Multifunctional interleukin-1beta promotes metastasis of human lung cancer cells in SCID mice via enhanced expression of adhesion-, invasion- and angiogenesis-related molecules.
We examined whether interleukin-1 (IL-1), a multifunctional proinflammatory cytokine, progresses or regresses metastasis of lung cancer. Exogenous IL-1beta enhanced expression of various cytokines (IL-6, IL-8, and vascular endothelial growth factor (VEGF)) and intracellular adhesion molecule-1 (ICAM-1) by A549, PC14, RERF-LC-AI, and SBC-3 cells expressing IL-1 receptors. A549 cells transduced with human IL-1beta-gene with the growth-hormone signaling-peptide sequence (A549/IL-1beta) secreted a large amount of IL-1beta protein. Overexpression of IL-1beta resulted in augmentation of expression of the cytokines, ICAM-1, and matrix metalloproteinase-2 (MMP-2). A549/IL-1beta cells intravenously inoculated into severe combined immunodeficiency (SCID) mice distributed to the lung more efficiently and developed lung metastasis much more rapidly than did control A549 cells. Treatment of SCID mice with anti-IL-1beta antibody inhibited formation of lung metastasis by A549/IL-1beta cells. Moreover, A549/IL-1beta cells inoculated in the subcutis grew more rapidly, without necrosis, than did control A549 cells, which produced smaller tumors with central necrosis, suggesting involvement of angiogenesis in addition to enhanced binding in the high metastatic potential of A549/IL-1beta cells. Histological analyses showed that more host-cell infiltration, fewer apoptotic cells, more vascularization, and higher MMP activity were observed in tumors derived from A549/IL-1beta cells, compared with tumors derived from control A549 cells. These findings suggest that IL-1beta facilitates metastasis of lung cancer via promoting multiple events, including adhesion, invasion and angiogenesis.
Yano
Seiji
S
Department of Internal Medicine and Molecular Therapeutics, University of Tokushima School of Medicine.
Nokihara
Hiroshi
H
Yamamoto
Akihiko
A
Goto
Hisatsugu
H
Ogawa
Hirohisa
H
Kanematsu
Takanori
T
Miki
Toyokazu
T
Uehara
Hisanori
H
Saijo
Yasuo
Y
Nukiwa
Toshihiro
T
Sone
Saburo
S
D043925:Angiogenesis Inducing Agents; D000818:Animals; D001483:Base Sequence; D001835:Body Weight; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology*; D008545:Melanoma; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D009929:Organ Size; D011994:Recombinant Proteins / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D043925:Angiogenesis Inducing Agents; D015815:Cell Adhesion Molecules; D017931:DNA Primers; D007375:Interleukin-1; D011994:Recombinant Proteins