A role for hypoxia and hypoxia-inducible transcription factors in tumor physiology

Acker, Till; Plate, Karl H.

doi:10.1007/s00109-002-0355-1

Cited by 87 publications

(53 citation statements)

References 153 publications

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“…More than one-third of the gene sets (23 of 60) are related to such processes. These responses have been observed in malignant tumor microenvironments where enhanced proliferation of tumor cells leads to low oxygen and glucose levels (26). The leading-edge subsets of the associated significant gene sets include hypoxia-response genes such as HIF1A, VEGF, CRK, PXN, EIF2B1, EIF2B2, EIF2S2, FADD, NFKB1, RELA, GADD45A, and also Ras͞MAPK activation genes (HRAS, RAF1, and MAP2K1).…”

Section: Comparing Two Studies Of Lung Cancermentioning

confidence: 98%

Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

Subramanian

Tamayo

Mootha

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

41,934

304

38,314

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Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.

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Section: Comparing Two Studies Of Lung Cancermentioning

confidence: 98%

Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

Subramanian

Tamayo

Mootha

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

41,934

304

38,314

View full text Add to dashboard Cite

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“…It is well established that tumour hypoxia activates DNA transcription factors, for example, HIF-1, and leads to increased expression of a large number of genes, and a high expression of these genes has been shown to be associated with poor prognosis in several histological types of cancer (Rofstad, 2000;Höckel and Vaupel, 2001;Acker and Plate, 2002;Harris, 2002;Wouters et al, 2002). Some of the genes that are activated under hypoxic conditions encode proteins involved in the metastatic process, for example, angiogenesis factors and proteolytic enzymes.…”

Section: Discussionmentioning

confidence: 99%

“…Steep gradients in pO 2 and pO 2 values ranging from 0 mmHg to those found in welloxygenated normal tissues are characteristic features of tumours, implying that tumour tissues may show extensive spatial heterogeneity in cellular radiation sensitivity (Wouters and Brown, 1997) and hypoxia-induced gene expression (Acker and Plate, 2002;Harris, 2002). In contrast, studies of the temporal heterogeneity in pO 2 in tumours are sparse (Dewhirst et al, 2000).…”

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confidence: 99%

Temporal heterogeneity in oxygen tension in human melanoma xenografts

2003

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The spatial heterogeneity of the oxygen tension (pO 2 ) in human and experimental tumours has been studied extensively, whereas studies of the temporal heterogeneity in pO 2 are sparse. In the work reported here, pO 2 was measured continuously over periods of at least 60 min in A-07 human melanoma xenografts by using the OxyLite fibre-optic oxygen-sensing device. The main purpose of the work was to establish the usefulness of the OxyLite system in measuring the temporal heterogeneity in pO 2 in tissues and to characterise the fluctuations in tissue pO 2 in A-07 tumours. The OxyLite device was found to be suitable for studies of the temporal heterogeneity in pO 2 in tumours. However, potential pitfalls were identified, and reliable pO 2 measurements require that precautions are taken to avoid these pitfalls, that is, erroneous pO 2 readings caused by tissue trauma induced by the probe, probe movements induced by reflex actions of the host mouse and occasional probe drift. Significant fluctuations in pO 2 were detected in the majority of the 70 tumour regions subjected to measurement. The fluctuations in different regions of the same tumour were in general temporally independent, implying that they were caused primarily by redistribution of the tumour perfusion rather than fluctuations in global perfusion. Fourier analysis of the pO 2 traces showed that the pO 2 usually fluctuated at frequencies lower than 1.5 -2.0 mHz, corresponding to less than 0.1 cycle min À1 . Haemodynamic effects may cause pO 2 fluctuations in this frequency range, and hence, the redistribution of the perfusion could have been caused by morphological abnormalities of the tumour microvasculature. Moreover, acute hypoxia, that is, pO 2 fluctuations around 10 or 5 mmHg, was detected in 20 of 70 regions, that is, 29% (10 mmHg), or 27 of 70 regions, that is, 39% (5 mmHg). The median fraction of the time these regions were acutely hypoxic was 73% (10 mmHg) or 53% (5 mmHg). Consequently, if A-07 tumours are adequate models of tumours in man, acute hypoxia may be a commonly occurring phenomenon in neoplastic tissues, and hence, acute hypoxia is likely to cause resistance to radiation therapy and promote tumour aggressiveness.

