Abstract
A novel paradigm in tumor biology suggests that non-small-cell lung cancer (NSCLC) growth is driven by lung cancer stem cell (LCSC) like cells, but t here are still not any effective strategies to remove LCSCs. The bispecific antibody (BsAb) is a novel antibody, which can target two different antigens and mediate specific killing effects by selectively redirecting effector cells to the target cells. Here, we designed and synthesized a new BsAb, BsAb-5, that can target cellular mesenchymal-to-epithelial transition factor (c-MET) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in CD166+ LCSCs with high affinity and specificity, for the first time. We showed that BsAb-5 could inhibit hepatocyte growth factor (HGF) mediated tumor development, including proliferation, migration, and apoptosis, serving as an inhibitory c-MET antibody. Moreover, we demonstrated that mechanisms responsible for BsAb-5 in CD166+ LCSCs included inducing c-MET degradation and inhibition of HGF-stimulated c-MET-Notch pathway by using AdHGF infection, nuclei location, and Western blot assays. In vivo, xenograft analysis revealed that mice on BsAb-5 group showed significantly reduced tumor volume. At the meantime, the observed antitumor effects of BsAb-5 were dependent on considerably suppressing T-regulatory cells (Tregs) and up-regulating effector T cells. On the basis of these results, we have identified a potential BsAb drug, which can effectively target c-MET and CTLA-4 in CD166+ LCSCs for the treatment of human NSCLC.
Highlights
Non-small-cell lung cancer (NSCLC) remains a major cause of cancer-related deaths worldwide [1]
We demonstrated that mechanisms responsible for bispecific antibody (BsAb)-5 in CD166+ lung cancer stem cell (LCSC) included inducing cellular mesenchymal-to-epithelial transition factor (c-MET) degradation and inhibition of hepatocyte growth factor (HGF)-stimulated c-MET-Notch pathway by using AdHGF infection, nuclei location, and Western blot assays
By exploring whether BsAb-5 inhibits HGF-triggered c-MET molecules, BsAb-5 was found to down-regulate c-MET protein expression in both dose- and time-dependent manners in LCSCs by Western blot assay (Figure 3A,B), which suggests that BsAb-5 could induce c-MET degradation
Summary
Non-small-cell lung cancer (NSCLC) remains a major cause of cancer-related deaths worldwide [1]. Despite numerous advances in our knowledge of NSCLC, development of clinical effective therapies has met with limited success [2]. It underscores the urgent need for refined investigation on a viable therapeutic option for advancing anticancer therapy. Nowadays, accumulating evidence have shown a subpopulation of cancer cells with stem cell-like features, including self-renewal, differentiation, tumorigenesis, and tumor heterogeneity. This subpopulation of cancer cells was named cancer stem cell (CSC) like cells [3,4]. CSCs are reported as the major source of tumor recurrence after radiation or chemotherapy [5]. There are still not any effective strategies helping remove LCSCs
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