No 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.

Triple‐negative breast cancer (TNBC), the most refractory subtype of breast cancer to current treatments, accounts disproportionately for the majority of breast cancer‐related deaths. This is largely due to cancer plasticity and the development of cancer stem cells (CSCs). Recently, distinct yet interconvertible mesenchymal‐like and epithelial‐like states have been revealed in breast CSCs. Thus, strategies capable of simultaneously inhibiting bulk and CSC populations in both mesenchymal and epithelial states have yet to be developed. Wnt/β‐catenin and Hippo/YAP pathways are crucial in tumorigenesis, but importantly also possess tumor suppressor functions in certain contexts. One possibility is that TNBC cells in epithelial or mesenchymal state may differently affect Wnt/β‐catenin and Hippo/YAP signaling and CSC phenotypes. In this report, we found that YAP signaling and CD44high/CD24−/low CSCs were upregulated while Wnt/β‐catenin signaling and ALDH+ CSCs were downregulated in mesenchymal‐like TNBC cells, and vice versa in their epithelial‐like counterparts. Dual knockdown of YAP and Wnt/β‐catenin, but neither alone, was required for effective suppression of both CD44high/CD24−/low and ALDH+ CSC populations in mesenchymal and epithelial TNBC cells. These observations were confirmed with cultured tumor fragments prepared from patients with TNBC after treatment with Wnt inhibitor ICG‐001 and YAP inhibitor simvastatin. In addition, a clinical database showed that decreased gene expression of Wnt and YAP was positively correlated with decreased ALDH and CD44 expression in patients’ samples while increased patient survival. Furthermore, tumor growth of TNBC cells in either epithelial or mesenchymal state was retarded, and both CD44high/CD24−/low and ALDH+ CSC subpopulations were diminished in a human xenograft model after dual administration of ICG‐001 and simvastatin. Tumorigenicity was also hampered after secondary transplantation. These data suggest a new therapeutic strategy for TNBC via dual Wnt and YAP inhibition.

Triple-negative breast cancer (TNBC) is the most refractory subtype of breast cancer and disproportionately accounts for the majority of breast cancer related deaths. Effective treatment of this disease remains an unmet medical need. Over the past several decades, TNBC cell lines have been used as the foundation for drug development and disease modeling. However, ever-mounting research demonstrates striking differences between cell lines and clinical TNBC tumors, disconnecting bench research and actual clinical responses. In this review, we discuss the limitations of cell lines and the importance of using patients’ tumors for translational research, and highlight the usage of patient-derived xenograft (PDXs) models that have emerged as a clinically relevant platform for preclinical studies. PDX tumors possess tumor heterogeneity with similar cellular, molecular, genetic and epigenetic properties akin to those found within patients’ tumors. Moreover, PDX and clinical tumors possess abnormal vasculature with higher blood vessel permeability, a feature that is not always demonstrated in in vivo cell line xenografts. Development of clinically relevant, novel drug-nanoparticles capable of accumulating in PDX tumors through the enhanced permeability and retention effect in tumor vasculature may lead to new and effective TNBC treatments.