The Hypoxic Environment in Tumor-Stromal Cells Accelerates Pancreatic Cancer Progression via the Activation of Paracrine Hepatocyte Growth Factor/c-Met Signaling

Ide, Takao; Kitajima, Yoshihiko; Miyoshi, Anderson; Ohtsuka, Takao; Mitsuno, Mayumi; Ohtaka, Kazuma; Miyazaki, Kohji

doi:10.1245/s10434-007-9435-3

Cited by 86 publications

(83 citation statements)

References 28 publications

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“…[3][4][5][6][7][8] This association has also been shown for PDAC, where a more hypoxic phenotype is associated with a worse prognosis. 38,39 We hypothesize that the clinical outcome for patients treated with the triplet treatment may be more favorable than doublet nab-paclitaxel and gemcitabine, given the multiple therapeutic modalities employed including hypoxia-selective targeting.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

Sun

Liu

Ahluwalia

et al. 2015

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 99%

Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

Sun

Liu

Ahluwalia

et al. 2015

Cancer Biology & Therapy

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“…Low microvascular density (MVD) and reduced blood flow have been shown to be signs of tumor aggressiveness [10][11][12], and high MVD in peripheral hot spots has been found to correlate with poor prognosis, suggesting that highly heterogeneous microcirculation aggravates the outcome [6,13]. It has also been revealed that poor prognosis is associated with severe hypoxia in the primary tumor [14][15][16]. Moreover, the interstitial fluid pressure (IFP) has been reported to be elevated [17][18][19], and it has been suggested that highly elevated IFP together with a dense and extensive stroma may cause resistance to treatment by inhibiting the distribution of chemotherapeutic agents [19].…”

Section: Introductionmentioning

confidence: 99%

Dynamic contrast-enhanced MRI of the microenvironment of pancreatic adenocarcinoma xenografts

et al. 2017

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Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor outcome. Resistance to treatment is associated with impaired vascularity, extensive hypoxia, and interstitial hypertension. In this study, the potential of dynamic contrast-enhanced (DCE)-MRI as a method for assessing the microvascular density (MVD), the fraction of hypoxic tissue, and the interstitial fluid pressure (IFP) of PDACs was investigated. Material and methods: Intramuscular BxPC-3, Capan-2, MIAPaCa-2, and Panc-1 PDAC xenografts were used as preclinical models of human PDACs. DCE-MRI with Gd-DOTA as contrast agent was conducted with a 7.05-T scanner, and the DCE-MRI series were analyzed voxelwise by using the Tofts pharmacokinetic model. Tumor MVD and hypoxia were measured in histological preparations by using pimonidazole as a hypoxia marker and CD31 as a marker of endothelial cells. IFP was measured with a Millar catheter. Results: K trans (the volume transfer constant of Gd-DOTA) increased with increasing MVD and decreased with increasing hypoxic fraction, but was not associated with IFP. Any association between v e (the fractional distribution volume of Gd-DOTA) and MVD, hypoxic fraction, or IFP could not be detected. Conclusions: This study shows that DCE-MRI is a useful modality for assessing important features of the microenvironment of PDAC xenografts and thus provides the basis for future preclinical and clinical DCE-MRI investigations of PDAC.

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“…We previously demonstrated that tumor-stromal cell interactions under hypoxia increase the invasiveness of pancreatic cancer cells through up-regulated HGF/c-Met signaling via HIF-1· (31). We further reported a significant correlation between the HIF-1· expression and poor prognosis in patients with pancreatic cancer (32). Other studies have also reported a significant association between HIF-1· expression and prognosis in a variety of human cancers including stomach (17), esophagus (18), pancreas (19), lung (20), breast (21), upper urinary tract (22), uterine cervix (23) and ovarian cancer (24).…”

Section: Discussionmentioning

confidence: 81%

“…Immunohistochemical staining was performed according to the procedures described in a previous study with slight modifications (31,32). Briefly, the paraffinembedded samples were cut into 4-μm thick sections and then were deparaffinized in xylene and rehydrated in a graded series of ethanol.…”

Section: Patientsmentioning

confidence: 99%

Hypoxia-inducible factor-1α expression predicts the response to 5-fluorouracil-based adjuvant chemotherapy in advanced gastric cancer

Miyazaki¹

2009

Oncol Rep

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Abstract. Hypoxia frequently occurs in various solid tumors, thereby accelerating cancer progression and treatment resistance. Hypoxia-inducible factor-1· (HIF-1·) plays a central role in tumor hypoxia by up-regulating the gene expression related to angiogenesis, cancer invasion and anti-apoptosis. The present study immunohistochemically investigated HIF-1· expression in 63 gastric cancer specimens. Those specimens were obtained from 44 patients that received 5-FU chemotherapy post-operatively whereas the remaining 19 patients did not. The immunostaining pattern of HIF-1· was classified into 3 patterns: diffuse-positive within the tumor (DP), positive at the invasive front of the tumor (FP) and negative (N). Thirty-six of 63 (57.1%) patients exhibited DP, 24 (38.1%) revealed FP and the remaining 3 (4.8%) patients were judged as N. The HIF-1· expression pattern grouped into DP and FP/N correlated with the clinicopathological factors and survival. As a result, the HIF-1· expression did not show a significant correlation with the clinicopathological factors, such as the depth of invasion, lymph node metastasis and tumor stage, nor patient survival in the 63 patients. However, in the 44 patients that underwent chemotherapy, patients with the FP/N pattern showed longer survival than those with the DP pattern. On the other hand, no significant difference in survival was found between the 2 patterns among 19 patients without the chemotherapy. These results indicated that the diffuse expression of HIF-1· in gastric tumors might lead to drug resistance against adjuvant chemotherapy using 5-FU. In conclusion, the assessment of the HIF-1· expression in the resected tissues might predict the drug response to adjuvant 5-FU chemotherapy in advanced gastric cancer patients.

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The Hypoxic Environment in Tumor-Stromal Cells Accelerates Pancreatic Cancer Progression via the Activation of Paracrine Hepatocyte Growth Factor/c-Met Signaling

Abstract: These data suggest that the HGF/c-Met signaling via HIF-1alpha ?may therefore negatively affect the prognosis in patients with pancreatic cancer, and targeting tumor stroma under hypoxia might thus be potentially useful as a novel therapy for this cancer.

Cited by 86 publications

References 28 publications

Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

Dynamic contrast-enhanced MRI of the microenvironment of pancreatic adenocarcinoma xenografts

Hypoxia-inducible factor-1α expression predicts the response to 5-fluorouracil-based adjuvant chemotherapy in advanced gastric cancer

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