Activation of the VEGFC/VEGFR3 Pathway Induces Tumor Immune Escape in Colorectal Cancer

Francesco Ungaro, Vincenzo Arena, Adriano Spinelli, Marinella Mazzone, Silvio Danese, Carlotta Tacconi, Federica Ungaro, Carmen Correale, Luca Massimino, Michael Detmar, Antonino Spinelli, Michele Carvello, Massimiliano Mazzone, Ana I. Oliveira, Federica Rubbino, Valentina Garlatti, Salvatore Spano, Enrico Lugli, Federico S. Colombo, Alberto MalesciLaurent Peyrin-Biroulet, Stefania Vetrano, Silvia D'Alessio

Risultato della ricerca: Contributo in rivistaArticolo in rivista

16 Citazioni (Scopus)


Colorectal cancer is a major cause of cancer-related death in Western countries and is associated with increased numbers of lymphatic vessels (LV) and tumor-associated macrophages (TAM). The VEGFC/VEGFR3 pathway is regarded as the principal inducer of lymphangiogenesis and it contributes to metastases; however, no data are available regarding its role during primary colorectal cancer development. We found that both VEGFC and VEGFR3 were upregulated in human non-metastatic colorectal cancer, with VEGFR3 expressed on both LVs and TAMs. With the use of three different preclinical models of colorectal cancer, we also discovered that the VEGFC/VEGFR3 axis can shape both lymphatic endothelial cells and TAMs to synergistically inhibit antitumor immunity and promote primary colorectal cancer growth. Therefore, VEGFR3-directed therapy could be envisioned for the treatment of nonmetastatic colorectal cancer.Significance: The prolymphangiogenic factor VEGFC is abundant in colorectal cancer and activates VEGFR3 present on cancer-associated macrophages and lymphatic vessels; activation of VEGFR3 signaling fosters cancer immune escape, resulting in enhanced tumor growth.
Lingua originaleEnglish
pagine (da-a)4196-4210
Numero di pagine15
RivistaCancer Research
Stato di pubblicazionePubblicato - 2019


  • Animals
  • Cancer Vaccines
  • Colorectal Neoplasms
  • Female
  • Humans
  • Lymphatic Vessels
  • Macrophages
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms, Experimental
  • Tumor Escape
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor Receptor-3


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