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

doi:10.1073/pnas.0611660104

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

Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

374 Citations (SciVal)

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 language	English
Pages (from-to)	3460-3465
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	104
Issue number	9
DOIs	https://doi.org/10.1073/pnas.0611660104
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.0611660104

Cite this

Kano, M. R., Bae, Y., Iwata, C., Morishita, Y., Yashiro, M., Oka, M., Fujii, T., Komuro, A., Kiyono, K., Kaminishi, M., Hirakawa, K., Ouchi, Y., Nishiyama, N., Kataoka, K., & Miyazono, K. (2007). Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-β signaling. Proceedings of the National Academy of Sciences of the United States of America, 104(9), 3460-3465. https://doi.org/10.1073/pnas.0611660104

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

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.",

keywords = "Angiogenesis, Gastric cancer, Molecular targeting therapy, Pancreatic cancer",

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

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 supportedthroughaS{\~a}oPauloResearch Foundation(FAPESP)andMedicalResearch CouncilCADDEpartnershipaward(MR/S0195/1 andFAPESP18/14389-0)(http://caddecentre.org/).",

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doi = "10.1073/pnas.0611660104",

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Kano, MR, Bae, Y, Iwata, C, Morishita, Y, Yashiro, M, Oka, M, Fujii, T, Komuro, A, Kiyono, K, Kaminishi, M, Hirakawa, K, Ouchi, Y, Nishiyama, N, Kataoka, K & Miyazono, K 2007, 'Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-β signaling', Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 9, pp. 3460-3465. https://doi.org/10.1073/pnas.0611660104

Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-β signaling. / Kano, Mitsunobu R.; Bae, Younsoo; Iwata, Caname et al.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 9, 27.02.2007, p. 3460-3465.

Research output: Contribution to journal › Article › peer-review

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AU - Kano, Mitsunobu R.

AU - Bae, Younsoo

AU - Iwata, Caname

AU - Morishita, Yasuyuki

AU - Yashiro, Masakazu

AU - Oka, Masako

AU - Fujii, Tomoko

AU - Komuro, Akiyoshi

AU - Kiyono, Kunihiko

AU - Kaminishi, Michio

AU - Hirakawa, Kosei

AU - Ouchi, Yasuyoshi

AU - Nishiyama, Nobuhiro

AU - Kataoka, Kazunori

AU - Miyazono, Kohei

N1 - 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/).

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Y1 - 2007/2/27

N2 - 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.

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KW - Molecular targeting therapy

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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