Acidic microenvironments induce lymphangiogenesis and IL-8 production via TRPV1 activation in human lymphatic endothelial cells.
Local acidosis is one of the characteristic features of the cancer microenvironment. Many reports indicate that acidosis accelerates the proliferation and invasiveness of cancer cells. However, whether acidic conditions affect lymphatic metastasis is currently unknown. In the present study, we focused on the effects of acidosis on lymphatic endothelial cells (LECs) to assess the relationship between acidic microenvironments and lymph node metastasis. We demonstrated that normal human LECs express various acid receptors by immunohistochemistry and reverse transcriptase-polymerase chain reaction (PCR). Acidic stimulation with low pH medium induced morphological changes in LECs to a spindle shape, and significantly promoted cellular growth and tube formation. Moreover, real-time PCR revealed that acidic conditions increased the mRNA expression of interleukin (IL)-8. Acidic stimulation increased IL-8 production in LECs, whereas a selective transient receptor potential vanilloid subtype 1 (TRPV1) antagonist, 5'-iodoresiniferatoxin, decreased IL-8 production. IL-8 accelerated the proliferation of LECs, and inhibition of IL-8 diminished tube formation and cell migration. In addition, phosphorylation of nuclear factor (NF)-κB was induced by acidic conditions, and inhibition of NF-κB activation reduced acid-induced IL-8 expression. These results suggest that acidic microenvironments in tumors induce lymphangiogenesis via TRPV1 activation in LECs, which in turn may promote lymphatic metastasis.
Department of Pathology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan. Electronic address: n-masako@wakayama-med.ac.jp.
Masako
M
Nakanishi
Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan; Department of Oral and Maxillofacial Surgery, Seichokai Hannan Municipal Hospital, Hannan, Osaka 599-0202, Japan.
Yoshihiro
Y
Morita
Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan.
Kenji
K
Hata
Department of Pathology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan. Electronic address: ymuragak@wakayama-med.ac.jp.
Yasuteru
Y
Muragaki
D000143:Acids / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D060833:Cellular Microenvironment / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D042583:Lymphangiogenesis / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D053700:Receptors, Interleukin-8 / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism*
D000143:Acids; C508606:CXCL8 protein, human; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D053700:Receptors, Interleukin-8; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human
Acidic microenvironment; IL-8; Lymphatic endothelial cells; TRPV1