Suppression of Tumor Lymphangiogenesis and Lymph Node Metastasis by Blocking Vascular Endothelial Growth Factor Receptor 3 Signaling
Identifieur interne : 009562 ( Main/Exploration ); précédent : 009561; suivant : 009563Suppression of Tumor Lymphangiogenesis and Lymph Node Metastasis by Blocking Vascular Endothelial Growth Factor Receptor 3 Signaling
Auteurs : Yulong He [Finlande] ; Ken-Ichi Kozaki [Finlande] ; Terhi Karpanen [Finlande] ; Katsumi Koshikawa [Finlande] ; Seppo Yla-Herttuala [Finlande] ; Takashi Takahashi [Finlande] ; Kari Alitalo [Finlande]Source :
- Journal of the National Cancer Institute [ 0027-8874 ] ; 2002-06-05.
Abstract
Background: Vascular endothelial growth factor C (VEGF-C) stimulates tumor lymphangiogenesis (i.e., formation of lymphatic vessels) and metastasis to regional lymph nodes by interacting with VEGF receptor 3 (VEGFR-3). We sought to determine whether inhibiting VEGFR-3 signaling, and thus tumor lymphangiogenesis, would inhibit tumor metastasis. Methods: We used the highly metastatic human lung cancer cell line NCI-H460-LNM35 (LNM35) and its parental line NCI-H460-N15 (N15) with low metastatic capacity. We inserted genes by transfection and established a stable N15 cell line secreting VEGF-C and a LNM35 cell line secreting the soluble fusion protein VEGF receptor 3-immunoglobulin (VEGFR-3-Ig, which binds VEGF-C and inhibits VEGFR-3 signaling). Control lines were transfected with mock vectors. Tumor cells were implanted subcutaneously into severe combined immunodeficient mice (n = 6 in each group), and tumors and metastases were examined 6 weeks later. In another approach, recombinant adenoviruses expressing VEGFR-3-Ig (AdR3-Ig) or β-galactosidase (AdLacZ) were injected intravenously into LNM35 tumor-bearing mice (n = 14 and 7, respectively). Results: LNM35 cells expressed higher levels of VEGF-C RNA and protein than did N15 cells. Xenograft mock vector-transfected LNM35 tumors showed more intratumoral lymphatic vessels (15.3 vessels per grid; 95% confidence interval [CI] = 13.3 to 17.4) and more metastases in draining lymph nodes (12 of 12) than VEGFR-3-Ig-transfected LNM35 tumors (4.1 vessels per grid; 95% CI = 3.4 to 4.7; P<.001, two-sided t test; and four lymph nodes with metastases of 12 lymph nodes examined). Lymph node metastasis was also inhibited in AdR3-Ig-treated mice (AdR3-Ig = 0 of 28 lymph nodes; AdLacZ = 11 of 14 lymph nodes). However, metastasis to the lungs occurred in all mice, suggesting that LNM35 cells can also spread via other mechanisms. N15 tumors overexpressing VEGF-C contained more lymphatic vessels than vector-transfected tumors but did not have increased metastatic ability. Conclusions: Lymph node metastasis appears to be regulated by additional factors besides VEGF-C. Inhibition of VEGFR-3 signaling can suppress tumor lymphangiogenesis and metastasis to regional lymph nodes but not to lungs.
