Abstract

In this study we employ a near-infrared fluorescence lymphatic imaging (NIRFLI) technique to longitudinally image spatial and temporal changes in the lymphatics in mice bearing vascular endothelial growth factor (VEGF)-C overexpressing B16F10 (VEGF-C-B16F10) or mock-transduced B16F10 (mock-B16F10) melanoma tumors. Our NIRFLI data show that ICG-laden lymph accumulates into a VEGF-C-B16F10 tumor compared to mock-B16F10 at 3 days post implantation, presumably due to increased lymphatic vessel permeability. Quantification shows a significantly greater percentage of ICG-perfused area in VEGF-C-B16F10 (7.6 ± 2) as compared to MOCK-B16F10 (1 ± 0.5; p = 0.02), which is also confirmed by quantification of the lymphatic leakage of evans blue dye (optical density at 610nm; VEGF-C-B16F10, 10.5 ± 2; mock-B16F10, 5.1 ± 0.5; p = 0.009); thereafter, lymphatic leakage is visualized only in the peritumoral region. Our imaging data also show that anti-VEGF-C treatment in VEGF-C-B16F10 restores normal lymphatic vessel integrity and reduces dye extravasation. Because NIRFLI technology can be used to non-invasively detect lymphatic changes associated with cancer, it may provide a new diagnostic to assess the lack of lymphatic vessel integrity that promotes lymphovascular invasion and to assess therapies that could arrest invasion through normalization of the lymphatic vasculature.

© 2018 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

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References

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  1. S. A. Stacker, M. G. Achen, L. Jussila, M. E. Baldwin, and K. Alitalo, “Lymphangiogenesis and cancer metastasis,” Nat. Rev. Cancer 2(8), 573–583 (2002).
    [Crossref] [PubMed]
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    [Crossref] [PubMed]
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    [PubMed]
  4. J. L. Su, C. J. Yen, P. S. Chen, S. E. Chuang, C. C. Hong, I. H. Kuo, H. Y. Chen, M. C. Hung, and M. L. Kuo, “The role of the VEGF-C/VEGFR-3 axis in cancer progression,” Br. J. Cancer 96(4), 541–545 (2007).
    [Crossref] [PubMed]
  5. T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, L. L. Munn, and R. K. Jain, “Lymphatic metastasis in the absence of functional intratumor lymphatics,” Science 296(5574), 1883–1886 (2002).
    [Crossref] [PubMed]
  6. N. Isaka, T. P. Padera, J. Hagendoorn, D. Fukumura, and R. K. Jain, “Peritumor lymphatics induced by vascular endothelial growth factor-C exhibit abnormal function,” Cancer Res. 64(13), 4400–4404 (2004).
    [Crossref] [PubMed]
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    [Crossref] [PubMed]
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    [Crossref] [PubMed]
  9. S. Kwon and E. M. Sevick-Muraca, “Functional lymphatic imaging in tumor-bearing mice,” J. Immunol. Methods 360(1-2), 167–172 (2010).
    [Crossref] [PubMed]
  10. B. Zhu, H. Robinson, S. Zhang, G. Wu, and E. M. Sevick-Muraca, “Longitudinal far red gene-reporter imaging of cancer metastasis in preclinical models: a tool for accelerating drug discovery,” Biomed. Opt. Express 6(9), 3346–3351 (2015).
    [Crossref] [PubMed]
  11. M. R. Dreher, W. Liu, C. R. Michelich, M. W. Dewhirst, F. Yuan, and A. Chilkoti, “Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers,” J. Natl. Cancer Inst. 98(5), 335–344 (2006).
    [Crossref] [PubMed]
  12. B. Pytowski, J. Goldman, K. Persaud, Y. Wu, L. Witte, D. J. Hicklin, M. Skobe, K. C. Boardman, and M. A. Swartz, “Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody,” J. Natl. Cancer Inst. 97(1), 14–21 (2005).
    [Crossref] [PubMed]
  13. T. Hoshida, N. Isaka, J. Hagendoorn, E. di Tomaso, Y. L. Chen, B. Pytowski, D. Fukumura, T. P. Padera, and R. K. Jain, “Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications,” Cancer Res. 66(16), 8065–8075 (2006).
    [Crossref] [PubMed]
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    [Crossref] [PubMed]
  15. G. Baronzio, G. Parmar, and M. Baronzio, “overview of methods for overcoming hindrance to drug delivery to tumors, with special attention to tumor interstitial fluid,” Front. Oncol.  5165 (2015).
  16. J. C. Rasmussen, I. C. Tan, S. Naqvi, M. B. Aldrich, E. A. Maus, A. I. Blanco, R. J. Karni, and E. M. Sevick-Muraca, “Longitudinal monitoring of the head and neck lymphatics in response to surgery and radiation,” Head Neck 39(6), 1177–1188 (2017).
    [Crossref] [PubMed]

2017 (1)

J. C. Rasmussen, I. C. Tan, S. Naqvi, M. B. Aldrich, E. A. Maus, A. I. Blanco, R. J. Karni, and E. M. Sevick-Muraca, “Longitudinal monitoring of the head and neck lymphatics in response to surgery and radiation,” Head Neck 39(6), 1177–1188 (2017).
[Crossref] [PubMed]

2015 (2)

B. Zhu, H. Robinson, S. Zhang, G. Wu, and E. M. Sevick-Muraca, “Longitudinal far red gene-reporter imaging of cancer metastasis in preclinical models: a tool for accelerating drug discovery,” Biomed. Opt. Express 6(9), 3346–3351 (2015).
[Crossref] [PubMed]

G. Baronzio, G. Parmar, and M. Baronzio, “overview of methods for overcoming hindrance to drug delivery to tumors, with special attention to tumor interstitial fluid,” Front. Oncol.  5165 (2015).

