Cited by 348Cancer, Hypoxia, and MetabolismCancer Cells and MetastasisAngiogenesis and VEGF in Cancer

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Tumour Hypoxia Affects the Responsiveness of Cancer Cells to Chemotherapy and Promotes Cancer Progression

Cosse, Jean-Philippe, Michiels, Carine·2008·Anti-Cancer Agents in Medicinal Chemistry

DOI 10.2174/187152008785914798

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Abstract

A solid tumour forms an organ-like structure that is comprised of cancer cells as well as stroma cells (fibroblasts, inflammatory cells) that are embedded in an extracellular matrix and are nourished by vascular network. However, tumoral microenvironment is heterogeneous due to the abnormal vasculature network and high proliferation rate of cancer cells. Because of these features, some regions are starved from oxygen, a phenomenon called hypoxia. Transient hypoxia is associated with inadequate blood flow while chronic hypoxia is the consequence of the increased oxygen diffusion distance due to tumour expansion. Both types of hypoxia are correlated with poor outcome for patients. Moreover, hypoxia also enhances chemoresistance of cancer cells. Firstly, the delivery of drugs in hypoxic area and cellular uptake of it are affected by hypoxia or associated acidity. Secondly, some chemotherapeutic drugs require oxygen to generate free radicals that contribute to cytotoxicity. Last, hypoxia induces cellular adaptations that compromise the effectiveness of chemotherapy. In response to nutrient deprivation due to hypoxia, the rate of proliferation of cancer cells decreases but chemotherapeutic drugs are more effective against proliferating cells. On the other hand, hypoxia induces adaptation by post-translational and transcriptional changes that promote cell survival and resistance to chemotherapy. Through these changes, hypoxia promotes angiogenesis, shift to glycolytic metabolism, expression of ABC transporters, cell survival by inducing the expression of genes encoding growth factors and the modulation of apoptotic process. The aim of this review is to provide a description of known hypoxia-induced mechanisms of chemoresistance at a cellular level.