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DOI: 10.1093/jnci/94.11.819
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He, T. Karpanen, K. Alitalo, Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute and Helsinki University Central Hospital, Biomedicum Helsinki, University of Helsinki, Finland; K. Kozaki, K. Koshikawa, T. Takahashi, Division of Molecular Oncology, Aichi Cancer Center Research Institute, 464-8681 Nagoya, Japan; S. Yla-Herttuala, A. I. Virtanen Institute, University of Kuopio</wicri:regionArea><wicri:noRegion>University of Kuopio</wicri:noRegion></affiliation></author><author><name sortKey="Kozaki, Ken Ichi" sort="Kozaki, Ken Ichi" uniqKey="Kozaki K" first="Ken-Ichi" last="Kozaki">Ken-Ichi Kozaki</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Affiliations of authors: Y. He, T. Karpanen, K. Alitalo, Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute and Helsinki University Central Hospital, Biomedicum Helsinki, University of Helsinki, Finland; K. Kozaki, K. Koshikawa, T. Takahashi, Division of Molecular Oncology, Aichi Cancer Center Research Institute, 464-8681 Nagoya, Japan; S. Yla-Herttuala, A. I. Virtanen Institute, University of Kuopio</wicri:regionArea><wicri:noRegion>University of Kuopio</wicri:noRegion></affiliation></author><author><name sortKey="Karpanen, Terhi" sort="Karpanen, Terhi" uniqKey="Karpanen T" first="Terhi" last="Karpanen">Terhi Karpanen</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Affiliations of authors: Y. He, T. Karpanen, K. Alitalo, Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute and Helsinki University Central Hospital, Biomedicum Helsinki, University of Helsinki, Finland; K. Kozaki, K. Koshikawa, T. Takahashi, Division of Molecular Oncology, Aichi Cancer Center Research Institute, 464-8681 Nagoya, Japan; S. Yla-Herttuala, A. I. Virtanen Institute, University of Kuopio</wicri:regionArea><wicri:noRegion>University of Kuopio</wicri:noRegion></affiliation></author><author><name sortKey="Koshikawa, Katsumi" sort="Koshikawa, Katsumi" uniqKey="Koshikawa K" first="Katsumi" last="Koshikawa">Katsumi Koshikawa</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Affiliations of authors: Y. He, T. Karpanen, K. Alitalo, Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute and Helsinki University Central Hospital, Biomedicum Helsinki, University of Helsinki, Finland; K. Kozaki, K. Koshikawa, T. Takahashi, Division of Molecular Oncology, Aichi Cancer Center Research Institute, 464-8681 Nagoya, Japan; S. Yla-Herttuala, A. I. Virtanen Institute, University of Kuopio</wicri:regionArea><wicri:noRegion>University of Kuopio</wicri:noRegion></affiliation></author><author><name sortKey="Yla Herttuala, Seppo" sort="Yla Herttuala, Seppo" uniqKey="Yla Herttuala S" first="Seppo" last="Yla-Herttuala">Seppo Yla-Herttuala</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Affiliations of authors: Y. He, T. Karpanen, K. Alitalo, Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute and Helsinki University Central Hospital, Biomedicum Helsinki, University of Helsinki, Finland; K. Kozaki, K. Koshikawa, T. Takahashi, Division of Molecular Oncology, Aichi Cancer Center Research Institute, 464-8681 Nagoya, Japan; S. Yla-Herttuala, A. I. Virtanen Institute, University of Kuopio</wicri:regionArea><wicri:noRegion>University of Kuopio</wicri:noRegion></affiliation></author><author><name sortKey="Takahashi, Takashi" sort="Takahashi, Takashi" uniqKey="Takahashi T" first="Takashi" last="Takahashi">Takashi Takahashi</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Affiliations of authors: Y. He, T. Karpanen, K. Alitalo, Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute and Helsinki University Central Hospital, Biomedicum Helsinki, University of Helsinki, Finland; K. Kozaki, K. Koshikawa, T. Takahashi, Division of Molecular Oncology, Aichi Cancer Center Research Institute, 464-8681 Nagoya, Japan; S. Yla-Herttuala, A. I. 