Perinecrotic Hypoxia Contributes to Ischemia/Reperfusion-Accelerated Outgrowth of Colorectal Micrometastases

Bilt, Jarmila D. W. van der; Soeters, Marije; Duyverman, Annique M.; Nijkamp, Maarten W.; Witteveen, Petronella O.; Diest, Paul J. van; Kranenburg, Onno; Rinkes, Inne H.M. Borel

doi:10.2353/ajpath.2007.061028

Cited by 54 publications

(57 citation statements)

References 71 publications

(63 reference statements)

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“…Although Hsp90 and extracellular Hsp90a undoubtedly contribute to cell migration and metastasis (16,41), there has recently been some controversy due to prometastatic effects of Hsp90 inhibition observed in other models (42,43). For 17-DMAG, there are only few reported studies that address antimetastatic activity based on different models reflecting parts of the metastatic cascade (44,45). Thus, we tested 17-DMAG in a spontaneously The control shows nodular metastases predominantly in the right lung and progression to extensive disease.…”

Section: Discussionmentioning

confidence: 99%

Targeting Focal Adhesion Kinase with Dominant-Negative FRNK or Hsp90 Inhibitor 17-DMAG Suppresses Tumor Growth and Metastasis of SiHa Cervical Xenografts

et al. 2009

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Focal adhesion kinase (FAK), a nonreceptor protein tyrosine kinase and key modulator of integrin signaling, is widely expressed in different tissues and cell types. Recent evidence indicates a central function of FAK in neoplasia where the kinase contributes to cell proliferation, resistance to apoptosis and anoikis, invasiveness, and metastasis. FAK, like other signaling kinases, is dependent on the chaperone heat shock protein 90 (Hsp90) for its stability and proper function. Thus, inhibition of Hsp90 might be a way of disrupting FAK signaling and, consequently, tumor progression. FAK is expressed in high-grade squamous intraepithelial lesions and metastatic cervical carcinomas but not in nonneoplastic cervical mucosa. In SiHa, a cervical cancer cell line with characteristics of epithelial-to-mesenchymal transition, the stable expression of dominant-negative FAK-related nonkinase decreases anchorage independence and delays xenograft growth. FAK-related nonkinase as well as the Hsp90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin both negatively interfere with FAK signaling and focal adhesion turnover. Short-term 17-dimethylaminoethylamino-17-demethoxygeldanamycin treatment prolongs survival in a SiHa lung metastasis model and chronic administration suppresses tumor growth as well as metastatic spread in orthotopic xenografts. Taken together, our data suggest that FAK is of importance for tumor progression in cervical cancer and that disruption of FAK signaling by Hsp90 inhibition might be an avenue to restrain tumor growth as well as metastatic spread. [Cancer Res 2009;69(11):4750-9]

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Section: Discussionmentioning

confidence: 99%

Targeting Focal Adhesion Kinase with Dominant-Negative FRNK or Hsp90 Inhibitor 17-DMAG Suppresses Tumor Growth and Metastasis of SiHa Cervical Xenografts

et al. 2009

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“…I/R in the liver generates long-term microcirculatory disturbances and chronic hypoxia, which play an important role in accelerated tumor outgrowth following hepatic I/R [8]. Hypoxia can stimulate motility and invasion of tumor cells through induction of matrix-metalloproteinases (MMPs), urokinase plasminogen activator receptor (uPAR), and/or c-Met [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

A role for CD95 signaling in ischemia/reperfusion‐induced invasion and outgrowth of colorectal micrometastases in mouse liver

Nijkamp

Hoogwater

Govaert

et al. 2011

Journal of Surgical Oncology

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“…12 Accordingly, seen under the pro-inflammatory and tumor promoting aspects, HIF-1a exerts adverse effects and strategies to prevent its accumulation or to block its transcriptional coactivation have been suggested for therapeutic use. 13,14 Thus, accumulation of HIF-1a may have opposite consequences on acute and long-term cellular survival, probably also depending on the type of tissue injury/ diseases. In any case, however, its impact on conditions of ischemia-reperfusion and inflammation is significant, and consequently, it has moved in the focus of interest in transplantation research.…”

Section: Introductionmentioning

confidence: 99%

Organ preservation solutions attenuate accumulation and nuclear translocation of hypoxia‐inducible factor‐1α in the hepatoma cell line HepG2

Paddenberg¹,

Howold²,

Hoger³

et al. 2009

Cell Biochemistry & Function

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Hypoxia-inducible factor-1alpha (HIF-1alpha) is a key transcription factor orchestrating hypoxic and inflammatory reactions. Here, we determined the impact of organ preservation solutions (Celsior; histidine-tryptophan-ketoglutarate solution, HTK; University of Wisconsin solution; UW), oxygen supply, and temperature on HIF-1alpha accumulation, recorded by Western blotting and immunocytochemistry, in the human hepatoma cell line HepG2. Generation of reactive oxygen species (ROS), NO, and cell viability were concomitantly assessed. At 4 degrees C, HIF-1alpha accumulation was not detectable. In normothermic (37 degrees C) cell culture medium (Dulbecco's Modified Eagle's Medium, DMEM), HepG2 cells accumulated HIF-1alpha even in normoxia (21% O(2)) which was not observed in either of the preservation solutions. This correlated to high generation of NO, a normoxic stabilizer of HIF-1alpha, and L-arginine content (substrate for NO synthesis) in DMEM, and low NO production and absence of L-arginine in preservation solutions. In normothermic hypoxia up to 24 h, intracellular HIF-1alpha accumulated in all conditions, but less in preservation solutions compared to DMEM. The inhibitory effect on accumulation and nuclear translocation was most prominent for HTK, the only solution containing the activator of HIF-1alpha degradation, alpha-ketoglutarate. Addition of other intermediates of the tricarbon acid cycle-succinate, fumarate, malate-did not alter HIF-1alpha accumulation, although succinate exhibited a beneficial effect on cell viability in cold storage. In conclusion, preservation solutions attenuate accumulation and nuclear translocation of the transcription factor HIF-1alpha, and this property is seemingly related to their chemical composition (L-arginine, alpha-ketoglutarate). Thus, it appears feasible to design preservation solution specifically to modify HIF-1alpha accumulation and nuclear translocation.

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Perinecrotic Hypoxia Contributes to Ischemia/Reperfusion-Accelerated Outgrowth of Colorectal Micrometastases

Abstract: Ischemia/reperfusion (I/R) is often inevitable dur-The liver is the most common site for metastases, developing in more than 50% of colorectal cancer patients. In selected cases, hepatic resection is the only curative option offering 5-year survival rates of 30 to 40%.

Cited by 54 publications

References 71 publications

Targeting Focal Adhesion Kinase with Dominant-Negative FRNK or Hsp90 Inhibitor 17-DMAG Suppresses Tumor Growth and Metastasis of SiHa Cervical Xenografts

Targeting Focal Adhesion Kinase with Dominant-Negative FRNK or Hsp90 Inhibitor 17-DMAG Suppresses Tumor Growth and Metastasis of SiHa Cervical Xenografts

A role for CD95 signaling in ischemia/reperfusion‐induced invasion and outgrowth of colorectal micrometastases in mouse liver

Organ preservation solutions attenuate accumulation and nuclear translocation of hypoxia‐inducible factor‐1α in the hepatoma cell line HepG2

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