Hypoxia-Driven Gene Expression Is an Independent Prognostic Factor in Stage II and III Colon Cancer Patients

Dekervel, Jeroen; Hompes, Daphne; Malenstein, Hannah van; Popović, Dušan; Moor, Bart De; Cutsem, Éric Van; D’Hoore, André; Verslype, Chris; Pelt, Jos van

doi:10.1158/1078-0432.ccr-13-2958

Cited by 31 publications

(23 citation statements)

References 26 publications

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“…Multiple clinical studies in prostate cancer have reported an association between hypoxia and poor clinical outcome in patients with various types of cancer following chemotherapy or surgery (1, 2). A study of 247 prostate cancer patients with localized intermediate-risk disease showed that tumor hypoxia is associated with early biochemical relapse and local recurrence in the prostate gland (3).…”

Section: Introductionmentioning

confidence: 99%

PIM Kinase Inhibitors Kill Hypoxic Tumor Cells by Reducing Nrf2 Signaling and Increasing Reactive Oxygen Species

Warfel

Sainz

Song

et al. 2016

Molecular Cancer Therapeutics

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Intratumoral hypoxia is a significant obstacle to the successful treatment of solid tumors, and it is highly correlated with metastasis, therapeutic resistance, and disease recurrence in cancer patients. As a result, there is an urgent need to develop effective therapies that target hypoxic cells within the tumor microenvironment. The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases is a pro-survival pathway that is upregulated in response to hypoxia, in a HIF-1-independent manner. We demonstrate that pharmacological or genetic inhibition of PIM kinases is significantly more toxic toward cancer cells in hypoxia as compared to normoxia. Xenograft studies confirm that PIM kinase inhibitors impede tumor growth and selectively kill hypoxic tumor cells in vivo. Experiments show that PIM kinases enhance the ability of tumor cells to adapt to hypoxia-induced oxidative stress by increasing the nuclear localization and activity of Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), which functions to increase the expression of antioxidant genes. Small molecule PIM kinase inhibitors prevent Nrf2 from accumulating in the nucleus, reducing the transcrption of cytoprotective genes and leading to the build up of intracellular reactive oxygen species (ROS) to toxic levels in hypoxic tumor cells. This toxic effect of PIM inhibitors can be successfully blocked by ROS scavengers, including N-acetyl cystine and superoxide dismutase. Thus, inhibition of PIM kinases has the potential to oppose hypoxia-mediate therapeutic resistance and induce cell death in the hypoxic tumor microenvironment.

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Section: Introductionmentioning

confidence: 99%

PIM Kinase Inhibitors Kill Hypoxic Tumor Cells by Reducing Nrf2 Signaling and Increasing Reactive Oxygen Species

Warfel

Sainz

Song

et al. 2016

Molecular Cancer Therapeutics

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“…Recently, using an in vivo gene-tagging method, it was demonstrated that tumor cells in hypoxic regions could be the origin of recurrence after radiotherapy [8]. It was also reported that change of gene expression in chronic hypoxia was associated with high recurrence rates in colorectal cancer patients [9]. Investigating the biology of tumor cells in hypoxic conditions might be critical for improving therapeutic efficacy and for eradication of cancer.…”

Section: Introductionmentioning

confidence: 99%

Dormancy of Cancer Cells with Suppression of AKT Activity Contributes to Survival in Chronic Hypoxia

et al. 2014

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A hypoxic microenvironment in tumors has been recognized as a cause of malignancy or resistance to various cancer therapies. In contrast to recent progress in understanding the acute response of cancer cells to hypoxia, the characteristics of tumor cells in chronic hypoxia remain elusive. We have identified a pancreatic cancer cell line, AsPC-1, that is exceptionally able to survive for weeks under 1% oxygen conditions while most tested cancer cell lines die after only some days under these conditions. In chronic hypoxia, AsPC-1 cells entered a state of dormancy characterized by no proliferation, no death, and metabolic suppression. They reversibly switched to active status after being placed again in optimal culture conditions. ATP turnover, an indicator of energy demand, was markedly decreased and accompanied by reduced AKT phosphorylation. Forced activation of AKT resulted in increased ATP turnover and massive cell death in vitro and a decreased number of dormant cells in vivo. In contrast to most cancer cell lines, primary-cultured colorectal cancer cells easily entered the dormant status with AKT suppression under hypoxia combined with growth factor–depleted conditions. Primary colorectal cancer cells in dormancy were resistant to chemotherapy. Thus, the ability to survive in a deteriorated microenvironment by entering into dormancy under chronic hypoxia might be a common property among cancer cells. Targeting the regulatory mechanism inducing this dormant status could provide a new strategy for treating cancer.

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“…We used the following existing gene expression signatures for predicting rectal cancer outcomes: the Ghadimi et al 54-gene signature, the Watanabe et al 33 gene signature and the Kim et al 95 gene signature [18–20]. Next, we added an Epithelial-to-Mesenchymal (EMT) signature and a hypoxia signature for colorectal cancer [23,24]. Finally, a five-gene signature for predicting metastasis of colorectal cancer was applied [25].…”

Section: Methodsmentioning

confidence: 99%

Quantitative imaging outperforms molecular markers when predicting response to chemoradiotherapy for rectal cancer

Joye

Debucquoy

Deroose

et al. 2017

Radiotherapy and Oncology

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Background and purpose To explore the integration of imaging and molecular data for response prediction to chemoradiotherapy (CRT) for rectal cancer. Material and Methods Eighty-five rectal cancer patients underwent preoperative CRT. 18F-FDG PET/CT and diffusion-weighted imaging (DWI) were acquired before (TP1) and during CRT (TP2) and prior to surgery (TP3). Inflammatory cytokines and gene expression were analyzed. Tumour response was defined as ypT0-1N0. Multivariate models were built combining the obtained parameters. Final models were calculated on the data combination with the highest AUC. Results Twenty-two patients (26%) achieved ypT0-1N0 response. 18F-FDG PET/CT had worse predictive performance than DWI and T2-volumetry (AUC 0.61 ± 0.04, 0.72 ± 0.03, and 0.72 ± 0.02, respectively). Combining all imaging parameters increased the AUC to 0.81 ± 0.03. Adding cytokines or gene expression did not improve the AUC (AUC of 0.72 ± 0.06 and 0.79 ± 0.04 respectively). Final models combining 18F-FDG PET/CT, DWI, and T2-weighted volumetry at all TPs and using only TP1 and TP3, allowed ypT0-1N0 prediction with a 75% sensitivity, 94% specificity and PPV of 80%. Conclusions Combining 18F-FDG PET/CT, DWI, and T2-weighted MRI volumetry obtained before CRT and prior to surgery may help physicians in selecting rectal cancer patients for organ-preservation.

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Hypoxia-Driven Gene Expression Is an Independent Prognostic Factor in Stage II and III Colon Cancer Patients

Cited by 31 publications

References 26 publications

PIM Kinase Inhibitors Kill Hypoxic Tumor Cells by Reducing Nrf2 Signaling and Increasing Reactive Oxygen Species

PIM Kinase Inhibitors Kill Hypoxic Tumor Cells by Reducing Nrf2 Signaling and Increasing Reactive Oxygen Species

Dormancy of Cancer Cells with Suppression of AKT Activity Contributes to Survival in Chronic Hypoxia

Quantitative imaging outperforms molecular markers when predicting response to chemoradiotherapy for rectal cancer

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