Abstract
Stromal cells, infiltrating immune cells, paracrine factors and extracellular matrix have been extensively studied in cancers. However, autocrine factors produced by tumor cells and communications between autocrine factors and intracellular signaling pathways in the development of drug resistance, cancer stem-like cells (CSCs) and tumorigenesis have not been well investigated, and the precise mechanism and tangible approaches remain elusive. Here we reveal a new mechanism by which cytokines produced by breast cancer cells after chemotherapy withdrawal activate both Wnt/β-catenin and NF-κB pathways, which in turn further promote breast cancer cells to produce and secrete cytokines, forming an autocrine inflammatory forward-feedback loop to facilitate the enrichment of drug-resistant breast cancer cells and/or CSCs. Such an unexpected autocrine forward-feedback loop and CSC enrichment can be effectively blocked by inhibition of Wnt/β-catenin and NF-κB signaling. It can also be diminished by IL8-neutralizing antibody or blockade of IL8 receptors CXCR1/2 with reparixin. Administration of reparixin after chemotherapy withdrawal effectively attenuates tumor masses in a human xenograft model and abolishes paclitaxel-enriched CSCs in the secondary transplantation. These results are partially supported by the latest clinical data set. Breast cancer patients treated with chemotherapeutic drugs exhibited poor survival rate (66.7 vs 282.8 months, P=0.00071) and shorter disease-free survival time if their tumor samples expressed high level of IL8, CXCR1, CXCR2 genes and Wnt target genes. Taken together, this study provides new insights into the communication between autocrine niches and signaling pathways in the development of chemotherapy resistance and CSCs; it also offers a tangible approach in breast cancer treatment.
Highlights
Breast cancer is a leading cause of death in women, with about 1.7 million new cases and more than half a million deaths in the world each year.[1]
Autocrine factors produced by tumor cells and their communication with intracellular signaling pathways in drug resistance, cancer stem-like cells (CSCs) development and tumorigenesis after chemotherapy withdrawal have not been well investigated, and precise mechanistic insight remains lacking
Cytokines and their signaling pathways have been demonstrated to have important roles in breast cancer initiation, migration, invasion and disease progression.[16,17,18]. It remains unclear whether breast cancer cells are capable of producing large amount of cytokines acting as autocrine factors to self-propel the development of drug resistance and CSCs after chemotherapy withdrawal
Summary
Breast cancer is a leading cause of death in women, with about 1.7 million new cases and more than half a million deaths in the world each year.[1]. Stromal cells, infiltrating immune cells, paracrine factors and extracellular matrix components contribute to cancer microenvironments that have been extensively studied.[15] autocrine factors produced by tumor cells and their communication with intracellular signaling pathways in drug resistance, CSC development and tumorigenesis after chemotherapy withdrawal have not been well investigated, and precise mechanistic insight remains lacking. Cytokines (such as IL6, IL8 and CCL2) and their signaling pathways have been demonstrated to have important roles in breast cancer initiation, migration, invasion and disease progression.[16,17,18] it remains unclear whether breast cancer cells are capable of producing large amount of cytokines acting as autocrine factors to self-propel the development of drug resistance and CSCs after chemotherapy withdrawal. These cytokines activate both NF-κB and Wnt/β-catenin pathways, which in turn promote the production and secretion of more cytokines, Ontario, Canada
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