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.

VEGF-A/Neuropilin 1 Pathway Confers Cancer Stemness via Activating Wnt/β-Catenin Axis in Breast Cancer Cells

“…Although endocrine therapy, targeting therapy and chemotherapeutics have greatly improved the overall survival of breast cancer patients, the drug resistance is the main clinical problem [24]. Recent studies have demonstrated that CSCs are the major factor contributing to drug resistance because of their relatively quiescent or dormant state [25]. Since many chemotherapeutic drugs preferentially target cells that grow fast, the relatively dormant CSCs would be more resistant to drugs [26].…”

Evidence of lateral transmission of aggressive features between different types of breast cancer cells

“…Soluble factors secreted by chemoresistant tumor cells and also by cancer stem cells (CSCs) promote resistance of chemo-sensitive cancer cells ( 10 ). Moreover, Mukherjee et al showed that non-migratory CSCs confer metastatic potential to non-CSCs ( 11 ).…”

The chemokine receptor CXCR4 promotes granuloma formation by sustaining a mycobacteria-induced angiogenesis programme

“…During inflammatory responses, CXCR4 also sustains the trafficking of leukocytes to sites of inflammation5. Additionally, CXCR4 signalling on other cells is involved in key migratory mechanisms during development and has been linked to the metastatic behaviour of cancer cells6789101112. CXCR4 signalling has also been connected to tumour-sustained angiogenesis131415.…”