Cancer-associated fibroblasts barrier breaking via TGF-β blockade paved way for docetaxel micelles delivery to treat pancreatic cancer

TGF-beta is a crucial regulator in tumor microenvironment (TME), especially for myofibroblastic cancer-associated fibroblasts (myCAFs). The myCAFs can be motivated by TGF-beta signaling to erect pro-tumor TME, meanwhile, myCAFs overexpress TGF-beta to mediate the crosstalk between tumor and stromal cells. The blockade of TGF-beta can break cancer-associated fibroblasts barrier, consequently opening the access for drugs into tumor. The TGF-beta is a promising target in anti-tumor therapy. Herein, we introduced a two-stage combination therapy (TC-Therapy), including TGF-beta receptor I inhibitor SB525334 (SB) and cytotoxicity agent docetaxel micelle (DTX-M). We found that SB and DTX-M synergistically inhibited myCAFs proliferation and elevated p53 protein expression in BxPC-3/3T3 mixed cells. Gene and protein tests demonstrated that SB cut off TGF-beta signaling via receptor blockade and it did not arouse TGF-beta legend compensated internal autocrine. On the contrary, two agents combined decreased TGF-beta secretion and inhibited myCAFs viability marked by alpha-SMA and FAP alpha. TC-Therapy was applied in BxPc-3/3T3 mixed tumor-bearing mice model. After TC-Therapy, the alpha-SMA(+)/ FAP alpha(+) myCAFs faded increasingly and collagenous fibers mainly secreted by myCAFs decreased dramatically as well. More than that, the myCAFs barrier breaking helped to normalize micro-vessels and paved way for micelle penetration. The TGF-beta protein level of TC-Therapy in TME was much lower than that of simplex DTX-M, which might account for TME restoration. In conclusion, TGF-beta inhibitor acted as the pioneer before nano chemotherapeutic agents. The TC-Therapy of TGF-beta signaling inhibition and anti-tumor agent DTX-M is a promising regimen without arising metastasis risk to treat pancreatic cancer. The therapeutic regimen focused on TGF-beta related myCAFs reminds clinicians to have a comprehensive understanding of pancreatic cancer.