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“…24 It has long been noted that the rapidly proliferating malignant cells generates greater oxygen consumption, which jointly favor the formation of hypoxic areas within the solid tumors. 25 Cycling hypoxia is a well-recognized phenomenon within solid tumors that contributes to the resistance to chemotherapy or radiotherapy. 26 Studies demonstrated that cells in hypoxic regions tend to be arrested at G1 phase.…”

Section: Discussionmentioning

confidence: 99%

Influence of c-Src on hypoxic resistance to paclitaxel in human ovarian cancer cells and reversal of FV-429

Guo

Liao

et al. 2018

Cell Death Dis

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SRC family kinase was documented to have vital roles in adjusting cancer cell malignant behaviors. To date, the role of c-Src, a member of SRC family kinase, in resistance to paclitaxel in human ovarian cancer cells under hypoxia has not been investigated. In the present study, we discovered that hypoxic environment suppressed paclitaxel-induced G2/M phase arrest and blockade of c-Src improved ovarian cancer cells' sensitivity to paclitaxel. FV-429, a derivative of natural flavonoid wogonin, could suppress gene expression and activation of c-Src, followed by deteriorated Stat3 nuclear translocation and its binding to HIF-1α, resulting in paclitaxel resistance reversal through G2/M arrest potentiation. Our study demonstrated that c-Src contributed to hypoxic microenvironment-rendered paclitaxel resistance in human epithelial ovarian cancer cells by G2/M phase arrest deterioration, and through c-Src suppression, FV-429 was capable of reversing the resistance by blocking c-Src/Stat3/HIF-1α pathway. Cell Death and Disease (2018) 8, e3178; doi:10.1038/cddis.2017.367; published online 11 January 2018In solid tumor, cells in hypoxic region becomes resistant to chemotherapy and radiotherapy, the reason for which is that hypoxia helps cancer cells survive by inducing several genes involved that accelerate the progression of malignancy. 1Physiological hypoxia occurs when the oxygen tension falls below 2%, thus a cultivating environment containing 1% oxygen is commonly used to mimic hypoxic environment in vitro.2-5 Ovarian cancer is a common gynecological cancer and one of the lethal cause of death from gynecological malignancy; 6 however, failure or relapse always exists due to the emergence of constant resistance. It has been reported that around 69% ovarian tumors from patients overexpress hypoxia inducible factor-1α (HIF-1α), 7,8 indicating that hypoxia may be closely related to ovarian tumors. Study showed that hypoxia increased G0/G1 phase percentage in ovarian cancer cells.9 However, the effect of paclitaxel is based on the inhibition of microtubule depolymerization, leading to G2/M phase arrest in cancer cells, which can be weakened by the effect induced by hypoxia. Considering on the uncertainty, the resistance to paclitaxel is probably due to G1 phase promotion rendered by hypoxic environment. However, the inner mechanism of the regulation on this cell cycle arrest still remains unclear.Non-receptor tyrosine kinase c-Src seems to be associated with hypoxia.1,10-12 Signal transducer and activator of transcription 3 (Stat3), a transcription factor having vital roles in malignancy, can be activated by c-Src. 13 Mccann et al.14 found that Stat3 activation contributed to hypoxia-induced resistance. Moreover, Huang et al. 9 found that blocking HIF-1α can improve G2/M arrest induced by paclitaxel under hypoxia.Thus we supposed that c-Src/Stat3/HIF-1α axis may regulate hypoxic resistance to paclitaxel under hypoxia.FV-429, a derivative of wogonin, which is one of the main components extracted from Scutellaria baicalensis...

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A role for hypoxia and hypoxia-inducible transcription factors in tumor physiology

Cited by 87 publications

References 153 publications

Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

Temporal heterogeneity in oxygen tension in human melanoma xenografts

Influence of c-Src on hypoxic resistance to paclitaxel in human ovarian cancer cells and reversal of FV-429

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