Abstract 1968: Tumor Necrosis Factor-Α Upregulation of CCR7 Induces Prostate Cancer Cell Migration in Lymphatic Metastasis

Objectives: Prostate cancer (PCa) with lymph node (LN) metastasis has a poor patient prognosis. Broader understanding of the causes of LN metastasis and disease dissemination will assist in developing novel treatments. C-C chemokine receptor 7 (CCR7) and its ligand CCL21 are abundantly expressed in LN metastasis and during PCa progression. Tumor necrosis factor-alpha (TNF-α) is present at low levels within the tumor microenvironment. TNF-α and C-C chemokines interact in tumorigenesis. The study aim was to determine whether TNF-α might promote PCa dissemination from metastatic LN by activating the CCL21/CCR7 axis.Methods: TNF-α and CCR7 mRNA and protein expression were assayed in PC-3, DU145, and LNCaP, and human PCa cells by reverse transcription-polymerase chain reaction and western blotting. Promotion of transmembrane migration by TNF-α was assayed in CCL21-pretreated PCa cells. Phosphorylation of several mitogen-activated protein kinases expressed downstream of TNF-α was assayed.Results: Low-dose TNF-α induced CCR7 expression in PCa cells and promoted migration of CCL21-pretreated PCa cells. TNF-α-mediated CCR7 upregulation via the ERK signaling pathway. p38 was a downstream target of CCL21/CCR7 signaling and a key factor in the promotion of PCa cell migration.Conclusions: This is the first demonstration of the influence of the TNF-α-CCL21/CCR7 axis on PCa cell migration in the microenvironment of LN metastasis. Because it is activated in PCa LN metastasis, the CCL21/CCR7 axis might be a novel therapeutic target and biomarker of PCa.Citation Format: Tomoyuki Makino, Kouji Izumi, Aerken Maolake, Ariunbold Natsagdorj, Hiroaki Iwamoto, Suguru Kadomoto, Renato Naito, Kaoru Hiratsuka, Yoshifumi Kadono, Atsushi Mizokami. Tumor necrosis factor-α upregulation of CCR7 induces prostate cancer cell migration in lymphatic metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1968.