Abstract
New approaches to block the function of tumor stromal cells such as cancer-associated fibroblasts and pericytes is an emerging field in cancer therapeutics as these cells play a crucial role in promoting angiogenesis and tumor growth via paracrine signals. Because of immunomodulatory and other antitumor activities, IFNγ, a pleiotropic cytokine, has been used as an anticancer agent in clinical trials. Unfortunately only modest beneficial effects, but severe side effects, were seen. In this study, we delivered IFNγ to stromal fibroblasts and pericytes, considering its direct antifibrotic activity, using our platelet-derived growth factor-beta receptor (PDGFβR)-binding carrier (pPB-HSA), as these cells abundantly express PDGFβR. We chemically conjugated IFNγ to pPB-HSA using a heterobifunctional PEG linker. In vitro in NIH3T3 fibroblasts, pPB-HSA-IFNγ conjugate activated IFNγ-signaling (pSTAT1α) and inhibited their activation and migration. Furthermore, pPB-HSA-IFNγ inhibited fibroblasts-induced tube formation of H5V endothelial cells. In vivo in B16 tumor-bearing mice, pPB-HSA-IFNγ rapidly accumulated in tumor stroma and pericytes and significantly inhibited the tumor growth while untargeted IFNγ and pPB-HSA carrier were ineffective. These antitumor effects of pPB-HSA-IFNγ were attributed to the inhibition of tumor vascularization, as shown with α-SMA and CD-31 staining. Moreover, pPB-HSA-IFNγ induced MHC-II expression specifically in tumors compared with untargeted IFNγ, indicating the specificity of this approach. This study thus shows the impact of drug targeting to tumor stromal cells in cancer therapy as well as provides new opportunities to use cytokines for therapeutic application.
Highlights
In the past decade, the complexity of the tumor microenvironment has been extensively studied, and this knowledge has contributed to the development of new therapies for cancer [1]
The high platelet-derived growth factor-beta receptor (PDGFbR) expression on tumor stromal cells in tumors relative to all other tissues supports our notion for the suitability of this receptor for cell-selective targeting of IFNg
In our fibroblasts-induced angiogenesis in vitro model, we found that the conditioned media derived from TGFb-stimulated fibroblasts but after removal of stimuli enhanced tube formation compared with that of unstimulated media (Fig. 3A and B), which was similar to that achieved with VEGF, an endogenous angiogenesis-inducing growth factor
Summary
The complexity of the tumor microenvironment has been extensively studied, and this knowledge has contributed to the development of new therapies for cancer [1]. In addition to CAFs, pericytes are another important cell type, having phenotypic characteristics of mesenchymal cells and fibroblasts These pericytes stabilize endothelium by surrounding the blood vessels and support angiogenesis by secreting VEGF [1]. Studies have shown that inhibition of the functions of these stromal cells using a PDGFbR inhibitor (imatinib) leads to inhibition of angiogenesis and thereby reduction in tumor growth [7, 8] These data indicate the key role of the tumor stromal cells in tumor development; selective targeting to stromal cells for cancer therapeutics is of great interest and could provide highly attractive strategies to treat cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