2014 (2)

S. Liao and P. Y. von der Weid, “Inflammation-induced lymphangiogenesis and lymphatic dysfunction,” Angiogenesis 17(2), 325–334 (2014).
[Crossref] [PubMed]

E. M. Sevick-Muraca, S. Kwon, and J. C. Rasmussen, “Emerging lymphatic imaging technologies for mouse and man,” J. Clin. Invest. 124(3), 905–914 (2014).
[Crossref] [PubMed]

2012 (1)

A. Alitalo and M. Detmar, “Interaction of tumor cells and lymphatic vessels in cancer progression,” Oncogene 31(42), 4499–4508 (2012).
[Crossref] [PubMed]

2010 (1)

S. Kwon and E. M. Sevick-Muraca, “Functional lymphatic imaging in tumor-bearing mice,” J. Immunol. Methods 360(1-2), 167–172 (2010).
[Crossref] [PubMed]

2007 (1)

J. L. Su, C. J. Yen, P. S. Chen, S. E. Chuang, C. C. Hong, I. H. Kuo, H. Y. Chen, M. C. Hung, and M. L. Kuo, “The role of the VEGF-C/VEGFR-3 axis in cancer progression,” Br. J. Cancer 96(4), 541–545 (2007).
[Crossref] [PubMed]

2006 (2)

M. R. Dreher, W. Liu, C. R. Michelich, M. W. Dewhirst, F. Yuan, and A. Chilkoti, “Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers,” J. Natl. Cancer Inst. 98(5), 335–344 (2006).
[Crossref] [PubMed]

T. Hoshida, N. Isaka, J. Hagendoorn, E. di Tomaso, Y. L. Chen, B. Pytowski, D. Fukumura, T. P. Padera, and R. K. Jain, “Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications,” Cancer Res. 66(16), 8065–8075 (2006).
[Crossref] [PubMed]

2005 (2)

Y. He, I. Rajantie, K. Pajusola, M. Jeltsch, T. Holopainen, S. Yla-Herttuala, T. Harding, K. Jooss, T. Takahashi, and K. Alitalo, “Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels,” Cancer Res. 65(11), 4739–4746 (2005).
[Crossref] [PubMed]

B. Pytowski, J. Goldman, K. Persaud, Y. Wu, L. Witte, D. J. Hicklin, M. Skobe, K. C. Boardman, and M. A. Swartz, “Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody,” J. Natl. Cancer Inst. 97(1), 14–21 (2005).
[Crossref] [PubMed]

2004 (1)

N. Isaka, T. P. Padera, J. Hagendoorn, D. Fukumura, and R. K. Jain, “Peritumor lymphatics induced by vascular endothelial growth factor-C exhibit abnormal function,” Cancer Res. 64(13), 4400–4404 (2004).
[Crossref] [PubMed]

2002 (2)

S. A. Stacker, M. G. Achen, L. Jussila, M. E. Baldwin, and K. Alitalo, “Lymphangiogenesis and cancer metastasis,” Nat. Rev. Cancer 2(8), 573–583 (2002).
[Crossref] [PubMed]

T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, L. L. Munn, and R. K. Jain, “Lymphatic metastasis in the absence of functional intratumor lymphatics,” Science 296(5574), 1883–1886 (2002).
[Crossref] [PubMed]

1996 (1)

V. Joukov, K. Pajusola, A. Kaipainen, D. Chilov, I. Lahtinen, E. Kukk, O. Saksela, N. Kalkkinen, and K. Alitalo, “A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases,” EMBO J. 15(7), 1751 (1996).
[PubMed]

Achen, M. G.

S. A. Stacker, M. G. Achen, L. Jussila, M. E. Baldwin, and K. Alitalo, “Lymphangiogenesis and cancer metastasis,” Nat. Rev. Cancer 2(8), 573–583 (2002).
[Crossref] [PubMed]

Aldrich, M. B.

J. C. Rasmussen, I. C. Tan, S. Naqvi, M. B. Aldrich, E. A. Maus, A. I. Blanco, R. J. Karni, and E. M. Sevick-Muraca, “Longitudinal monitoring of the head and neck lymphatics in response to surgery and radiation,” Head Neck 39(6), 1177–1188 (2017).
[Crossref] [PubMed]

Alitalo, A.

A. Alitalo and M. Detmar, “Interaction of tumor cells and lymphatic vessels in cancer progression,” Oncogene 31(42), 4499–4508 (2012).
[Crossref] [PubMed]

Alitalo, K.

Y. He, I. Rajantie, K. Pajusola, M. Jeltsch, T. Holopainen, S. Yla-Herttuala, T. Harding, K. Jooss, T. Takahashi, and K. Alitalo, “Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels,” Cancer Res. 65(11), 4739–4746 (2005).
[Crossref] [PubMed]

S. A. Stacker, M. G. Achen, L. Jussila, M. E. Baldwin, and K. Alitalo, “Lymphangiogenesis and cancer metastasis,” Nat. Rev. Cancer 2(8), 573–583 (2002).
[Crossref] [PubMed]

V. Joukov, K. Pajusola, A. Kaipainen, D. Chilov, I. Lahtinen, E. Kukk, O. Saksela, N. Kalkkinen, and K. Alitalo, “A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases,” EMBO J. 15(7), 1751 (1996).
[PubMed]

Baldwin, M. E.

