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The tumor microenvironment as driver of stemness and therapeutic resistance in breast cancer: New challenges and therapeutic opportunities

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Abstract

Background

Breast cancer (BC), the second most common cause of cancer-related deaths, remains a significant threat to the health and wellness of women worldwide. The tumor microenvironment (TME), comprising cellular components, such as cancer-associated fibroblasts (CAFs), immune cells, endothelial cells and adipocytes, and noncellular components such as extracellular matrix (ECM), has been recognized as a critical contributor to the development and progression of BC. The interplay between TME components and cancer cells promotes phenotypic heterogeneity, cell plasticity and cancer cell stemness that impart tumor dormancy, enhanced invasion and metastasis, and the development of therapeutic resistance. While most previous studies have focused on targeting cancer cells with a dismal prognosis, novel therapies targeting stromal components are currently being evaluated in preclinical and clinical studies, and are already showing improved efficacies. As such, they may offer better means to eliminate the disease effectively.

Conclusions

In this review, we focus on the evolving concept of the TME as a key player regulating tumor growth, metastasis, stemness, and the development of therapeutic resistance. Despite significant advances over the last decade, several clinical trials focusing on the TME have failed to demonstrate promising effectiveness in cancer patients. To expedite clinical efficacy of TME-directed therapies, a deeper understanding of the TME is of utmost importance. Secondly, the efficacy of TME-directed therapies when used alone or in combination with chemo- or radiotherapy, and the tumor stage needs to be studied. Likewise, identifying molecular signatures and biomarkers indicating the type of TME will help in determining precise TME-directed therapies.

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Acknowledgements

Umar Mehraj is a recipient of a junior research fellowship (JRF) from UGC-CSIR, Govt. of India. Muzafar Ahmad Macha and Rais A. Ganai are recipients of a Ramanujan Fellowship from the Science & Engineering Research Board (SERB), Department of Science and Technology, Govt. of India, New Delhi. Figure 1 was designed using BioRender.com web resource.

Funding

The work was supported by a Ramalinga Swami Fellowship, Grant No. BT/HRD/35/02/2006, to Nissar Ahmad Wani from the Department of Biotechnology (DBT), Ministry of Science & Technology, New Delhi.

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Authors and Affiliations

  1. Department of Bioresources, University of Kashmir, Srinagar, Jammu & Kashmir, India

    Umar Mehraj & Manzoor A. Mir Ph. D Post Doc

  2. Watson-Crick Centre for Molecular Medicine, Islamic University of Science & Technology , Awantipora, Jammu & Kashmir, India

    Rais A. Ganai & Muzafar A. Macha

  3. Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India

    Abid Hamid, Mohammed A. Zargar & Nissar Ahmad Wani

  4. Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar

    Ajaz A. Bhat & Mohammad Haris

  5. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

    Mohd Wasim Nasser & Surinder K. Batra

  6. Laboratory of Animal Research, Qatar University, Doha, Qatar

    Mohammad Haris

  7. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska, Lincoln, NE, USA

    Surinder K. Batra

  8. Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA

    Surinder K. Batra

  9. Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Almajmaah, Kingdom of Saudi Arabia

    Bader Alshehri & Raid Saleem Al-Baradie

Authors
  1. Umar Mehraj
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  2. Rais A. Ganai
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  3. Muzafar A. Macha
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  11. Raid Saleem Al-Baradie
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  12. Manzoor A. Mir Ph. D Post Doc
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  13. Nissar Ahmad Wani
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Contributions

N.A.W., M.A.M. (Manzoor A Mir) & UM initiated the study. U.M. M.A.M and N.A.W. collected the data, wrote the manuscript, and designed the figures and tables. R.A.G., M.A.M. (Muzafar A. Macha), A.H., M.A.Z., A.A.B., M.W.N., M.H., S.K.B. B.A., R.S.A.B, & M.A.M (Manzoor A Mir) critically revised and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Manzoor A. Mir Ph. D Post Doc or Nissar Ahmad Wani.

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Mehraj, U., Ganai, R.A., Macha, M.A. et al. The tumor microenvironment as driver of stemness and therapeutic resistance in breast cancer: New challenges and therapeutic opportunities. Cell Oncol. 44, 1209–1229 (2021). https://doi.org/10.1007/s13402-021-00634-9

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  • DOI: https://doi.org/10.1007/s13402-021-00634-9

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