Cytokines, breast cancer stem cells (BCSCs) and chemoresistance

Abstract

Chemotherapy resistance of breast cancer poses a great challenge to the survival of patients. During breast cancer treatment, the development of intrinsic and acquired drug resistance tends to further induce adverse prognosis, such as metastasis. In recent years, the progress of research on cytokine-modulated tumor microenvironment and breast cancer stem cells (BCSCs) has shed light on defining the mechanisms of drug resistance gradually. In this review, we have discussed cytokine regulation on breast cancer chemoresistance. Cytokines can affect tumor cell behavior or reprogram tumor niche through specific signaling pathways, thereby regulating the progress of drug resistance. In addition, we summarized the mutually regulatory networks between cytokines and BCSCs in mediating chemoresistance. Cytokines in the tumor microenvironment can regulate the self-renewal and survival of BCSCs in a variety of ways, sequentially promoting chemotherapeutic resistance. Therefore, the combinational treatment of BCSC targeting and cytokine blockade may have a positive effect on the clinical treatment of breast cancer.

Keywords: Breast cancer stem cells (BCSCs); Chemoresistance; Cytokine; Tumor microenvironment.

Fig. 1

The IL-6 and IL-8 signal transduction pathways. a The binding of IL-6 to its receptor IL-6R leads to homodimerization of gp130, resulting in phosphorylation of JAKs which further phosphorylates and activates STAT3. The activated STAT3 binds with other STAT proteins (STATs) to form homodimers or heterodimers, which facilitates the transcription of diverse downstream genes. b IL-8 binds to its receptor CXCR1 or CXCR2 (belonging to GPCR superfamily), activating G protein. The G protein subunits activate PLC and PI3K, which further lead to the phosphorylation of PKC and AKT, respectively. Besides, the Rho-GTPase family and non-receptor tyrosine kinases (such as Src and FAK) can be activated by IL-8 signaling. And activated MAPK signaling cascade (Raf-1/MEK/ERK) also transduces the IL-8 stimuli

Fig. 2

The interplay between microRNAs and TGF-β signaling in regulating chemoresistance of cancer cells. There exists reciprocal modulation between TGF-β and diverse microRNAs. On one hand, TGF-β can affect the transcription of some microRNAs via specific effectors; On the other hand, TGF-β ligand or its receptor TGFBR are the targets of the corresponding microRNAs. These processes control the expression of EMT-related genes, leading to the morphology alteration accompanied with drug resistance in breast cancer

Fig. 3

Retinoic acid signaling catalyzed by ALDH modulates the chemoresistance of cancer cells. Retinal is oxidized into retinoic acid by ALDH and then binds with RARs or RXRs. Activated RAR and RXR forms heterodimer to bind with retinoic acid response element, promoting the transcription of retinoic acid-responsive genes of which some play a vital role in driving chemotherapeutic resistance. In addition, RXRs can assemble into a homodimer to modulate the transcription while RARs cannot

Fig. 4

The interplay of cytokines and BCSCs on regulating chemotherapeutic resistance. Under the stress of chemotherapeutic drugs, a variety of different sources of cytokines can regulate the self-renewal and promote the survival of BCSCs, leading to drug resistance. Cytokines are a convenient “bridge” between BCSCs and chemoresistance (left panel). If the regulatory signaling to BCSCs is interfered by cytokine blockade, the support of cytokine signals for BCSC chemo-resistance will be broken, increasing the sensitivity of breast cancer chemotherapy (right panel)