S. A. Stacker, M. G. Achen, L. Jussila, M. E. Baldwin, and K. Alitalo, “Lymphangiogenesis and cancer metastasis,” Nat. Rev. Cancer 2(8), 573–583 (2002).
[Crossref] [PubMed]

Baronzio, G.

G. Baronzio, G. Parmar, and M. Baronzio, “overview of methods for overcoming hindrance to drug delivery to tumors, with special attention to tumor interstitial fluid,” Front. Oncol.  5165 (2015).

Baronzio, M.

G. Baronzio, G. Parmar, and M. Baronzio, “overview of methods for overcoming hindrance to drug delivery to tumors, with special attention to tumor interstitial fluid,” Front. Oncol.  5165 (2015).

Blanco, A. I.

J. C. Rasmussen, I. C. Tan, S. Naqvi, M. B. Aldrich, E. A. Maus, A. I. Blanco, R. J. Karni, and E. M. Sevick-Muraca, “Longitudinal monitoring of the head and neck lymphatics in response to surgery and radiation,” Head Neck 39(6), 1177–1188 (2017).
[Crossref] [PubMed]

Boardman, K. C.

B. Pytowski, J. Goldman, K. Persaud, Y. Wu, L. Witte, D. J. Hicklin, M. Skobe, K. C. Boardman, and M. A. Swartz, “Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody,” J. Natl. Cancer Inst. 97(1), 14–21 (2005).
[Crossref] [PubMed]

Boucher, Y.

T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, L. L. Munn, and R. K. Jain, “Lymphatic metastasis in the absence of functional intratumor lymphatics,” Science 296(5574), 1883–1886 (2002).
[Crossref] [PubMed]

Brown, E. B.

T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, L. L. Munn, and R. K. Jain, “Lymphatic metastasis in the absence of functional intratumor lymphatics,” Science 296(5574), 1883–1886 (2002).
[Crossref] [PubMed]

Carreira, C. M.

T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, L. L. Munn, and R. K. Jain, “Lymphatic metastasis in the absence of functional intratumor lymphatics,” Science 296(5574), 1883–1886 (2002).
[Crossref] [PubMed]

Chen, H. Y.

J. L. Su, C. J. Yen, P. S. Chen, S. E. Chuang, C. C. Hong, I. H. Kuo, H. Y. Chen, M. C. Hung, and M. L. Kuo, “The role of the VEGF-C/VEGFR-3 axis in cancer progression,” Br. J. Cancer 96(4), 541–545 (2007).
[Crossref] [PubMed]

Chen, P. S.

J. L. Su, C. J. Yen, P. S. Chen, S. E. Chuang, C. C. Hong, I. H. Kuo, H. Y. Chen, M. C. Hung, and M. L. Kuo, “The role of the VEGF-C/VEGFR-3 axis in cancer progression,” Br. J. Cancer 96(4), 541–545 (2007).
[Crossref] [PubMed]

Chen, Y. L.

T. Hoshida, N. Isaka, J. Hagendoorn, E. di Tomaso, Y. L. Chen, B. Pytowski, D. Fukumura, T. P. Padera, and R. K. Jain, “Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications,” Cancer Res. 66(16), 8065–8075 (2006).
[Crossref] [PubMed]

Chilkoti, A.

M. R. Dreher, W. Liu, C. R. Michelich, M. W. Dewhirst, F. Yuan, and A. Chilkoti, “Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers,” J. Natl. Cancer Inst. 98(5), 335–344 (2006).
[Crossref] [PubMed]

Chilov, D.

V. Joukov, K. Pajusola, A. Kaipainen, D. Chilov, I. Lahtinen, E. Kukk, O. Saksela, N. Kalkkinen, and K. Alitalo, “A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases,” EMBO J. 15(7), 1751 (1996).
[PubMed]

Choi, N. C.

T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, L. L. Munn, and R. K. Jain, “Lymphatic metastasis in the absence of functional intratumor lymphatics,” Science 296(5574), 1883–1886 (2002).
[Crossref] [PubMed]

Chuang, S. E.

J. L. Su, C. J. Yen, P. S. Chen, S. E. Chuang, C. C. Hong, I. H. Kuo, H. Y. Chen, M. C. Hung, and M. L. Kuo, “The role of the VEGF-C/VEGFR-3 axis in cancer progression,” Br. J. Cancer 96(4), 541–545 (2007).
[Crossref] [PubMed]

Detmar, M.

A. Alitalo and M. Detmar, “Interaction of tumor cells and lymphatic vessels in cancer progression,” Oncogene 31(42), 4499–4508 (2012).
[Crossref] [PubMed]

Dewhirst, M. W.

M. R. Dreher, W. Liu, C. R. Michelich, M. W. Dewhirst, F. Yuan, and A. Chilkoti, “Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers,” J. Natl. Cancer Inst. 98(5), 335–344 (2006).
[Crossref] [PubMed]

di Tomaso, E.

T. Hoshida, N. Isaka, J. Hagendoorn, E. di Tomaso, Y. L. Chen, B. Pytowski, D. Fukumura, T. P. Padera, and R. K. Jain, “Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications,” Cancer Res. 66(16), 8065–8075 (2006).
[Crossref] [PubMed]

T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, L. L. Munn, and R. K. Jain, “Lymphatic metastasis in the absence of functional intratumor lymphatics,” Science 296(5574), 1883–1886 (2002).
[Crossref] [PubMed]

Dreher, M. R.

