title: Non-migratory tumorigenic intrinsic cancer stem cells ensure breast cancer metastasis by generation of CXCR4(+) migrating cancer stem cells.
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.
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, India.
authors.forename: S
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, India.
authors.forename: A
authors.initials: A
authors.lastname: Manna
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, India.
authors.forename: P
authors.initials: P
authors.lastname: Bhattacharjee
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, India.
authors.forename: M
authors.initials: M
authors.lastname: Mazumdar
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, India.
authors.forename: S
authors.initials: S
authors.lastname: Saha
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, India.
authors.forename: S
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, India.
authors.forename: D
authors.initials: D
authors.lastname: Guha
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, India.
authors.forename: A
authors.initials: A
authors.lastname: Adhikary
authors.affiliation: Department of Surgery, SSKM Hospital, Kolkata, India.
authors.forename: D
authors.initials: D
authors.lastname: Jana
authors.affiliation: Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science (NCCS), NCCS Complex, Pune, India.
authors.forename: M
authors.initials: M
authors.lastname: Gorain
authors.affiliation: Department of Physiology, Bankura Sammilani Medical College, Kenduadihi, Bankura, India.
authors.forename: S A
authors.initials: SA
authors.lastname: Mukherjee
authors.affiliation: Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science (NCCS), NCCS Complex, Pune, India.
authors.forename: G C
authors.initials: GC
authors.lastname: Kundu
authors.affiliation: Department of Surgery, SSKM Hospital, Kolkata, India.
authors.forename: D K
authors.initials: DK
authors.lastname: Sarkar
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, India.
authors.forename: T
authors.initials: T
authors.lastname: Das
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D002465:Cell Movement / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D061986:MCF-7 Cells; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C527276:CXCR4 protein, human; D019718:Receptors, CXCR4