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Hypoxia and the Metastatic Cascade

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Hypoxia in Cancer: Significance and Impact on Cancer Therapy

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Abstract

Metastasis is a leading cause of mortality in cancer patients. The journey of a detached primary tumour cell to a secondary homing site is a multi-step process with several intercellular interactions. In this process, a metastatic cell overcomes many barriers and adapts to the changing microenvironment. Our understanding of motility, invasion and epithelial to mesenchymal transition has led to the identification of targetable signalling networks and regulatory pathways. Emerging research has also identified genetic heterogeneity and variable microenvironment in the primary tumour cell as different from its metastatic progeny, leading to differential immune response. Therapeutic regimes with both standard chemotherapy and, in some cases, targeted therapy have only marginally improved the overall survival in metastatic cancer patients. It is for this reason that the current research strives to understand metastatic cancer, its origin and the role of the tumour microenvironment in genesis and persistence of metastasis. The hypoxic tumour microenvironment is known to arise in such growing primary tumours, where the vasculature is unable to keep pace with the high rate of proliferation, forming hypoxic niche within the tumours. Hypoxia, therefore, will always precede metastasis, thus implicating that the former plays a larger role in the development of the aggressive phenotype. Some of the leading research of our times is trying to understand latency of cancer cells, immune-metastatic cell interaction and epigenetic changes that promote metastasis and chemoresistance. With exciting possibilities of immunotherapeutic and other intervention strategies, a comprehensive understanding of the role of hypoxia in promoting metastasis will be useful. In this review, we dissect how hypoxia, hypoxia-inducible factors and other associated molecules dynamically modulate various stages of metastasis.

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Acknowledgement

Funding from University of Delhi IoE-Faculty Research Program and Science and Engineering Research Board to TS are gratefully acknowledged. TS, JC, SG, SK (1), DC, SK (2) and PG wrote and edited the manuscript. SK (1), DC, SK (2) and PG created the illustrations.

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Authors and Affiliations

  1. Cancer Biology lab, Department of Genetics, University of Delhi South Campus, New Delhi, India

    Sanchit Gandhi, Shruti Khanna, Shikha Kaushik, Deepali Chaudhry, Pooja Ghorawat, Jonita Chongtham & Tapasya Srivastava

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Correspondence to Tapasya Srivastava .

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  1. Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India

    Sukhes Mukherjee

  2. Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India

    Jagat Rakesh Kanwar

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Gandhi, S. et al. (2023). Hypoxia and the Metastatic Cascade. In: Mukherjee, S., Kanwar, J.R. (eds) Hypoxia in Cancer: Significance and Impact on Cancer Therapy. Springer, Singapore. https://doi.org/10.1007/978-981-99-0313-9_9

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