M. R. Dreher, W. Liu, C. R. Michelich, M. W. Dewhirst, F. Yuan, and A. Chilkoti, “Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers,” J. Natl. Cancer Inst. 98(5), 335–344 (2006).
[Crossref] [PubMed]

Fukumura, D.

T. Hoshida, N. Isaka, J. Hagendoorn, E. di Tomaso, Y. L. Chen, B. Pytowski, D. Fukumura, T. P. Padera, and R. K. Jain, “Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications,” Cancer Res. 66(16), 8065–8075 (2006).
[Crossref] [PubMed]

N. Isaka, T. P. Padera, J. Hagendoorn, D. Fukumura, and R. K. Jain, “Peritumor lymphatics induced by vascular endothelial growth factor-C exhibit abnormal function,” Cancer Res. 64(13), 4400–4404 (2004).
[Crossref] [PubMed]

Goldman, J.

B. Pytowski, J. Goldman, K. Persaud, Y. Wu, L. Witte, D. J. Hicklin, M. Skobe, K. C. Boardman, and M. A. Swartz, “Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody,” J. Natl. Cancer Inst. 97(1), 14–21 (2005).
[Crossref] [PubMed]

Hagendoorn, J.

T. Hoshida, N. Isaka, J. Hagendoorn, E. di Tomaso, Y. L. Chen, B. Pytowski, D. Fukumura, T. P. Padera, and R. K. Jain, “Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications,” Cancer Res. 66(16), 8065–8075 (2006).
[Crossref] [PubMed]

N. Isaka, T. P. Padera, J. Hagendoorn, D. Fukumura, and R. K. Jain, “Peritumor lymphatics induced by vascular endothelial growth factor-C exhibit abnormal function,” Cancer Res. 64(13), 4400–4404 (2004).
[Crossref] [PubMed]

Harding, T.

Y. He, I. Rajantie, K. Pajusola, M. Jeltsch, T. Holopainen, S. Yla-Herttuala, T. Harding, K. Jooss, T. Takahashi, and K. Alitalo, “Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels,” Cancer Res. 65(11), 4739–4746 (2005).
[Crossref] [PubMed]

He, Y.

Y. He, I. Rajantie, K. Pajusola, M. Jeltsch, T. Holopainen, S. Yla-Herttuala, T. Harding, K. Jooss, T. Takahashi, and K. Alitalo, “Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels,” Cancer Res. 65(11), 4739–4746 (2005).
[Crossref] [PubMed]

Hicklin, D. J.

B. Pytowski, J. Goldman, K. Persaud, Y. Wu, L. Witte, D. J. Hicklin, M. Skobe, K. C. Boardman, and M. A. Swartz, “Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody,” J. Natl. Cancer Inst. 97(1), 14–21 (2005).
[Crossref] [PubMed]

Holopainen, T.

Y. He, I. Rajantie, K. Pajusola, M. Jeltsch, T. Holopainen, S. Yla-Herttuala, T. Harding, K. Jooss, T. Takahashi, and K. Alitalo, “Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels,” Cancer Res. 65(11), 4739–4746 (2005).
[Crossref] [PubMed]

Hong, C. C.

J. L. Su, C. J. Yen, P. S. Chen, S. E. Chuang, C. C. Hong, I. H. Kuo, H. Y. Chen, M. C. Hung, and M. L. Kuo, “The role of the VEGF-C/VEGFR-3 axis in cancer progression,” Br. J. Cancer 96(4), 541–545 (2007).
[Crossref] [PubMed]

Hoshida, T.

T. Hoshida, N. Isaka, J. Hagendoorn, E. di Tomaso, Y. L. Chen, B. Pytowski, D. Fukumura, T. P. Padera, and R. K. Jain, “Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications,” Cancer Res. 66(16), 8065–8075 (2006).
[Crossref] [PubMed]

Hung, M. C.

J. L. Su, C. J. Yen, P. S. Chen, S. E. Chuang, C. C. Hong, I. H. Kuo, H. Y. Chen, M. C. Hung, and M. L. Kuo, “The role of the VEGF-C/VEGFR-3 axis in cancer progression,” Br. J. Cancer 96(4), 541–545 (2007).
[Crossref] [PubMed]

Isaka, N.

T. Hoshida, N. Isaka, J. Hagendoorn, E. di Tomaso, Y. L. Chen, B. Pytowski, D. Fukumura, T. P. Padera, and R. K. Jain, “Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications,” Cancer Res. 66(16), 8065–8075 (2006).
[Crossref] [PubMed]

N. Isaka, T. P. Padera, J. Hagendoorn, D. Fukumura, and R. K. Jain, “Peritumor lymphatics induced by vascular endothelial growth factor-C exhibit abnormal function,” Cancer Res. 64(13), 4400–4404 (2004).
[Crossref] [PubMed]

Jain, R. K.

T. Hoshida, N. Isaka, J. Hagendoorn, E. di Tomaso, Y. L. Chen, B. Pytowski, D. Fukumura, T. P. Padera, and R. K. Jain, “Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications,” Cancer Res. 66(16), 8065–8075 (2006).
[Crossref] [PubMed]

N. Isaka, T. P. Padera, J. Hagendoorn, D. Fukumura, and R. K. Jain, “Peritumor lymphatics induced by vascular endothelial growth factor-C exhibit abnormal function,” Cancer Res. 64(13), 4400–4404 (2004).
[Crossref] [PubMed]

T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, L. L. Munn, and R. K. Jain, “Lymphatic metastasis in the absence of functional intratumor lymphatics,” Science 296(5574), 1883–1886 (2002).
[Crossref] [PubMed]

Jeltsch, M.

