Tumour Hypoxia Affects the Responsiveness of Cancer Cells to Chemotherapy and Promotes Cancer Progression
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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Drug delivery and cellular uptake of drugs in hypoxic regions are affected by hypoxia or associated acidity, resulting in relative resistance of hypoxic tumor cells to chemotherapy.
“Drug delivery and cellular uptake of drugs in hypoxic regions are known to be affected by hypoxia or associated acidity, resulting in the relative resistance of hypoxic tumor cells to chemotherapy. 376 , 377”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [376]
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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 69 · see citing works
Imaging of Tumor Hypoxia for Radiotherapy: Current Status and Future Directions
Busk, M., Overgaard, J., & Horsman, M. R. (2020) · Seminars in Nuclear Medicine · doi:10.1053/j.semnuclmed.2020.05.003 · Cited by 66 · see citing works
Role of hypoxia and autophagy in MDA‐MB‐231 invasiveness
Indelicato, M., Pucci, B., Schito, L., Reali, V., Aventaggiato, M., Mazzarino, M. C., Stivala, F., Fini, M., Russo, M. A., & Tafani, M. (2010) · Journal of Cellular Physiology · doi:10.1002/jcp.22041 · Cited by 67 · see citing works
“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…”
BackgroundMethodChen, M., Zou, X., Luo, H., et al. (2009) · Cell Biology International · doi:10.1016/j.cellbi.2009.05.004 · Cited by 63 · see citing works
“However, the normal cells are almost unable to survive in the same microenvironment (Morita et al., 1992; Cosse and Michiels, 2008).”
BackgroundPeluso, J. J., Gawkowska, A., Liu, X., et al. (2009) · Endocrinology · doi:10.1210/en.2009-0730 · Cited by 62 · see citing works
“Moreimportantly,thereducedvascularnetworkofPGRMC1deplete tumors could adversely affect the delivery of CDDP and P4, which would result in a reduced responsiveness to these agents (32).”
BackgroundRodríguez, M. E., Catrinacio, C., Ropolo, A., Rivarola, V. A., & Vaccaro, M. I. (2017) · Photochemical & Photobiological Sciences · doi:10.1039/c7pp00161d · Cited by 59 · see citing works
Investigations into the cancer stem cell niche using in-vitro 3-D tumor models and microfluidics
Sreepadmanabh, M., & Toley, B. J. (2018) · Biotechnology Advances · doi:10.1016/j.biotechadv.2018.03.009 · Cited by 57 · see citing works
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 · see citing works
Oxygen Nanoshuttles for Tumor Oxygenation and Enhanced Cancer Treatment
Feng, L., Betzer, O., Tao, D., Sadan, T., Popovtzer, R., & Liu, Z. (2019) · CCS Chemistry · doi:10.31635/ccschem.019.20190010 · Cited by 56 · see citing works
Leopoldino, A. M., SQUARIZE, C. H., Garcia, C. B., Almeida, L. O., Pestana, C. R., Sobral, L. M., Uyemura, S. A., Tajara, E. H., Gutkind, J. S., & Curti, C. (2012) · Oral Oncology · doi:10.1016/j.oraloncology.2012.05.014 · Cited by 56 · see citing works
“Recently, it has been reported resistance of cancer cells to radiation or cisplatin therapies in association with increased cell response to oxidative stress.(24,34,56) In this context, we asked whether SET accumulated in HNSCC may contribute to cell survival and response to oxidative stress.”
Haga, C. L., Velagapudi, S. P., Strivelli, J., Yang, W., Disney, M. D., & Phinney, D. G. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00265 · Cited by 55 · see citing works
The Linkage between Breast Cancer, Hypoxia, and Adipose Tissue
Rausch, L. K., Netzer, N. C., Hoegel, J. J., & Pramsohler, S. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00211 · Cited by 56 · see citing works
“org September 2017 | Volume 7 | Article 211 to be above its diffusion limit of oxygen, chronic hypoxia occurs (44).”
BackgroundEpigenetic Therapy for Solid Tumors: Highlighting the Impact of Tumor Hypoxia
Ramachandran, S., Ient, J., Göttgens, E., Krieg, A. J., & Hammond, E. M. (2015) · Genes · doi:10.3390/genes6040935 · Cited by 55 · see citing works
“Hypoxia is linked to increased aggressiveness of the tumor, and resistance to all available modalities of cancer treatment, including chemotherapy, radiotherapy and indirectly surgery [35,58,59].”
BackgroundSong, J., Guo, X., Xie, X., Zhao, X., Li, D., Deng, W.-J., Song, Y., Shen, F., Wu, M., & Wei, L. (2011) · Journal of Cellular Biochemistry · doi:10.1002/jcb.23274 · Cited by 55 · see citing works
“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.”
BackgroundJanonienė, 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 · see citing works
Shou, Y., Teo, X. Y., Li, X., Le, Z., Liu, L., Sun, X., Jonhson, W., Ding, J., Lim, C. T., & Tay, A. K. P. (2023) · ACS Nano · doi:10.1021/acsnano.2c11278 · Cited by 53 · see citing works
Sun, J. D., Liu, Q., Ahluwalia, D., Li, W., Meng, F., Wang, Y., Bhupathi, D., Ruprell, A. S., & Hart, C. P. (2015) · Cancer Biology & Therapy · doi:10.1080/15384047.2014.1003005 · Cited by 53 · see citing works
Sun, J., Yin, M., Zhu, S., Liu, L., Zhu, Y., Wang, Z., Xu, R. X., & Chang, S. (2015) · Ultrasonics Sonochemistry · doi:10.1016/j.ultsonch.2015.08.009 · Cited by 52 · see citing works
Nano versus Molecular: Optical Imaging Approaches to Detect and Monitor Tumor Hypoxia
Cheng, M. H. Y., Mo, Y., & Zheng, G. (2020) · Advanced Healthcare Materials · doi:10.1002/adhm.202001549 · Cited by 52 · see citing works
- 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
- 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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