Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-β signaling

Mitsunobu R. Kano, Younsoo Bae, Caname Iwata, Yasuyuki Morishita, Masakazu Yashiro, Masako Oka, Tomoko Fujii, Akiyoshi Komuro, Kunihiko Kiyono, Michio Kaminishi, Kosei Hirakawa, Yasuyoshi Ouchi, Nobuhiro Nishiyama, Kazunori Kataoka, Kohei Miyazono

Research output: Contribution to journalArticlepeer-review

386 Scopus citations

Abstract

Transforming growth factor (TGF)-β plays a pivotal role in regulation of progression of cancer through effects on tumor microenvironment as well as on cancer cells. TGF-β inhibitors have recently been shown to prevent the growth and metastasis of certain cancers. However, there may be adverse effects caused by TGF-β signaling inhibition, including the induction of cancers by the repression of TGF-β-mediated growth inhibition. Here, we present an application of a short-acting, small-molecule TGF-β type I receptor (TβR-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 TβR-I inhibitor altered neither TGF-β 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 TβR-I inhibitor, anticancer nanocarriers exhibited potent growth-inhibitory effects on these cancers in the presence of TβR-I inhibitor. The use of TβR-I inhibitor combined with nanocarriers may thus be of significant clinical and practical importance in treating intractable solid cancers.

Original languageEnglish
Pages (from-to)3460-3465
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number9
DOIs
StatePublished - Feb 27 2007

Bibliographical note

Funding Information:
Funding: NRF, ECS, OGP, SCH, NL and RdS were supported through a S?o Paulo Research Foundation (FAPESP) and Medical Research Council CADDE partnership award (MR/S0195/1 and FAPESP 18/14389-0) (http://caddecentre.org/). NRF and SCH were supported by a Wellcome Trust and Royal Society Sir Henry Dale Fellowship awarded to NRF (grant 204311/Z/16/Z). The research was supported by an internal HEFCE GCRF grant 005073 and John Fell Research Fund Grant 005166, awarded to NRF. ECS was supported by grants CNPq #400354/2016-0 and FAPESP# 2016/01735-2. OGP, NRF and LdP were supported by the Oxford Martin School. SD is supported by the Fonds National de la Recherche Scientifique (FNRS, Belgium) and was previously funded by the Fonds Wetenschappelijk Onderzoek (FWO, Belgium). LCJA was supported by CNPq/ MCTI Decit/SCTIE/MoH (440685/2016-8) and CAPES (88887.130716/2016-00). MG was supported by Funda??o de Amparo ? Pesquisa do Estado do Rio de Janeiro ? FAPERJ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank the IAL and the USPTM staff, in particular the team from N?cleo de Doen?as de Transmiss?o Vetorial and from the Centro de Patologia.

Funding Information:
Funding:NRF,ECS,OGP,SCH,NLandRdSwere supportedthroughaSãoPauloResearch Foundation(FAPESP)andMedicalResearch CouncilCADDEpartnershipaward(MR/S0195/1 andFAPESP18/14389-0)(http://caddecentre.org/).

Keywords

  • Angiogenesis
  • Gastric cancer
  • Molecular targeting therapy
  • Pancreatic cancer

ASJC Scopus subject areas

  • General

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