Y. He, I. Rajantie, K. Pajusola, M. Jeltsch, T. Holopainen, S. Yla-Herttuala, T. Harding, K. Jooss, T. Takahashi, and K. Alitalo, “Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels,” Cancer Res. 65(11), 4739–4746 (2005).
[Crossref] [PubMed]

Jooss, K.

Y. He, I. Rajantie, K. Pajusola, M. Jeltsch, T. Holopainen, S. Yla-Herttuala, T. Harding, K. Jooss, T. Takahashi, and K. Alitalo, “Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels,” Cancer Res. 65(11), 4739–4746 (2005).
[Crossref] [PubMed]

Joukov, V.

V. Joukov, K. Pajusola, A. Kaipainen, D. Chilov, I. Lahtinen, E. Kukk, O. Saksela, N. Kalkkinen, and K. Alitalo, “A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases,” EMBO J. 15(7), 1751 (1996).
[PubMed]

Jussila, L.

S. A. Stacker, M. G. Achen, L. Jussila, M. E. Baldwin, and K. Alitalo, “Lymphangiogenesis and cancer metastasis,” Nat. Rev. Cancer 2(8), 573–583 (2002).
[Crossref] [PubMed]

Kadambi, A.

T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, L. L. Munn, and R. K. Jain, “Lymphatic metastasis in the absence of functional intratumor lymphatics,” Science 296(5574), 1883–1886 (2002).
[Crossref] [PubMed]

Kaipainen, A.

V. Joukov, K. Pajusola, A. Kaipainen, D. Chilov, I. Lahtinen, E. Kukk, O. Saksela, N. Kalkkinen, and K. Alitalo, “A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases,” EMBO J. 15(7), 1751 (1996).
[PubMed]

Kalkkinen, N.

V. Joukov, K. Pajusola, A. Kaipainen, D. Chilov, I. Lahtinen, E. Kukk, O. Saksela, N. Kalkkinen, and K. Alitalo, “A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases,” EMBO J. 15(7), 1751 (1996).
[PubMed]

Karni, R. J.

J. C. Rasmussen, I. C. Tan, S. Naqvi, M. B. Aldrich, E. A. Maus, A. I. Blanco, R. J. Karni, and E. M. Sevick-Muraca, “Longitudinal monitoring of the head and neck lymphatics in response to surgery and radiation,” Head Neck 39(6), 1177–1188 (2017).
[Crossref] [PubMed]

Kukk, E.

V. Joukov, K. Pajusola, A. Kaipainen, D. Chilov, I. Lahtinen, E. Kukk, O. Saksela, N. Kalkkinen, and K. Alitalo, “A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases,” EMBO J. 15(7), 1751 (1996).
[PubMed]

Kuo, I. H.

J. L. Su, C. J. Yen, P. S. Chen, S. E. Chuang, C. C. Hong, I. H. Kuo, H. Y. Chen, M. C. Hung, and M. L. Kuo, “The role of the VEGF-C/VEGFR-3 axis in cancer progression,” Br. J. Cancer 96(4), 541–545 (2007).
[Crossref] [PubMed]

Kuo, M. L.

J. L. Su, C. J. Yen, P. S. Chen, S. E. Chuang, C. C. Hong, I. H. Kuo, H. Y. Chen, M. C. Hung, and M. L. Kuo, “The role of the VEGF-C/VEGFR-3 axis in cancer progression,” Br. J. Cancer 96(4), 541–545 (2007).
[Crossref] [PubMed]

Kwon, S.

E. M. Sevick-Muraca, S. Kwon, and J. C. Rasmussen, “Emerging lymphatic imaging technologies for mouse and man,” J. Clin. Invest. 124(3), 905–914 (2014).
[Crossref] [PubMed]

S. Kwon and E. M. Sevick-Muraca, “Functional lymphatic imaging in tumor-bearing mice,” J. Immunol. Methods 360(1-2), 167–172 (2010).
[Crossref] [PubMed]

Lahtinen, I.

V. Joukov, K. Pajusola, A. Kaipainen, D. Chilov, I. Lahtinen, E. Kukk, O. Saksela, N. Kalkkinen, and K. Alitalo, “A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases,” EMBO J. 15(7), 1751 (1996).
[PubMed]

Liao, S.

S. Liao and P. Y. von der Weid, “Inflammation-induced lymphangiogenesis and lymphatic dysfunction,” Angiogenesis 17(2), 325–334 (2014).
[Crossref] [PubMed]

Liu, W.

M. R. Dreher, W. Liu, C. R. Michelich, M. W. Dewhirst, F. Yuan, and A. Chilkoti, “Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers,” J. Natl. Cancer Inst. 98(5), 335–344 (2006).
[Crossref] [PubMed]

Mark, E. J.

T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, L. L. Munn, and R. K. Jain, “Lymphatic metastasis in the absence of functional intratumor lymphatics,” Science 296(5574), 1883–1886 (2002).
[Crossref] [PubMed]

Mathisen, D.

T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, L. L. Munn, and R. K. Jain, “Lymphatic metastasis in the absence of functional intratumor lymphatics,” Science 296(5574), 1883–1886 (2002).
[Crossref] [PubMed]

Maus, E. A.

J. C. Rasmussen, I. C. Tan, S. Naqvi, M. B. Aldrich, E. A. Maus, A. I. Blanco, R. J. Karni, and E. M. Sevick-Muraca, “Longitudinal monitoring of the head and neck lymphatics in response to surgery and radiation,” Head Neck 39(6), 1177–1188 (2017).
[Crossref] [PubMed]

Michelich, C. R.

