Abstract
Breast cancer (BC) mortality is mainly due to metastatic disease, which is primarily driven by cancer stem cells (CSC). The chemokine C-X-C motif ligand-1 (CXCL1) is involved in BC metastasis, but the question of whether it regulates breast cancer stem cell (BCSC) behavior is yet to be explored. Here, we demonstrate that BCSCs express CXCR2 and produce CXCL1, which stimulates their proliferation and self-renewal, and that CXCL1 blockade inhibits both BCSC proliferation and mammosphere formation efficiency. CXCL1 amplifies its own production and remarkably induces both tumor-promoting and immunosuppressive factors, including SPP1/OPN, ACKR3/CXCR7, TLR4, TNFSF10/TRAIL and CCL18 and, to a lesser extent, immunostimulatory cytokines, including IL15, while it downregulates CCL2, CCL28, and CXCR4. CXCL1 downregulates TWIST2 and SNAI2, while it boosts TWIST1 expression in association with the loss of E-Cadherin, ultimately promoting BCSC epithelial-mesenchymal transition. Bioinformatic analyses of transcriptional data obtained from BC samples of 1,084 patients, reveals that CXCL1 expressing BCs mostly belong to the Triple-Negative (TN) subtype, and that BC expression of CXCL1 strongly correlates with that of pro-angiogenic and cancer promoting genes, such as CXCL2-3-5-6, FGFBP1, BCL11A, PI3, B3GNT5, BBOX1, and PTX3, suggesting that the CXCL1 signaling cascade is part of a broader tumor-promoting signaling network. Our findings reveal that CXCL1 functions as an autocrine growth factor for BCSCs and elicits primarily tumor progression and immune escape programs. Targeting the CXCL1/CXCR2 axis could restrain the BCSC compartment and improve the treatment of aggressive BC.
Highlights
Breast cancer (BC) is the second most common cause of death from cancer in women (Sung et al, 2021)
breast cancer stem cell (BCSC) fulfilled the functional properties of Cancer stem cells (CSC), such as the ability to grow in tumor spheres and to reproduce the histological and immunophenotipical features of the tumor of origin, when implanted, at low cell numbers, in immunocompromised mice (Todaro et al, 2013)
To investigate whether BCSCs are responsive to C-X-C motif ligand-1 (CXCL1), we first analyzed, by flow cytometry, the expression of its cognate receptor CXCR2
Summary
Breast cancer (BC) is the second most common cause of death from cancer in women (Sung et al, 2021). Cancer stem cells (CSC), endowed with high plasticity and self-renewal properties, are the driving force of cancer progression and metastasis (Dittmer, 2018). Their quiescent, slow cycling, state accounts for chemo- and radiotherapy resistance (De Angelis et al, 2019), while their exit from dormancy and cell cycle re-activation, which precedes spreading and proliferation to distant organs, accounts for cancer relapse (De Angelis et al, 2019). The transition between these two CSC states is tightly regulated by cell-intrinsic mechanisms, systemic factors and interactions with the microenvironment, such as those mediated by immunoregulatory messengers (Prager et al, 2019)
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