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Virtanen Institute, University of Kuopio</wicri:regionArea><wicri:noRegion>University of Kuopio</wicri:noRegion><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName><orgName type="university">Université d'Helsinki</orgName></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of the National Cancer Institute</title><title level="j" type="abbrev">JNCI J Natl Cancer Inst</title><idno type="ISSN">0027-8874</idno><idno type="eISSN">1460-2105</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2002-06-05">2002-06-05</date><biblScope unit="volume">94</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="819">819</biblScope><biblScope unit="page" to="825">825</biblScope></imprint><idno type="ISSN">0027-8874</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0027-8874</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Background: Vascular endothelial growth factor C (VEGF-C) stimulates tumor lymphangiogenesis (i.e., formation of lymphatic vessels) and metastasis to regional lymph nodes by interacting with VEGF receptor 3 (VEGFR-3). We sought to determine whether inhibiting VEGFR-3 signaling, and thus tumor lymphangiogenesis, would inhibit tumor metastasis. Methods: We used the highly metastatic human lung cancer cell line NCI-H460-LNM35 (LNM35) and its parental line NCI-H460-N15 (N15) with low metastatic capacity. We inserted genes by transfection and established a stable N15 cell line secreting VEGF-C and a LNM35 cell line secreting the soluble fusion protein VEGF receptor 3-immunoglobulin (VEGFR-3-Ig, which binds VEGF-C and inhibits VEGFR-3 signaling). Control lines were transfected with mock vectors. Tumor cells were implanted subcutaneously into severe combined immunodeficient mice (n = 6 in each group), and tumors and metastases were examined 6 weeks later. In another approach, recombinant adenoviruses expressing VEGFR-3-Ig (AdR3-Ig) or β-galactosidase (AdLacZ) were injected intravenously into LNM35 tumor-bearing mice (n = 14 and 7, respectively). Results: LNM35 cells expressed higher levels of VEGF-C RNA and protein than did N15 cells. Xenograft mock vector-transfected LNM35 tumors showed more intratumoral lymphatic vessels (15.3 vessels per grid; 95% confidence interval [CI] = 13.3 to 17.4) and more metastases in draining lymph nodes (12 of 12) than VEGFR-3-Ig-transfected LNM35 tumors (4.1 vessels per grid; 95% CI = 3.4 to 4.7; P<.001, two-sided t test; and four lymph nodes with metastases of 12 lymph nodes examined). Lymph node metastasis was also inhibited in AdR3-Ig-treated mice (AdR3-Ig = 0 of 28 lymph nodes; AdLacZ = 11 of 14 lymph nodes). However, metastasis to the lungs occurred in all mice, suggesting that LNM35 cells can also spread via other mechanisms. N15 tumors overexpressing VEGF-C contained more lymphatic vessels than vector-transfected tumors but did not have increased metastatic ability. Conclusions: Lymph node metastasis appears to be regulated by additional factors besides VEGF-C. Inhibition of VEGFR-3 signaling can suppress tumor lymphangiogenesis and metastasis to regional lymph nodes but not to lungs.</div></front></TEI><affiliations><list><country><li>Finlande</li></country><region><li>Uusimaa</li></region><settlement><li>Helsinki</li></settlement><orgName><li>Université d'Helsinki</li></orgName></list><tree><country name="Finlande"><noRegion><name sortKey="He, Yulong" sort="He, Yulong" uniqKey="He Y" first="Yulong" last="He">Yulong He</name></noRegion><name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name><name sortKey="Karpanen, Terhi" sort="Karpanen, Terhi" uniqKey="Karpanen T" first="Terhi" last="Karpanen">Terhi Karpanen</name><name sortKey="Koshikawa, Katsumi" sort="Koshikawa, Katsumi" uniqKey="Koshikawa K" first="Katsumi" last="Koshikawa">Katsumi Koshikawa</name><name sortKey="Kozaki, Ken Ichi" sort="Kozaki, Ken Ichi" uniqKey="Kozaki K" first="Ken-Ichi" last="Kozaki">Ken-Ichi Kozaki</name><name sortKey="Takahashi, Takashi" sort="Takahashi, Takashi" uniqKey="Takahashi T" first="Takashi" last="Takahashi">Takashi Takahashi</name><name sortKey="Yla Herttuala, Seppo" sort="Yla Herttuala, Seppo" uniqKey="Yla Herttuala S" first="Seppo" last="Yla-Herttuala">Seppo Yla-Herttuala</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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