Radiation‐induced lung injury (RILI) is a common complication in radiotherapy of thoracic tumors and limits the therapeutic dose of radiation that can be given to effectively control tumors. RILI develops through a complex pathological process, resulting in induction and activation of various cytokines, infiltration by inflammatory cells, cytokine‐induced activation of fibroblasts, and subsequent tissue remodeling by activated fibroblasts, ultimately leading to impaired lung function and respiratory failure. Increasing evidence shows that mesenchymal stem cells (MSCs) may play a main role in modulating inflammation and immune responses, promoting survival and repair of damaged resident cells and enhancing regeneration of damaged tissue through soluble paracrine factors and therapeutic extracellular vesicles. Therefore, the use of the MSC‐derived secretome and exosomes holds promising potential for RILI therapy. Here, we review recent progress on the potential mechanisms of MSC therapy for RILI, with an emphasis on soluble paracrine factors of MSCs. Hypotheses on how MSC derived exosomes or MSC‐released exosomal miRNAs could attenuate RILI are also proposed. Problems and translational challenges of the therapies based on the MSC‐derived secretome and exosomes are further summarized and underline the need for caution on rapid clinical translation. Stem Cells Translational Medicine 2019

Basal-like breast cancer is an aggressive disease for which targeted therapies are lacking. Recent studies showed that basal-like breast cancer is frequently associated with an increased activity of the phosphatidylinositol 3-kinase (PI3K) pathway, which is critical for cell growth, survival, and angiogenesis. To investigate the therapeutic potential of PI3K pathway inhibition in the treatment of basal-like breast cancer, we evaluated the antitumor effect of the mTOR inhibitor MK-8669 and AKT inhibitor MK-2206 in WU-BC4 and WU-BC5, two patient-derived xenograft models of basal-like breast cancer. Both models showed high levels of AKT phosphorylation and loss of PTEN expression. We observed a synergistic effect of MK-8669 and MK-2206 on tumor growth and cell proliferation in vivo. In addition, MK-8669 and MK-2206 inhibited angiogenesis as determined by CD31 immunohistochemistry. Biomarker studies indicated that treatment with MK-2206 inhibited AKT activation induced by MK-8669. To evaluate the effect of loss of PTEN on tumor cell sensitivity to PI3K pathway inhibition, we knocked down PTEN in WU-BC3, a basal-like breast cancer cell line with intact PTEN. Compared with control (GFP) knockdown, PTEN knockdown led to a more dramatic reduction in cell proliferation and tumor growth inhibition in response to MK-8669 and MK-2206 both in vitro and in vivo. Furthermore, a synergistic effect of these two agents on tumor volume was observed in WU-BC3 with PTEN knockdown. Our results provide a preclinical rationale for future clinical investigation of this combination in basal-like breast cancer with loss of PTEN. Mol Cancer Ther; 12(8); 1665–75. ©2013 AACR.