Paracrine secretion of IL8 by breast cancer stem cells promotes therapeutic resistance and metastasis of the bulk tumor cells

Abstract

Background Breast tumors consist of heterogeneous cellular subpopulations that differ in molecular properties and functional attributes. Cancer stem cells (CSCs) play pivotal roles in cancer therapeutic failure and metastasis. However, it remains indeterminate how CSCs determine the progression of the bulk cancer cell population. Methods Co-culture systems in vitro and co-implantation systems in vivo were designed to characterize the interactions between breast cancer stem cells (BCSCs) and bulk cancer cells. RNA sequencing was performed to study the functional and mechanistic implications of the BCSC secretome on bulk cancer cells. A cytokine antibody array was employed to screen the differentially secreted cytokines in the BCSC secretome. Tail vein injection metastatic models and orthotopic xenograft models were applied to study the therapeutic potential of targeting IL8. Results We identified that the BCSC secretome potentiated estrogen receptor (ER) activity in the bulk cancer cell population. The BCSC secretome rendered the bulk cancer cell population resistant to anti-estrogen and CDK4/6 inhibitor therapy; as well as increased the metastatic burden attributable to bulk cancer cells. Screening of the BCSC secretome identified IL8 as a pivotal factor that potentiated ERα activity, endowed tamoxifen resistance and enhanced metastatic burden by regulation of bulk cancer cell behavior. Pharmacological inhibition of IL8 increased the efficacy of fulvestrant and/or palbociclib by reversing tamoxifen resistance and abrogated metastatic burden. Conclusion Taken together, this study delineates the mechanism by which BCSCs determine the therapeutic response and metastasis of bulk cancer cells; and thereby suggests potential therapeutic strategies to ameliorate breast cancer outcomes.

A study with cancer stem cells and three-dimensional tumoroids: investigation of the combined effects of 5-fluorouracil and doxorubicin in breast cancer

“…In addition, when 2D and 3D culture conditions were evaluated together, it was determined that breast cancer stem cells were more resistant than the MCF-7 cancer cell line and required higher drug doses and longer incubation periods to observe a significant antiproliferative effect [ 24 , 25 ]. This result also shows high compatibility with the relevant literature [ 4 , 6 , 23 , 24 ]. In this study designed with MCF-7, a HER2-negative breast cancer cell line, the observation of a synergistic effect for 5-Fu and Dox is of extra importance, together with the data presented in another study published by Mody et al in 2023.…”

“…As in all types of cancer, many studies are being carried out today to neutralize these powerful cells in breast cancer and to ensure permanent success in cancer treatment [ 4 , 5 ]. Metastasis, which involves in a wide systematic process, makes treatment difficult and sometimes even impossible [ 6 ]. Therefore, the CSC-metastasis relationship has attracted much attention recently.…”

Vertical pathway inhibition of receptor tyrosine kinases and BAD with synergistic efficacy in triple negative breast cancer

“…All in vitro based assays were performed in medium containing 2% FBS. Transwell migration assay was performed as previously described 69 . Briefly, 1 × 10 5 cells suspended in serum-free medium containing 0.2% BSA were plated in the top chamber of 8 μm pore size (Corning, MA, USA).…”

The role of the tumor microenvironment in endocrine therapy resistance in hormone receptor-positive breast cancer

“…Once they adapt to the new environment, they lose dormancy and enter the cell cycle to differentiate into new tumor cells to achieve metastasis (66). Breast cancer stem cells were found to secrete IL-8 which increased ERa activity, induced tamoxifen resistance and elevated metastatic potential whereas the pharmacological inhibition of IL-8 counteracted tamoxifen resistance with reduction of metastatic potential (67). Mesenchymal stem cells promote tumor metastasis by secreting chemokine ligand 5 (CCL5) and TGF-b, which are responsible for the EMT of tumor cells and the maintenance of stem cell properties (68).…”