Inhibition of c-Met Reduces Lymphatic Metastasis in RIP-Tag2 Transgenic Mice
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Abstract
Inhibition of VEGF signaling can promote lymph node metastasis in preclinical models, but the mechanism is not fully understood, and successful methods of prevention have not been found. Signaling of hepatocyte growth factor (HGF) and its receptor c-Met can promote the growth of lymphatics and metastasis of some tumors. We sought to explore the contributions of c-Met signaling to lymph node metastasis after inhibition of VEGF signaling. In particular, we examined whether c-Met is upregulated in lymphatics in or near pancreatic neuroendocrine tumors in RIP-Tag2 transgenic mice and whether lymph node metastasis can be reduced by concurrent inhibition of VEGF and c-Met signaling. Inhibition of VEGF signaling by anti-VEGF antibody or sunitinib in mice from the age of 14 to 17 weeks was accompanied by more intratumoral lymphatics, more tumor cells inside lymphatics, and more lymph node metastases. Under these conditions, lymphatic endothelial cells, like tumor cells, had strong immunoreactivity for c-Met and phospho-c-Met. c-Met blockade by the selective inhibitor, PF-04217903, significantly reduced metastasis to local lymph nodes. Together, these results indicate that inhibition of VEGF signaling in RIP-Tag2 mice upregulates c-Met expression in lymphatic endothelial cells, increases the number of intratumoral lymphatics and number of tumor cells within lymphatics, and promotes metastasis to local lymph nodes. Prevention of lymph node metastasis by PF-04217903 in this setting implicates c-Met signaling in tumor cell spread to lymph nodes. Cancer Res; 73(12); 3692–703. ©2013 AACR.
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Lymphatic metastasis is a key mechanism by which cancer cells detach from the primary tumor, migrate to adjacent regional lymph nodes, and eventually spread to other organs or body sites.
“Lymphatic metastasis is a key mechanism by which cancer cells detach from the primary tumor, migrate to adjacent regional lymph nodes, and eventually spread to other organs or body sites222.”
From Organic small-molecule NIR-II fluorophores for tumor phototheranostics (2026) · cites this paper as [222]
The Introduction (page unavailable) says tumor cells enter lymphatics within or near tumors and drain to regional sentinel nodes, supporting the lymph-node portion of the claim. Our copy does not establish that those cells subsequently spread from the nodes to other organs or body sites. (LLM, conf=0.87)
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Organic small-molecule NIR-II fluorophores for tumor phototheranostics
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“…formation and disassembly, MC-PSE provided an effective platform for the accurate detection of GSH. Lymphatic metastasis is a key mechanism by which cancer cells detach from the primary tumor, migrate to adjacent regional lymph nodes, and eventually spread to other organs or body sites 222 .”
- Authors
- Sennino, B., Ishiguro-Oonuma, T., Schriver, B. J., Christensen, J. G., & McDonald, D. M.
- Affiliations
- University of California, San Francisco (US)
- Authors' Affiliations: 1Department of Anatomy, Comprehensive Cancer Center, Cardiovascular Research Institute, University of California-San Francisco, San Francisco; and 2Pfizer Global Research and Development, La Jolla Labs, La Jolla, California
- Corresponding author
- McDonald, Donald M.
- Venue
- Cancer Research
- Published
- 2013-06-13
- Volume
- 73
- Issue
- 12
- Pages
- 3692-3703
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3686901
- OpenAlex
- W2039097790
- Cited by
- 60
- References
- 61
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 3 · 2019: 5 · 2018: 3 · 2017: 3 · 2016: 6 · 2015: 11 · 2014: 12 · 2013: 3
- FWCI
- 5.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL059157, HL 24136, HL 59157, P01HL024136)
- National Cancer Institute (CA-82923, R01CA082923)
- Topics
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- c-Met, lymph node metastasis, VEGF signaling, hepatocyte growth factor, pancreatic neuroendocrine tumors, lymphatic endothelial cells, sunitinib, anti-VEGF antibody, c-Met inhibitor, metastasis
- MeSH terms
- Sunitinib, Animals, Antibodies, Antineoplastic Agents, Immunohistochemistry, Indoles, Lymphatic Metastasis, Mice, Inbred C57BL, Mice, Transgenic, Pancreatic Neoplasms, Phosphorylation, Pyrazines, Pyrroles, Triazoles, Signal Transduction, Gene Expression Regulation, Neoplastic, Microscopy, Confocal, Proto-Oncogene Proteins c-met, Reverse Transcriptase Polymerase Chain Reaction, Vascular Endothelial Growth Factor C, Mice
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