M. R. Dreher, W. Liu, C. R. Michelich, M. W. Dewhirst, F. Yuan, and A. Chilkoti, “Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers,” J. Natl. Cancer Inst. 98(5), 335–344 (2006).
[Crossref] [PubMed]

Munn, L. L.

T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, L. L. Munn, and R. K. Jain, “Lymphatic metastasis in the absence of functional intratumor lymphatics,” Science 296(5574), 1883–1886 (2002).
[Crossref] [PubMed]

Naqvi, S.

J. C. Rasmussen, I. C. Tan, S. Naqvi, M. B. Aldrich, E. A. Maus, A. I. Blanco, R. J. Karni, and E. M. Sevick-Muraca, “Longitudinal monitoring of the head and neck lymphatics in response to surgery and radiation,” Head Neck 39(6), 1177–1188 (2017).
[Crossref] [PubMed]

Padera, T. P.

T. Hoshida, N. Isaka, J. Hagendoorn, E. di Tomaso, Y. L. Chen, B. Pytowski, D. Fukumura, T. P. Padera, and R. K. Jain, “Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications,” Cancer Res. 66(16), 8065–8075 (2006).
[Crossref] [PubMed]

N. Isaka, T. P. Padera, J. Hagendoorn, D. Fukumura, and R. K. Jain, “Peritumor lymphatics induced by vascular endothelial growth factor-C exhibit abnormal function,” Cancer Res. 64(13), 4400–4404 (2004).
[Crossref] [PubMed]

T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, L. L. Munn, and R. K. Jain, “Lymphatic metastasis in the absence of functional intratumor lymphatics,” Science 296(5574), 1883–1886 (2002).
[Crossref] [PubMed]

Pajusola, K.

Y. He, I. Rajantie, K. Pajusola, M. Jeltsch, T. Holopainen, S. Yla-Herttuala, T. Harding, K. Jooss, T. Takahashi, and K. Alitalo, “Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels,” Cancer Res. 65(11), 4739–4746 (2005).
[Crossref] [PubMed]

V. Joukov, K. Pajusola, A. Kaipainen, D. Chilov, I. Lahtinen, E. Kukk, O. Saksela, N. Kalkkinen, and K. Alitalo, “A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases,” EMBO J. 15(7), 1751 (1996).
[PubMed]

Parmar, G.

G. Baronzio, G. Parmar, and M. Baronzio, “overview of methods for overcoming hindrance to drug delivery to tumors, with special attention to tumor interstitial fluid,” Front. Oncol.  5165 (2015).

Persaud, K.

B. Pytowski, J. Goldman, K. Persaud, Y. Wu, L. Witte, D. J. Hicklin, M. Skobe, K. C. Boardman, and M. A. Swartz, “Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody,” J. Natl. Cancer Inst. 97(1), 14–21 (2005).
[Crossref] [PubMed]

Pytowski, B.

T. Hoshida, N. Isaka, J. Hagendoorn, E. di Tomaso, Y. L. Chen, B. Pytowski, D. Fukumura, T. P. Padera, and R. K. Jain, “Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications,” Cancer Res. 66(16), 8065–8075 (2006).
[Crossref] [PubMed]

B. Pytowski, J. Goldman, K. Persaud, Y. Wu, L. Witte, D. J. Hicklin, M. Skobe, K. C. Boardman, and M. A. Swartz, “Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody,” J. Natl. Cancer Inst. 97(1), 14–21 (2005).
[Crossref] [PubMed]

Rajantie, I.

Y. He, I. Rajantie, K. Pajusola, M. Jeltsch, T. Holopainen, S. Yla-Herttuala, T. Harding, K. Jooss, T. Takahashi, and K. Alitalo, “Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels,” Cancer Res. 65(11), 4739–4746 (2005).
[Crossref] [PubMed]

Rasmussen, J. C.

J. C. Rasmussen, I. C. Tan, S. Naqvi, M. B. Aldrich, E. A. Maus, A. I. Blanco, R. J. Karni, and E. M. Sevick-Muraca, “Longitudinal monitoring of the head and neck lymphatics in response to surgery and radiation,” Head Neck 39(6), 1177–1188 (2017).
[Crossref] [PubMed]

E. M. Sevick-Muraca, S. Kwon, and J. C. Rasmussen, “Emerging lymphatic imaging technologies for mouse and man,” J. Clin. Invest. 124(3), 905–914 (2014).
[Crossref] [PubMed]

Robinson, H.

Saksela, O.

V. Joukov, K. Pajusola, A. Kaipainen, D. Chilov, I. Lahtinen, E. Kukk, O. Saksela, N. Kalkkinen, and K. Alitalo, “A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases,” EMBO J. 15(7), 1751 (1996).
[PubMed]

Sevick-Muraca, E. M.

J. C. Rasmussen, I. C. Tan, S. Naqvi, M. B. Aldrich, E. A. Maus, A. I. Blanco, R. J. Karni, and E. M. Sevick-Muraca, “Longitudinal monitoring of the head and neck lymphatics in response to surgery and radiation,” Head Neck 39(6), 1177–1188 (2017).
[Crossref] [PubMed]

B. Zhu, H. Robinson, S. Zhang, G. Wu, and E. M. Sevick-Muraca, “Longitudinal far red gene-reporter imaging of cancer metastasis in preclinical models: a tool for accelerating drug discovery,” Biomed. Opt. Express 6(9), 3346–3351 (2015).
[Crossref] [PubMed]

E. M. Sevick-Muraca, S. Kwon, and J. C. Rasmussen, “Emerging lymphatic imaging technologies for mouse and man,” J. Clin. Invest. 124(3), 905–914 (2014).
[Crossref] [PubMed]

S. Kwon and E. M. Sevick-Muraca, “Functional lymphatic imaging in tumor-bearing mice,” J. Immunol. Methods 360(1-2), 167–172 (2010).
[Crossref] [PubMed]

Skobe, M.

