IFN-γ is a pleiotropic cytokine with immunomodulatory and tumoricidal functions. It has been used as an anti-tumor agent in adjuvant therapies for various cancers. Paradoxically, recent advances have also demonstrated pro-tumorigenic effects of IFN-γ, especially in promoting cancer metastasis, with the mechanism remains unclear. This will undoubtedly hinder the application of IFN-γ in cancer treatment. Here, we verified that IFN-γ treatment led to activation of the epithelial-to-mesenchymal transition (EMT) programme and metastasis in cell lines of various cancers, including the kidney cancer cell line Caki-1, the lung cancer cell line A549, the cervical carcinoma cell line CaSki, the breast cancer cell line BT549 and the colon cancer cell line HCT116. We further disclosed that midkine (MDK), an emerging oncoprotein and EMT inducer, is a common responsive target of IFN-γ in these cell lines. Mechanistically, IFN-γ upregulated MDK via STAT1, a principle downstream effector in the IFN-γ signalling. MDK is elevated in the majority of cancer types in the TCGA database, and its overexpression drove EMT activation and cancer metastasis in all examined cell lines. Targeting MDK using a specific MDK inhibitor (iMDK) broadly reversed IFN-γ-activated EMT, and subsequently abrogated IFN-γ-triggered metastasis. Collectively, our data uncover a MDK-dependent EMT inducing mechanism underlying IFN-γ-driven metastasis across cancers which could be attenuated by pharmacological inhibition of MDK. Based on these findings, we propose that MDK may be used as a potential therapeutic target to eliminate IFN-γ-elicited pro-metastatic adverse effect, and that combined MDK utilization may expand the application of IFN-γ in cancer and improve the clinical benefits from IFN-γ-based therapies.
Exosomes are important mediators of intercellular communication and participate in complex biological processes by transferring a variety of bioactive molecules between cells. Epithelial–mesenchymal transition (EMT) is a process in which the cell phenotype changes from epithelioid to mesenchymal-like. EMT is also an important process for cancer cells by which they acquire invasive and metastatic capabilities, which aggravates the degree of tumor malignancy. Numerous studies have demonstrated that exosomes encapsulate various components, such as microRNAs and proteins, and transfer information between tumor cells or between tumor cells and the tumor microenvironment, thereby regulating the EMT process. Exosomes can also be used for cancer diagnosis and treatment or as a drug delivery platform. Thus, they can be used as a therapeutic tool to control the occurrence of EMT and affect cancer progression. In this review, we summarize the latest research advancements in the regulation of the EMT process in tumor cells by the contents of exosomes. Furthermore, we discuss the potential and challenges of using exosomes as a tool for cancer treatment.