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Non-migratory tumorigenic intrinsic cancer stem cells ensure breast cancer metastasis by generation of CXCR4+ migrating cancer stem cells

Oncogene volume 35, pages 4937–4948 (2016)Cite this article

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Abstract

Although the role of metastatic cancer stem cells (mCSCs) in tumor progression has been well documented, our study reveals a hitherto unidentified role of tumorigenic intrinsic CSCs (iCSCs) in breast cancer metastasis. We show that unlike highly migratory mCSCs residing in the breast tumor disseminating/peripheral regions, iCSCs populate the inner mass of the tumor and are non-migratory. However iCSCs, via paracrine signaling, induce conversion of non-stem cancer cells to CSCs that (i) are identical to the previously reported mCSCs, and (ii) in contrast to iCSCs, express chemokine receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), which is crucial for their metastatic potential. These mCSCs also demonstrate high in vivo tumorigenicity. Physical non-participation of iCSCs in metastasis is further validated in vivo, where only mCSCs are found to exist in the metastatic sites, lymph nodes and bone marrow, whereas the primary tumor retains both iCSCs and mCSCs. However, iCSCs ensure metastasis since their presence is crucial for deliverance of highly metastatic CXCR4+ mCSCs to the migrating fraction of cells. Cumulatively, these results unveil a novel role of iCSCs in breast cancer metastasis as parental regulators of CXCR4+ mCSCs, and highlight the therapeutic requisite of targeting iCSCs, but not CXCR4+ mCSCs, to restrain breast cancer metastasis from the root by inhibiting the generation of mCSCs from iCSCs. Considering the pivotal role of iCSCs in tumor metastasis, the possibility of metastasis to be a ‘stem cell phenomena’ is suggested.

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Acknowledgements

We thank Gaurisankar Sa for his helpful discussions. Authors also acknowledge Uttam K. Ghosh and Ranjan Dutta for technical assistance. This work was supported by research grants from Council of Scientific and Industrial Research (CSIR), Department of Science and Technology (DST) and Department of Biotechnology (DBT), Government of India.

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Authors and Affiliations

  1. Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, India

    S Mukherjee, A Manna, P Bhattacharjee, M Mazumdar, S Saha, S Chakraborty, D Guha, A Adhikary & T Das

  2. Department of Surgery, SSKM Hospital, Kolkata, India

    D Jana & D K Sarkar

  3. Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science (NCCS), NCCS Complex, Pune, India

    M Gorain & G C Kundu

  4. Department of Physiology, Bankura Sammilani Medical College, Kenduadihi, Bankura, India

    S A Mukherjee

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  1. S Mukherjee
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Correspondence to T Das.

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Mukherjee, S., Manna, A., Bhattacharjee, P. et al. Non-migratory tumorigenic intrinsic cancer stem cells ensure breast cancer metastasis by generation of CXCR4+ migrating cancer stem cells. Oncogene 35, 4937–4948 (2016). https://doi.org/10.1038/onc.2016.26

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