadherin, a process called “cadherin switching”.

Bottom Line: According to this model, oncogenic K-ras induces PanIN formation but fails to promote the invasive stage.These results are consistent with epidemiologic studies showing that patients with chronic pancreatitis have a much higher risk of developing PC.In line with these observations, recent studies have revealed elevated expression of the pro-inflammatory protein tissue transglutaminase (TG2) in early PanINs, and its expression increases even more as the disease progresses.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. kmehta@mdanderson.org.

ABSTRACT
Pancreatic cancer (PC) is among the deadliest cancers, with a median survival of six months. It is generally believed that infiltrating PC arises through the progression of early grade pancreatic intraepithelial lesions (PanINs). In one model of the disease, the K-ras mutation is an early molecular event during progression of pancreatic cancer; it is followed by the accumulation of additional genetic abnormalities. This model has been supported by animal studies in which activated K-ras and p53 mutations produced metastatic pancreatic ductal adenocarcinoma in mice. According to this model, oncogenic K-ras induces PanIN formation but fails to promote the invasive stage. However, when these mice are subjected to caerulein treatment, which induces a chronic pancreatitis-like state and inflammatory response, PanINs rapidly progress to invasive carcinoma. These results are consistent with epidemiologic studies showing that patients with chronic pancreatitis have a much higher risk of developing PC. In line with these observations, recent studies have revealed elevated expression of the pro-inflammatory protein tissue transglutaminase (TG2) in early PanINs, and its expression increases even more as the disease progresses. In this review we discuss the implications of increased TG2 expression in initiation, progression, and pathogenesis of pancreatic cancer.

No MeSH data available.


Related in: MedlinePlus