Pancreatic tumors show high levels of hypoxia

Koong, Albert C.; Mehta, Vivek; Le, Quynh Thu; Fisher, George A.; Terris, David J.; Brown, J. Martin; Bastidas, Augusto J.; Vierra, Mark A.

doi:10.1016/s0360-3016(00)00803-8

Cited by 554 publications

(493 citation statements)

References 9 publications

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“…Severe intratumoural hypoxia is present in pancreatic cancer 25, 37, suggesting that hypoxia plays a role in the accumulation and activation of β‐catenin in pancreatic cancer cells. As a Wnt antagonists, it is reported that DKK3 overexpression does not affect nuclear/cytoplasmic accumulation of β‐catenin 11.…”

Section: Discussionmentioning

confidence: 99%

DKK3 blocked translocation of β‐catenin/EMT induced by hypoxia and improved gemcitabine therapeutic effect in pancreatic cancer Bxpc‐3 cell

Guo

Qin

2015

J Cellular Molecular Medi

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The Wnt/β‐catenin signalling pathway is activated in pancreatic cancer initiation and progression. Dickkopf‐related protein 3 (DKK3) is a member of the human Dickkopf family and an antagonist of Wnt ligand activity. However, the function of DKK3 in this pathway in pancreatic cancer is rarely known. We examined the expression of DKK3 in six human pancreatic cancer cell lines, 75 pancreatic cancer and 75 adjacent non‐cancerous tissues. Dickkopf‐related protein 3 was frequently silenced and methylation in pancreatic cancer cell lines (3/6). The expression of DKK3 was significantly lower in pancreatic cancer tissues than in adjacent normal pancreas tissues. Further, ectopic expression of DKK3 inhibits nuclear translocation of β‐catenin induced by hypoxia in pancreatic cancer Bxpc‐3 cell. The forced expression of DKK3 markedly suppressed migration and the stem cell‐like phenotype of pancreatic cancer Bxpc‐3 cell in hypoxic conditions through reversing epithelial–mesenchymal transition (EMT). The stable expression of DKK3 sensitizes pancreatic cancer Bxpc‐3 cell to gemcitabine, delays tumour growth and augments gemcitabine therapeutic effect in pancreatic cancer xenotransplantation model. Thus, we conclude from our finding that DKK3 is a tumour suppressor and improved gemcitabine therapeutic effect through inducing apoptosis and regulating β‐catenin/EMT signalling in pancreatic cancer Bxpc‐3 cell.

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Section: Discussionmentioning

confidence: 99%

DKK3 blocked translocation of β‐catenin/EMT induced by hypoxia and improved gemcitabine therapeutic effect in pancreatic cancer Bxpc‐3 cell

Guo

Qin

2015

J Cellular Molecular Medi

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“…21 Koong et al intraoperatively measured tumor oxygenation in cases of pancreatic cancer and revealed that a significant population of tumor cells is hypoxic. 12 Besides, pancreatic cancer often has abundant stromas and the tumor-stromal cell interactions play a critical role in tumor progression. 16,22 In the present study, we first hypothesized that a hypoxic environment might thus be present in cancer and stromal cells within pancreatic cancer tissue and that the tumorstromal cell interaction under hypoxia might increase the malignant behavior of this cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Using xenografted tumors of nude mice, the studies have shown pancreatic tumors to contain regions of extremely low pO 2 , in comparison to normal pancreatic tissue. 12 Clinically, it is also accepted that hypoxic tumor regions are responsible for resistance against chemotherapy and radiation therapy. 13,14 Moreover, interactions between cancer cells and the surrounding stromal fibroblasts have been reported to play a critical role in tumor invasion and metastasis.…”

