Hypoxia and Aggressive Tumor Phenotype: Implications for Therapy and Prognosis

Vaupel, Peter

doi:10.1634/theoncologist.13-s3-21

Cited by 345 publications

(271 citation statements)

References 31 publications

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“…Hypoxia is considered to be a potential barrier for treating tumors because it induces the development of cell clones with an aggressive and treatment-resistant phenotype, which leads to rapid progression and poor prognosis (Kizaka-Kondoh et al, 2003;Vaupel, 2008). It has been shown that hypoxia can decrease the therapeutic efficacy of radiation treatment, surgery, and some forms of chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Tumor hypoxia, mostly resulting from poor perfusion and anemia, is one of the key factors involved in the development of cell clones with an aggressive and treatment-resistant phenotype, which leads to rapid progression and poor prognosis (Semenza, 2001;Poellinger and Johnson, 2004;Vaupel, 2008). It has been reported that solid tumors in humans, even those less than 1 cm in diameter (i.e., at the limits of clinical detection), may have substantial hypoxic fractions (Bae et al, 1999).…”

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confidence: 99%

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Hypoxia Stabilizes Microtubule Networks and Decreases Tumor Cell Chemosensitivity to Anticancer Drugs Through Egr‐1

Peng¹,

Pan²,

Liu³

et al. 2010

The Anatomical Record

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The hypoxic environment of solid tumor causes the tumor cells survive and which could protect them from death by facilitating resistance to therapy. Here, we provide evidence that hypoxia can increase tumor cell viability and proliferation through an Egr-1-dependant pathway. Hypoxia protected the microtubules from disassembly, and Egr-1 was colocalized with microtubules in different cell cycle stages. Knockdown of Egr-1 with its siRNA overcame the protection effect of hypoxia and increased the sensitivity of tumor cells to vinblastine under hypoxic conditions. Our results suggest a novel approach for increasing the sensitivity of tumor cells to chemotherapeutics that target microtubule assembly. Anat Rec, 293:414-420, 2010. V V C 2010 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Hypoxia Stabilizes Microtubule Networks and Decreases Tumor Cell Chemosensitivity to Anticancer Drugs Through Egr‐1

Peng¹,

Pan²,

Liu³

et al. 2010

The Anatomical Record

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“…Hypoxia is a characteristic feature of locally advanced tumours and is coupled to tumour invasiveness, poor survival and treatment failure in cancer patients 21 . The cellular adaptation to hypoxia may also contribute to loss of polarity, tissue integrity and architecture.…”

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confidence: 99%

AmotL2 disrupts apical–basal cell polarity and promotes tumour invasion

et al. 2014

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The establishment and maintenance of apical-basal cell polarity is essential for the functionality of glandular epithelia. Cell polarity is often lost in advanced tumours correlating with acquisition of invasive and malignant properties. Despite extensive knowledge regarding the formation and maintenance of polarity, the mechanisms that deregulate polarity in metastasizing cells remain to be fully characterized. Here we show that AmotL2 expression correlates with loss of tissue architecture in tumours from human breast and colon cancer patients. We further show that hypoxic stress results in activation of c-Fos-dependent expression of AmotL2 leading to loss of polarity. c-Fos/hypoxia-induced p60 AmotL2 interacts with the Crb3 and Par3 polarity complexes retaining them in large vesicles and preventing them from reaching the apical membrane. The resulting loss of polarity potentiates the response to invasive cues in vitro and in vivo in mice. These data provide a molecular mechanism how hypoxic stress deregulates cell polarity during tumour progression.

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“…10,11 Hypoxia has also been found to result in cells with more aggressive phenotype, thereby increasing tumour malignancy. 12 In addition to tumour spheroids, micro-dissected tumour tissues have also been recently demonstrated to survive in culture within a microfluidic a) S. M. Grist and S. S. Nasseri contributed equally to this work.…”

Section: Introductionmentioning

confidence: 99%

On-chip clearing of arrays of 3-D cell cultures and micro-tissues

et al. 2016

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Three-dimensional (3-D) cell cultures are beneficial models for mimicking the complexities of in vivo tissues, especially in tumour studies where transport limitations can complicate response to cancer drugs. 3-D optical microscopy techniques are less involved than traditional embedding and sectioning, but are impeded by optical scattering properties of the tissues. Confocal and even two-photon microscopy limit sample imaging to approximately 100-200 lm depth, which is insufficient to image hypoxic spheroid cores. Optical clearing methods have permitted high-depth imaging of tissues without physical sectioning, but they are difficult to implement for smaller 3-D cultures due to sample loss in solution exchange. In this work, we demonstrate a microfluidic platform for high-throughput on-chip optical clearing of breast cancer spheroids using the SeeDB, Clear T2 , and ScaleSQ clearing methods. Although all three methods are able to effectively clear the spheroids, we find that SeeDB and ScaleSQ more effectively clear the sample than Clear T2 ; however, SeeDB induces green autofluorescence while ScaleS causes sample expansion. Our unique on-chip implementation permits clearing arrays of 3-D cultures using perfusion while monitoring the 3-D cultures throughout the process, enabling visualization of the clearing endpoint as well as monitoring of transient changes that could induce image artefacts. Our microfluidic device is compatible with on-chip 3-D cell culture, permitting the use of on-chip clearing at the endpoint after monitoring the same spheroids during their culture. This onchip method has the potential to improve readout from 3-D cultures, facilitating their use in cell-based assays for high-content drug screening and other applications. Published by AIP Publishing. [http://dx

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Hypoxia and Aggressive Tumor Phenotype: Implications for Therapy and Prognosis

Cited by 345 publications

References 31 publications

Hypoxia Stabilizes Microtubule Networks and Decreases Tumor Cell Chemosensitivity to Anticancer Drugs Through Egr‐1

Hypoxia Stabilizes Microtubule Networks and Decreases Tumor Cell Chemosensitivity to Anticancer Drugs Through Egr‐1

AmotL2 disrupts apical–basal cell polarity and promotes tumour invasion

On-chip clearing of arrays of 3-D cell cultures and micro-tissues

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