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Cited by 794Lymphatic System and DiseasesImmune cells in cancerAngiogenesis and VEGF in Cancer

Tumor-Associated Macrophages Express Lymphatic Endothelial Growth Factors and Are Related to Peritumoral Lymphangiogenesis

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Schoppmann, Sebastian F., Birner, Peter, Stöckl, Johannes, Kalt, Romana, Ullrich, Robert, Caucig, Carola, Kriehuber, Ernst, Nagy, Katalin +2 more·2002·The American Journal of Pathology
DOI 10.1016/s0002-9440(10)64255-1PMC PMC1867252
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Abstract

Formation of lymphatic metastasis is the initial step of generalized spreading of tumor cells and predicts poor clinical prognosis. Lymphatic vessels generally arise within the peritumoral stroma, although the lymphangiopoietic vascular endothelial growth factors (VEGF)-C and -D are produced by tumor cells. In a carefully selected collection of human cervical cancers (stage pT1b1) we demonstrate by quantitative immunohistochemistry and in situ hybridization that density of lymphatic microvessels is significantly increased in peritumoral stroma, and that a subset of stromal cells express large amounts of VEGF-C and VEGF-D. The density of cells producing these vascular growth factors correlates with peritumoral inflammatory stroma reaction, lymphatic microvessel density, and indirectly with peritumoral carcinomatous lymphangiosis and frequency of lymph node metastasis. The VEGF-C- and VEGF-D-producing stroma cells were identified in situ as a subset of activated tumor-associated macrophages (TAMs) by expression of a panel of macrophage-specific markers, including CD68, CD23, and CD14. These TAMs also expressed the VEGF-C- and VEGF-D-specific tyrosine kinase receptor VEGFR-3. As TAMs are derived from monocytes in the circulation, a search in peripheral blood for candidate precursors of VEGFR-3-expressing TAMs revealed a subfraction of CD14-positive, VEGFR-3-expressing monocytes, that, however, failed to express VEGF-C and VEGF-D. Only after in vitro incubation with tumor necrosis factor-alpha, lipopolysaccharide, or VEGF-D did these monocytes start to synthesize VEGF-C de novo. In conclusion VEGF-C-expressing TAMs play a novel role in peritumoral lymphangiogenesis and subsequent dissemination in human cancer.

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  • TAMs may aid tumor growth by facilitating chemotaxis of Th2 and Treg cells, and by promoting angiogenesis and lymphoangiogenesis via VEGF, VEGF-C and -D, PDGF, and TGF-β.

    “TAMs may aid tumor growth by facilitating the chemotaxis of Th2 and Treg cells, and by promoting angiogenesis and lymphoangiogenesis via production of VEGF, VEGF-C and -D, PDGF, and TGF-β (92).”

    From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [92]

    The Discussion reports that a subset of TAMs produces VEGF-C and VEGF-D and may contribute to peritumoral lymphatic vessel growth. Our copy does not support the attributed chemotaxis of Th2 or Treg cells, or TAM-driven angiogenesis through VEGF, PDGF, or TGF-β. Page numbers are not available in the indexed passages. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • TAMs have a dual role in neoplasms: they may kill neoplastic cells following activation by IL-2, interferon and IL-12, but they produce angiogenic and lymphangiogenic growth factors, cytokines and proteases that potentiate neoplastic progression.

    “TAMs have a dual role in neoplasms — although they may kill neoplastic cells following activation by IL-2, interferon and IL-12 (refs 15, 16), TAMs produce a number of potent angiogenic and lymphangiogenic growth factors, cytokines and proteases, all of which are mediators that potentiate neoplastic progression17.”

    From Inflammation and cancer (2002) · cites this paper as [17]

  • During human cervical carcinogenesis, TAMs express VEGF-C and VEGF-D as well as VEGFR-3, implicated in formation of lymphatic vessels and lymphatic metastases.

    “In addition to altering the local balance of pro-angiogenic factors during melanoma development, during human cervical carcinogenesis, TAMs express VEGF-C and VEGF-D as well as the VEGF receptor-3 (VEGFR-3), all of which are implicated in formation of lymphatic vessels and lymphatic metastases17.”

    From Inflammation and cancer (2002) · cites this paper as [17]

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Authors
Schoppmann, S. F., Birner, P., Stöckl, J., Kalt, R., Ullrich, R., Caucig, C., Kriehuber, E., Nagy, K., Alitalo, K., & Kerjaschki, D.
Affiliations
  • University of Vienna (AT)
  • University of Helsinki (FI)
Corresponding author
Kerjaschki, Dontscho
ORCID
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2002-09
Volume
161
Issue
3
Pages
947-956
ISSN
0002-9440 (ISSN-L)
DOI
10.1016/s0002-9440(10)64255-1
PMC
PMC1867252
OpenAlex
W2164757740
Cited by
794
References
0
Citations by year
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FWCI
11.59
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Austrian Science Fund (SFB 05, 007)
Topics
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords
tumor-associated macrophages, lymphangiogenesis, VEGF-C, VEGF-D, VEGFR-3, cervical cancer, lymph node metastasis, peritumoral stroma, lymphatic microvessel density, monocyte activation, tumor microenvironment
MeSH terms
Carcinoma, Squamous Cell, Uterine Cervical Neoplasms, Female, Humans, Immunohistochemistry, Lymphatic Metastasis, Macrophages, Antigens, CD, Immunophenotyping, Endothelial Growth Factors, Stromal Cells, Receptors, Growth Factor, U937 Cells, Receptor Protein-Tyrosine Kinases, Vascular Endothelial Growth Factor Receptor-3, Vascular Endothelial Growth Factor C, Vascular Endothelial Growth Factor D

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