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confidence: 99%

Tumor–stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c‐Met pathway

Ide

Kitajima

Miyoshi

et al. 2006

Intl Journal of Cancer

116

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The hypoxic environment in tumor is reported to play an important role in pancreatic cancer progression. The interaction between stromal and cancer cells also contributes to the malignant behavior of pancreatic cancer. In the present study, we investigated whether hypoxic stimulation affects stromal as well as pancreatic cancer cells. Our findings demonstrated that hypoxia remarkably elevated the HIF-1a expression in both pancreatic cancer (PK8) and fibroblast cells (MRC5). Hypoxic stimulation accelerated the invasive activity of PK8 cells, and invasiveness was thus further accelerated when the hypoxic PK8 cells were cultured with conditioned medium prepared from hypoxic MRC5 cells (hypoxic conditioned medium). MMP-2, MMP-7, MT1-MMP and c-Met expressions were increased in PK8 cells under hypoxia. Hypoxic stimulation also increased the hepatocyte growth factor (HGF) secretion from MRC5 cells, which led to an elevation of c-Met phosphorylation in PK8 cells. Conversely, the elevated cancer invasion, MMP activity and c-Met phosphorylation of PK8 cells were reduced by the removal of HGF from hypoxic conditioned medium. In immunohistochemical study, the HIF-1a expression was observed in surrounding stromal as well as pancreatic cancer cells, thus indicating hypoxia exists in both of cancer and stromal cells. Moreover, the stromal HGF expression was found to significantly correlate with not only the stromal HIF-1a expression but also the c-Met expression in cancer cells. These results indicate that the hypoxic environment within stromal as well as cancer cells activates the HGF/c-Met system, thereby contributing to the aggressive invasive features of pancreatic cancer. ' 2006 Wiley-Liss, Inc.Key words: hypoxia; tumor-stromal interaction; pancreatic cancer; hepatocyte growth factor; c-Met Most aggressive tumors have acquired the ability to develop their own blood vessels as they grow. However, the tumor cells grow faster than the endothelial cells, so the structure and function of the tumor vasculature is highly disorganized in comparison to normal tissues. 1,2 In this microenvironment, within tumor tissues, cancer cells are exposed to hypoxia. 3 Recent studies have revealed that hypoxia-inducible factor-1 (HIF-1) plays a key role in tumor progression under hypoxia. 4,5 HIF-1 is a heterodimeric basic helix-loop-helix PER/ARNT/SIM (HLH-PAS) transcription factor that consists of HIF-1a and a constitutively expressed aryl hydrocarbon receptor nuclear translocator (ARNT) known as HIF-1b. Under normoxic condition, HIF-1a is bound to the tumor suppressor Von Hippel-Lindau (VHL) protein. This protein complex causes HIF-1a to be targeted by proteasomes, thus leading to rapid protein degradation. Conversely, under hypoxic conditions, HIF-1a is stabilized and dimerized with HIF-1b, translocates to the nucleus and transactivates various gene expressions. HIF-1 is reported to regulate various gene expressions by binding to the hypoxia-responsive element on the target genes. More than 40 genes that are important for glucose transpo...

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“…As pancreatic cancer is characterized by severe hypoxia and nutrient deprivation (Koong et al, 2000;Akakura et al, 2001) we sought to determine whether periostin could promote the resistance to death of PDAC cells under these tumour-relevant conditions. CFPac1 and Panc1 cells were grown under hypoxic conditions (1% O 2 ) in the presence or absence of rPN and the population of surviving cells was followed using the MTT assay.…”

Section: Role Of Periostin In the Invasion Of Pdac Cellsmentioning

confidence: 99%

Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway

Baril¹,

Gangeswaran²,

Mahon³

et al. 2006

Oncogene

257

244

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Pancreatic ductal adenocarcinoma is a devastating disease, characterized by a rapid progression and poor treatment response. Using gene expression profiling of pancreatic cancer tissues, we previously identified periostin as a potential diagnostic and therapeutic target. In this study, we report the overexpression of periostin in a larger set of pancreatic cancer tissues and show that although the periostin transcript is exclusively expressed in tumour cells, the protein product is only detected in the extracellular matrix adjacent to cancer cells. Using an enzyme-linked immunosorbent assay (ELISA) assay, we show significantly increased levels of periostin in the sera of pancreatic cancer patients compared to non-cancer controls. We demonstrate that periostin promotes the invasiveness of tumour cells by increasing the motility of cells without inducing expression of proteases, and enhances the survival of tumour cells exposed to hypoxic conditions. At the molecular level, we provide evidence that the a 6 b 4 integrin complex acts as the cell receptor of periostin in pancreatic cancer cells and that interaction promotes phosphorylation of focal adhesion kinase (FAK) and protein kinase B (AKT) though activation of the PI3 kinase pathway, but not the RAS/MEK/ERK pathway. These findings suggest an important role of periostin in pancreatic cancer and provide a rationale to study periostin for diagnostic and therapeutic applications.

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Pancreatic tumors show high levels of hypoxia

Cited by 554 publications

References 9 publications

DKK3 blocked translocation of β‐catenin/EMT induced by hypoxia and improved gemcitabine therapeutic effect in pancreatic cancer Bxpc‐3 cell

DKK3 blocked translocation of β‐catenin/EMT induced by hypoxia and improved gemcitabine therapeutic effect in pancreatic cancer Bxpc‐3 cell

Tumor–stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c‐Met pathway

Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway

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