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Hypoxia-Induced Modulation of Apoptosis and BCL-2 Family Proteins in Different Cancer Cell Types
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“Hypoxia is frequently described to inhibit the damaging effect of chemotherapeutic agents [15].”
Self-citation
Ketorolac salt is a newly discovered DDX3 inhibitor to treat oral cancer
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Green light-induced apoptosis in cancer cells by a tetrapyridyl ruthenium prodrug offering two trans coordination sites
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“A significant decrease in cell proliferation is also observed under hypoxia and Dfx (Supplementary Figure S2), which is consistent with previous reports regarded with hypoxia and HIF-1α mediated events [29, 30].”
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“Hypoxia occurs in 90 % of solid tumors because angiogenesis in tumor cannot supply rapidly growing tumor masses with enough oxygen [7–10].”
Background
Clinical relevance of tumor microenvironment: immune cells, vessels, and mouse models
Katsuta, E., Rashid, O. M., & Takabe, K. (2020) · Human Cell · doi:10.1007/s13577-020-00380-4 · Cited by 72
“Chemotherapy efficacy is also decreased in hypoxic conditions, because of not only drug delivery efficiency, but also hypoxic condition leads cancer cells to quiescent which is resistant to therapy [52].”
Background
Drug-metabolising enzymes are down-regulated by hypoxia in differentiated human hepatoma HepaRG cells: HIF-1α involvement in CYP3A4 repression
Legendre, C., Hori, T., Loyer, P., Aninat, C., Ishida, S., Glaise, D., Lucas‐Clerc, C., Boudjéma, K., Guguen‐Guillouzo, C., Corlu, A., et al. (2009) · European Journal of Cancer · doi:10.1016/j.ejca.2009.07.010 · Cited by 73
“Indeed, vasculature disorders restrict drug delivery, most chemotherapeutic agents are dependent on cellular oxygenation for maximal efficacy/cytotoxicity and extracellular pH decrease (acidosis) modulates cellular drug accumulation/toxicity.(9,41) Furthermore, we demonstrated that hypoxia down-regulates hepatic DMEs,…”
Background
Angiostatic treatment prior to chemo- or photodynamic therapy improves anti-tumor efficacy
Weiss, A., Bonvin, D., Berndsen, R. H., Scherrer, E., Wong, T. J., Dyson, P. J., Griffioen, A. W., & Nowak-Sliwinska, P. M. (2015) · Scientific Reports · doi:10.1038/srep08990 · Cited by 71
Imaging of Tumor Hypoxia for Radiotherapy: Current Status and Future Directions
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Role of hypoxia and autophagy in MDA‐MB‐231 invasiveness
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“Since a controversial aspect in literature is if hypoxia stimulates or inhibits cell invasion (Qu et al., 2005; Cosse and Michiels, 2008), we used invasion assays to study the involvement of different oxygenation conditions in 366 I N D E L I C A T O E T A L . the regulation of invasiveness of…”
BackgroundMethod
Effects and mechanisms of proton pump inhibitors as a novel chemosensitizer on human gastric adenocarcinoma (SGC7901) cells
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“However, the normal cells are almost unable to survive in the same microenvironment (Morita et al., 1992; Cosse and Michiels, 2008).”
Background
Progesterone Receptor Membrane Component-1 Regulates the Development and Cisplatin Sensitivity of Human Ovarian Tumors in Athymic Nude Mice
Peluso, J. J., Gawkowska, A., Liu, X., et al. (2009) · Endocrinology · doi:10.1210/en.2009-0730 · Cited by 62
“Moreimportantly,thereducedvascularnetworkofPGRMC1deplete tumors could adversely affect the delivery of CDDP and P4, which would result in a reduced responsiveness to these agents (32).”
Background
A novel HIF-1α/VMP1-autophagic pathway induces resistance to photodynamic therapy in colon cancer cells
Rodríguez, M. E., Catrinacio, C., Ropolo, A., Rivarola, V. A., & Vaccaro, M. I. (2017) · Photochemical & Photobiological Sciences · doi:10.1039/c7pp00161d · Cited by 59
Investigations into the cancer stem cell niche using in-vitro 3-D tumor models and microfluidics
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Development of a red-light emission hypoxia-sensitive two-photon fluorescent probe for in vivo nitroreductase imaging
Gebremedhin, K. H., Li, Y., Yao, Q., Xiao, M. W., Gao, F., Fan, J., Du, J., Long, S., & Peng, X. (2018) · Journal of Materials Chemistry B · doi:10.1039/c8tb02635a · Cited by 58
Oxygen Nanoshuttles for Tumor Oxygenation and Enhanced Cancer Treatment
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SET protein accumulates in HNSCC and contributes to cell survival: Antioxidant defense, Akt phosphorylation and AVOs acidification
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Small Molecule Inhibition of miR-544 Biogenesis Disrupts Adaptive Responses to Hypoxia by Modulating ATM-mTOR Signaling
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“org September 2017 | Volume 7 | Article 211 to be above its diffusion limit of oxygen, chronic hypoxia occurs (44).”
Background
Epigenetic Therapy for Solid Tumors: Highlighting the Impact of Tumor Hypoxia
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Background
Autophagy in hypoxia protects cancer cells against apoptosis induced by nutrient deprivation through a beclin1‐dependent way in hepatocellular carcinoma
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“AMPK, in response to hypoxia-induced energy depletion, down-regulates mTOR through the activation of TSC complex [Liu et al., 2006; Cosse and Michiels, 2008], which just regulates autophagy positively through mTORdependent way.”
Background
A Versatile Carbonic Anhydrase IX Targeting Ligand-Functionalized Porous Silicon Nanoplatform for Dual Hypoxia Cancer Therapy and Imaging
Janonienė, A., Liu, Z., Baranauskienė, L., Mäkilä, E. M., Ma, M., Salonen, J., Hirvonen, J. J., Zhang, H., Petrikaitė, V., & Santos, H. A. (2017) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.7b04038 · Cited by 54
Dynamic Magneto-Softening of 3D Hydrogel Reverses Malignant Transformation of Cancer Cells and Enhances Drug Efficacy
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Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer
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Ultrasound-mediated destruction of oxygen and paclitaxel loaded lipid microbubbles for combination therapy in hypoxic ovarian cancer cells
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Authors: Cosse, J.-P., & Michiels, C.
Affiliations: University of Namur (BE)
Corresponding author: Michiels, Carine
ORCID: Michiels, Carine
Venue: Anti-Cancer Agents in Medicinal Chemistry
Publisher: Bentham Science Publishers Ltd.
Published: 2008-10-01
Volume: 8
Issue: 7
Pages: 790-797
ISSN: 1568-0118 (ISSN-L)
1871-5206
DOI: 10.2174/187152008785914798
OpenAlex: W2044149912
Cited by: 348
References: 0
Citations by year: 2026: 4 · 2025: 10 · 2024: 16 · 2023: 19 · 2022: 27 · 2021: 32 · 2020: 33 · 2019: 21 · 2018: 24 · 2017: 23 · 2016: 25 · 2015: 25 · 2014: 15 · 2013: 20 · 2012: 14
FWCI: 4.44
Type: journal article
Language: en
Open access: closed
Locations: Anti-Cancer Agents in Medicinal Chemistry (publishedVersion)
PubMed (publishedVersion)
Digital Access to Libraries (submittedVersion)
ORBi (University of Liège) (submittedVersion)
Repository of the University of Namur (submittedVersion)
Funders: Fonds De La Recherche Scientifique - FNRS
Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords: tumor hypoxia, chemoresistance, tumor microenvironment, tumor stroma, tumor vasculature, transcriptional adaptation, angiogenesis, glycolytic metabolism, ABC transporters, apoptosis, tumor progression
MeSH terms: Animals, Autophagy, Humans, Neoplasm Invasiveness, Neoplasms, Neovascularization, Pathologic, Cell Hypoxia, Tumor Suppressor Protein p53, Disease Progression, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-bcl-2, Angiogenesis Inhibitors, Cell Proliferation, Hypoxia-Inducible Factor 1

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Tumour Hypoxia Affects the Responsiveness of Cancer Cells to Chemotherapy and Promotes Cancer Progression

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