Hypoxia Enhances Metastatic Efficiency by Up-Regulating Mdm2 in KHT Cells and Increasing Resistance to Apoptosis

Zhang, Li; Hill, Richard P.

doi:10.1158/0008-5472.can-03-3038

Cited by 92 publications

(67 citation statements)

References 52 publications

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“…Hypoxia can give rise to loss of p53 function in hypoxic transformed mouse embryonic fibroblasts, as a consequence of the acquisition of mutations (Graeber et al, 1996). More recently, some cell lines exposed to hypoxia are reported to be less susceptible to apoptosis (Dong and Wang, 2004;Zhang and Hill, 2004). Thus the hypoxic environment provides a vehicle for the clonal evolution of tumours to more advanced stages of carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

In vitro hypoxia-conditioned colon cancer cell lines derived from HCT116 and HT29 exhibit altered apoptosis susceptibility and a more angiogenic profile in vivo

et al. 2005

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Hypoxia is an important selective force in the clonal evolution of tumours. Through HIF-1 and other transcription factors combined with tumour-specific genetic alterations, hypoxia is a dominant factor in the angiogenic phenotype. Cellular adaptation to hypoxia is an important requirement of tumour progression independent of angiogenesis. The adaptive changes, insofar as they alter hypoxiainduced apoptosis, are likely to determine responsiveness to antiangiogenic strategies. To investigate this adaptation of tumour cells to hypoxia, we recreated in vitro the in vivo situation of chronic intermittent exposure to low-oxygen levels. The colon carcinoma cell lines HT29 and HCT116 were subjected to 40 episodes of sublethal hypoxia (4 h) three times a week. The resulting two hypoxiaconditioned cell lines have been maintained in culture for more than 2 years. In both cell lines changes in doubling times occurred: in HT29 an increase, and in HCT116 a decrease. Cell survival in response to hypoxia and to DNA damage differed strikingly in the two cell lines. The HT29 hypoxia-conditioned cells were more resistant than the parental line to a 24 h hypoxic challenge, while those from HCT116 surprisingly were more sensitive. Sensitivity to cisplatin in vitro was also significantly different for the hypoxiaconditioned compared with the parental lines, suggesting a change in pathways leading to apoptosis following DNA damage signaling. The growth of both conditioned cell lines in vivo as xenografts in immunodeficient (SCID) mice was more rapid than their parental lines, and was accompanied in each by evidence of enhanced vascular proliferation as a consequence of the hypoxia-conditioning. Thus the changes in apoptotic susceptibility were independent of altered angiogenesis. The derivation of these lines provides a model for events within hypoxic regions of colon cancers, and for the acquisition of resistance and sensitivity characteristics that may have therapeutic implications for the use of antiangiogenesis drugs.

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Section: Discussionmentioning

confidence: 99%

In vitro hypoxia-conditioned colon cancer cell lines derived from HCT116 and HT29 exhibit altered apoptosis susceptibility and a more angiogenic profile in vivo

et al. 2005

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“…A number of other cellular pathways are differentially regulated in hypoxia and may also contribute to hypoxia-induced drug resistance [77][78][79][80][81] . It has been shown that the suppression of HIF-1α through gene knockdown or the use of small molecule inhibitors reduces resistance to cytostatics, such as cisplatin, etoposide, doxorubicin, and ellipticine, but does not suppress it completely 20,33,59,60 .…”

Section: Other Factors Responsible For Hypoxia-induced Chemoresistancementioning

confidence: 99%

Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1

Doktorova

Hraběta

Khalil

et al. 2015

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. The aim of this review is to provide the information about molecular basis of hypoxia-induced chemoresistance, focusing on the possibility of diagnostic and therapeutic use. Results. Hypoxia is a common feature of tumors and represents an independent prognostic factor in many cancers. It is the result of imbalances in the intake and consumption of oxygen caused by abnormal vessels in the tumor and the rapid proliferation of cancer cells. Hypoxia-induced resistance to cisplatin, doxorubicin, etoposide, melphalan, 5-flouoruracil, gemcitabine, and docetaxel has been reported in a number of experiments. Adaptation of tumor cells to hypoxia has important biological effects. The most studied factor responsible for these effects is hypoxia-inducible factor-1 (HIF-1) that significantly contributes to the aggressiveness and chemoresistance of different tumors. The HIF-1 complex, induced by hypoxia, binds to target genes, thereby increasing the expression of many genes. In addition, the expression of hundreds of genes can be also decreased in response to hypoxia in HIF-1 dependent manner, but without the detection of HIF-1 in these genes' promoters. HIF-1 independent mechanisms for drug resistance in hypoxia have been described, however, they are still rarely reported. The first clinical studies focusing on diagnosis of hypoxia and on inhibition of hypoxia-induced changes in cancer cells are starting to yield results. Conclusions. The adaptation to hypoxia requires many genetic and biochemical responses that regulate one another. Hypoxia-induced resistance is a very complex field and we still know very little about it. Different approaches to circumvent hypoxia in tumors are under development.

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“…The lung-trap assay was performed as described by (Zhang and Hill, 2004). Timp-3 À/À and wild-type mice were injected intravenously with B16F10 cells and mice were killed at 15 min, 48 and 96 h post-injection.…”

Section: Lung-trap Assaymentioning

confidence: 99%

Enhanced metastatic dissemination to multiple organs by melanoma and lymphoma cells in timp-3−/− mice

et al. 2006

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Identifying versatile inhibitors of metastasis that operate in multiple sites against distinct cancer cell types is important for designing novel therapeutics for metastasis. We show that multiple tissues of timp-3 À/À mice are more susceptible to metastatic colonization. Overall, a 5-14-fold increase in liver and kidney colonization occurred by EL-4 lymphoma cells, and a twofold increase upon targeting B16F10 melanoma cells to the bone or lung of timp-3 À/À mice. There was a general lack of macrophage or neutrophil localization to metastases in the liver, kidney and lung, and of osteoclasts to bone in both genotypes. Analysis of lung showed that proliferation or angiogenesis were unaltered within the metastatic colonies. Lung-trap assays revealed that initial tumor cell trapping was similar in the lung vasculature of timp-3 À/À and wild-type mice. However, more tumor cells were found in timp-3 À/À lungs at 48 and 96 h after tumor cell injection indicating more efficient extravasation and initial proliferation. Activation of pro-MMP-2 was greater in timp-3 À/À lungs at these time points. These data demonstrate TIMP-3 functions to inhibit metastatic dissemination of diverse cancer cells to multiple organs. TIMP-3 regulates MMP-2 activation to limit tumor cell extravasation and subsequent colonization of the lung, without augmenting inflammatory cell response.

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Hypoxia Enhances Metastatic Efficiency by Up-Regulating Mdm2 in KHT Cells and Increasing Resistance to Apoptosis

Cited by 92 publications

References 52 publications

In vitro hypoxia-conditioned colon cancer cell lines derived from HCT116 and HT29 exhibit altered apoptosis susceptibility and a more angiogenic profile in vivo

In vitro hypoxia-conditioned colon cancer cell lines derived from HCT116 and HT29 exhibit altered apoptosis susceptibility and a more angiogenic profile in vivo

Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1

Enhanced metastatic dissemination to multiple organs by melanoma and lymphoma cells in timp-3−/− mice

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