B. Pytowski, J. Goldman, K. Persaud, Y. Wu, L. Witte, D. J. Hicklin, M. Skobe, K. C. Boardman, and M. A. Swartz, “Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody,” J. Natl. Cancer Inst. 97(1), 14–21 (2005).
[Crossref] [PubMed]

Stacker, S. A.

S. A. Stacker, M. G. Achen, L. Jussila, M. E. Baldwin, and K. Alitalo, “Lymphangiogenesis and cancer metastasis,” Nat. Rev. Cancer 2(8), 573–583 (2002).
[Crossref] [PubMed]

Su, J. L.

J. L. Su, C. J. Yen, P. S. Chen, S. E. Chuang, C. C. Hong, I. H. Kuo, H. Y. Chen, M. C. Hung, and M. L. Kuo, “The role of the VEGF-C/VEGFR-3 axis in cancer progression,” Br. J. Cancer 96(4), 541–545 (2007).
[Crossref] [PubMed]

Swartz, M. A.

B. Pytowski, J. Goldman, K. Persaud, Y. Wu, L. Witte, D. J. Hicklin, M. Skobe, K. C. Boardman, and M. A. Swartz, “Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody,” J. Natl. Cancer Inst. 97(1), 14–21 (2005).
[Crossref] [PubMed]

Takahashi, T.

Y. He, I. Rajantie, K. Pajusola, M. Jeltsch, T. Holopainen, S. Yla-Herttuala, T. Harding, K. Jooss, T. Takahashi, and K. Alitalo, “Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels,” Cancer Res. 65(11), 4739–4746 (2005).
[Crossref] [PubMed]

Tan, I. C.

J. C. Rasmussen, I. C. Tan, S. Naqvi, M. B. Aldrich, E. A. Maus, A. I. Blanco, R. J. Karni, and E. M. Sevick-Muraca, “Longitudinal monitoring of the head and neck lymphatics in response to surgery and radiation,” Head Neck 39(6), 1177–1188 (2017).
[Crossref] [PubMed]

von der Weid, P. Y.

S. Liao and P. Y. von der Weid, “Inflammation-induced lymphangiogenesis and lymphatic dysfunction,” Angiogenesis 17(2), 325–334 (2014).
[Crossref] [PubMed]

Wain, J.

T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, L. L. Munn, and R. K. Jain, “Lymphatic metastasis in the absence of functional intratumor lymphatics,” Science 296(5574), 1883–1886 (2002).
[Crossref] [PubMed]

Witte, L.

B. Pytowski, J. Goldman, K. Persaud, Y. Wu, L. Witte, D. J. Hicklin, M. Skobe, K. C. Boardman, and M. A. Swartz, “Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody,” J. Natl. Cancer Inst. 97(1), 14–21 (2005).
[Crossref] [PubMed]

Wu, G.

Wu, Y.

B. Pytowski, J. Goldman, K. Persaud, Y. Wu, L. Witte, D. J. Hicklin, M. Skobe, K. C. Boardman, and M. A. Swartz, “Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody,” J. Natl. Cancer Inst. 97(1), 14–21 (2005).
[Crossref] [PubMed]

Yen, C. J.

J. L. Su, C. J. Yen, P. S. Chen, S. E. Chuang, C. C. Hong, I. H. Kuo, H. Y. Chen, M. C. Hung, and M. L. Kuo, “The role of the VEGF-C/VEGFR-3 axis in cancer progression,” Br. J. Cancer 96(4), 541–545 (2007).
[Crossref] [PubMed]

Yla-Herttuala, S.

Y. He, I. Rajantie, K. Pajusola, M. Jeltsch, T. Holopainen, S. Yla-Herttuala, T. Harding, K. Jooss, T. Takahashi, and K. Alitalo, “Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels,” Cancer Res. 65(11), 4739–4746 (2005).
[Crossref] [PubMed]

Yuan, F.

M. R. Dreher, W. Liu, C. R. Michelich, M. W. Dewhirst, F. Yuan, and A. Chilkoti, “Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers,” J. Natl. Cancer Inst. 98(5), 335–344 (2006).
[Crossref] [PubMed]

Zhang, S.

Zhu, B.

Angiogenesis (1)

S. Liao and P. Y. von der Weid, “Inflammation-induced lymphangiogenesis and lymphatic dysfunction,” Angiogenesis 17(2), 325–334 (2014).
[Crossref] [PubMed]

Biomed. Opt. Express (1)

Br. J. Cancer (1)

J. L. Su, C. J. Yen, P. S. Chen, S. E. Chuang, C. C. Hong, I. H. Kuo, H. Y. Chen, M. C. Hung, and M. L. Kuo, “The role of the VEGF-C/VEGFR-3 axis in cancer progression,” Br. J. Cancer 96(4), 541–545 (2007).
[Crossref] [PubMed]

Cancer Res. (3)

N. Isaka, T. P. Padera, J. Hagendoorn, D. Fukumura, and R. K. Jain, “Peritumor lymphatics induced by vascular endothelial growth factor-C exhibit abnormal function,” Cancer Res. 64(13), 4400–4404 (2004).
[Crossref] [PubMed]

