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

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

Research output: Contribution to journalArticlepeer-review


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 nonmetastatic 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.

Original languageEnglish
Pages (from-to)4196-4210
Number of pages15
JournalCancer Research
Issue number16
Publication statusPublished - Aug 15 2019


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