Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-beta signaling.
Transforming growth factor (TGF)-beta plays a pivotal role in regulation of progression of cancer through effects on tumor microenvironment as well as on cancer cells. TGF-beta inhibitors have recently been shown to prevent the growth and metastasis of certain cancers. However, there may be adverse effects caused by TGF-beta signaling inhibition, including the induction of cancers by the repression of TGF-beta-mediated growth inhibition. Here, we present an application of a short-acting, small-molecule TGF-beta type I receptor (TbetaR-I) inhibitor at a low dose in treating several experimental intractable solid tumors, including pancreatic adenocarcinoma and diffuse-type gastric cancer, characterized by hypovascularity and thick fibrosis in tumor microenvironments. Low-dose TbetaR-I inhibitor altered neither TGF-beta signaling in cancer cells nor the amount of fibrotic components. However, it decreased pericyte coverage of the endothelium without reducing endothelial area specifically in tumor neovasculature and promoted accumulation of macromolecules, including anticancer nanocarriers, in the tumors. Compared with the absence of TbetaR-I inhibitor, anticancer nanocarriers exhibited potent growth-inhibitory effects on these cancers in the presence of TbetaR-I inhibitor. The use of TbetaR-I inhibitor combined with nanocarriers may thus be of significant clinical and practical importance in treating intractable solid cancers.
Kano
Mitsunobu R
MR
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033 Japan.
Bae
Younsoo
Y
Iwata
Caname
C
Morishita
Yasuyuki
Y
Yashiro
Masakazu
M
Oka
Masako
M
Fujii
Tomoko
T
Komuro
Akiyoshi
A
Kiyono
Kunihiko
K
Kaminishi
Michio
M
Hirakawa
Kosei
K
Ouchi
Yasuyoshi
Y
Nishiyama
Nobuhiro
N
Kataoka
Kazunori
K
Miyazono
Kohei
K
D000818:Animals; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D011804:Quinolines
D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011758:Pyrroles; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C506615:HTS 466284; D011804:Quinolines