T. Hoshida, N. Isaka, J. Hagendoorn, E. di Tomaso, Y. L. Chen, B. Pytowski, D. Fukumura, T. P. Padera, and R. K. Jain, “Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications,” Cancer Res. 66(16), 8065–8075 (2006).
[Crossref] [PubMed]

Y. He, I. Rajantie, K. Pajusola, M. Jeltsch, T. Holopainen, S. Yla-Herttuala, T. Harding, K. Jooss, T. Takahashi, and K. Alitalo, “Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels,” Cancer Res. 65(11), 4739–4746 (2005).
[Crossref] [PubMed]

EMBO J. (1)

V. Joukov, K. Pajusola, A. Kaipainen, D. Chilov, I. Lahtinen, E. Kukk, O. Saksela, N. Kalkkinen, and K. Alitalo, “A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases,” EMBO J. 15(7), 1751 (1996).
[PubMed]

Front. Oncol (1)

G. Baronzio, G. Parmar, and M. Baronzio, “overview of methods for overcoming hindrance to drug delivery to tumors, with special attention to tumor interstitial fluid,” Front. Oncol.  5165 (2015).

Head Neck (1)

J. C. Rasmussen, I. C. Tan, S. Naqvi, M. B. Aldrich, E. A. Maus, A. I. Blanco, R. J. Karni, and E. M. Sevick-Muraca, “Longitudinal monitoring of the head and neck lymphatics in response to surgery and radiation,” Head Neck 39(6), 1177–1188 (2017).
[Crossref] [PubMed]

J. Clin. Invest. (1)

E. M. Sevick-Muraca, S. Kwon, and J. C. Rasmussen, “Emerging lymphatic imaging technologies for mouse and man,” J. Clin. Invest. 124(3), 905–914 (2014).
[Crossref] [PubMed]

J. Immunol. Methods (1)

S. Kwon and E. M. Sevick-Muraca, “Functional lymphatic imaging in tumor-bearing mice,” J. Immunol. Methods 360(1-2), 167–172 (2010).
[Crossref] [PubMed]

J. Natl. Cancer Inst. (2)

M. R. Dreher, W. Liu, C. R. Michelich, M. W. Dewhirst, F. Yuan, and A. Chilkoti, “Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers,” J. Natl. Cancer Inst. 98(5), 335–344 (2006).
[Crossref] [PubMed]

B. Pytowski, J. Goldman, K. Persaud, Y. Wu, L. Witte, D. J. Hicklin, M. Skobe, K. C. Boardman, and M. A. Swartz, “Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody,” J. Natl. Cancer Inst. 97(1), 14–21 (2005).
[Crossref] [PubMed]

Nat. Rev. Cancer (1)

S. A. Stacker, M. G. Achen, L. Jussila, M. E. Baldwin, and K. Alitalo, “Lymphangiogenesis and cancer metastasis,” Nat. Rev. Cancer 2(8), 573–583 (2002).
[Crossref] [PubMed]

Oncogene (1)

A. Alitalo and M. Detmar, “Interaction of tumor cells and lymphatic vessels in cancer progression,” Oncogene 31(42), 4499–4508 (2012).
[Crossref] [PubMed]

Science (1)

T. P. Padera, A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, L. L. Munn, and R. K. Jain, “Lymphatic metastasis in the absence of functional intratumor lymphatics,” Science 296(5574), 1883–1886 (2002).
[Crossref] [PubMed]

Supplementary Material (1)

NameDescription
» Visualization 1       NIR fluorescent image sequences from dynamic NIRFI after intradermal injection show ICG accumulation in the VEGF-C-B16F10 tumor.

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Figures (4)

Fig. 1
Fig. 1 Representative fused images of fluorescence with white light images in mice bearing VEGF-C or MOCK-B16F10 in the left hindlimb. NIRFLI showed dye accumulation in the tumor after ICG administration (See Visualization 1). The insets show magnified fluorescent images of the red rectangles. A dashed red circle in the inset indicates the location of a tumor. Arrow, tumor. Double arrow, ICG injection site. Asterisk, ILN. Scale, 1mm. I. The fluorescent intensity profiles in the VEGF-C- (n = 6; black) and MOCK- (n = 6; grey) B16F10 tumor region at 3 days p.i. were plotted as a function of time. Data was shown mean ± SE. J. Quantification showing percentage of ICG perfused area in VEGF-C (n = 6) and MOCK- (n = 6) B16F10. * P = 0.02.
Fig. 2
Fig. 2 A. Quantification of tissue retention of EBD normalized to tissue weight. * p = 0.009. B. In vivo growth of VEGF-C-B16F10 (circle; n = 8) and MOCK-B16F10 (square; n = 11).
Fig. 3
Fig. 3 White and fluorescence images in mice (n = 2 for each tumor) at 3 days p.i. of VEGF-C or MOCK-B16F10 following FITC-Dextran and ICG. The insets show magnified fluorescent images of the red rectangles. A dashed red circle in the inset indicates the location of a tumor. The injection sites were covered. Scale, 1mm.
Fig. 4
Fig. 4 A. Representative in vivo fluorescence images of mice at 3 days p.i. of iRFP-VEGF-C-B16F10 (red; n = 9 for each treatment) 20 mins after i.d. injection of ICG (green) to the base of the tail. The insets show magnified fluorescent images of the white dashed rectangles. For comparison of mock-B16F10, see Fig. 1. B. Quantification showing percentage of ICG perfused area in the tumor region. * P = 0.001. Scale, 1mm.

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