Tumor cell-derived 12(S)-hydroxyeicosatetraenoic acid induces microvascular endothelial cell retraction

Kenneth V. Honn, Dean G. Tang, Irma Grossi, Zofia M. Duniec, J. Tímár, Colette Renaud, Marie Leithauser, Ian Blair, Carl R. Johnson, Clement A. Diglio, Victoria A. Kimler, John D. Taylor, Lawrence J. Marnett

Research output: Article

105 Citations (Scopus)

Abstract

Our previous work demonstrated that the 12-lipoxygenase metabolite of arachidonic acid, 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] induced a nondestructive and reversible retraction of cultured endothelial cells. In the current study we tested the hypothesis that tumor cells produce 12(S)- HETE during their interactions with endothelial cells which in turn induces endothelial cell retraction. Coincubation of Lewis lung carcinoma cells or elutriated B16 amelanotic melanoma (B16a) cells but not 3T3 fibroblasts with microvascular endothelial cells (CD3) resulted in a time- and concentration- dependent retraction of the CD3 monolayers as revealed by quantitative binding assays and phase contrast microscopy. Lewis lung carcinoma cell- induced endothelial cell retraction was blocked by specific lipoxygenase inhibitors but not by cyclooxygenase inhibitors, suggesting the involvement of a lipoxygenase metabolite(s). Radioimmunoassay and high-performance liquid chromatography analysis of tumor cell extracts identified 12(S)-HETE as the major lipoxygenase metabolite of arachidonic acid and tumor cell generation of 12(S)-HETE was specifically blocked by a select 12-lipoxygenase inhibitor N-benzyl-N-hydroxy-5-phenyl-pentamide. The identity and stereochemistry of tumor cell-derived 12-HETE was substantiated by gas chromatography-mass spectrometry analysis and chiral phase high-performance liquid chromatography, respectively. Lewis lung carcinoma cell adhesion to CD3 monolayers was accompanied by an enhanced 12(S)-HETE biosynthesis by tumor cells, which paralleled the tumor cell-induced endothelial cell retraction in a cell number-dependent manner. Pretreatment of tumor cells with N-benzyl-N- hydroxy-5-phenylpentamide inhibited both increased 12-(S)-HETE biosynthesis and tumor cell-induced endothelial cell retraction. Highly metastatic variants of elutriated B16a cells which had been shown to produce large quantities of 12(S)-HETE induced significant CD3 cell retraction, while low metastatic subpopulations of B16a cells which synthesized no or little 12(S)- HETE did not induce endothelial cell retraction. These results suggest that 12(S)-HETE synthesis during tumor cell-endothelial cell interactions may represent a key contributory factor in cancer metastasis.

Original languageEnglish
Pages (from-to)565-574
Number of pages10
JournalCancer Research
Volume54
Issue number2
Publication statusPublished - jan. 15 1994

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12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
Endothelial Cells
Neoplasms
Amelanotic Melanoma
Lewis Lung Carcinoma
Experimental Melanomas
Lipoxygenase Inhibitors
High Pressure Liquid Chromatography
Arachidonate Lipoxygenases
Arachidonate 12-Lipoxygenase
Phase-Contrast Microscopy
3T3 Cells
Lipoxygenase
Cyclooxygenase Inhibitors
Cell Extracts
Arachidonic Acid
Cell Adhesion

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Honn, K. V., Tang, D. G., Grossi, I., Duniec, Z. M., Tímár, J., Renaud, C., ... Marnett, L. J. (1994). Tumor cell-derived 12(S)-hydroxyeicosatetraenoic acid induces microvascular endothelial cell retraction. Cancer Research, 54(2), 565-574.

Tumor cell-derived 12(S)-hydroxyeicosatetraenoic acid induces microvascular endothelial cell retraction. / Honn, Kenneth V.; Tang, Dean G.; Grossi, Irma; Duniec, Zofia M.; Tímár, J.; Renaud, Colette; Leithauser, Marie; Blair, Ian; Johnson, Carl R.; Diglio, Clement A.; Kimler, Victoria A.; Taylor, John D.; Marnett, Lawrence J.

In: Cancer Research, Vol. 54, No. 2, 15.01.1994, p. 565-574.

Research output: Article

Honn, KV, Tang, DG, Grossi, I, Duniec, ZM, Tímár, J, Renaud, C, Leithauser, M, Blair, I, Johnson, CR, Diglio, CA, Kimler, VA, Taylor, JD & Marnett, LJ 1994, 'Tumor cell-derived 12(S)-hydroxyeicosatetraenoic acid induces microvascular endothelial cell retraction', Cancer Research, vol. 54, no. 2, pp. 565-574.
Honn KV, Tang DG, Grossi I, Duniec ZM, Tímár J, Renaud C et al. Tumor cell-derived 12(S)-hydroxyeicosatetraenoic acid induces microvascular endothelial cell retraction. Cancer Research. 1994 jan. 15;54(2):565-574.
Honn, Kenneth V. ; Tang, Dean G. ; Grossi, Irma ; Duniec, Zofia M. ; Tímár, J. ; Renaud, Colette ; Leithauser, Marie ; Blair, Ian ; Johnson, Carl R. ; Diglio, Clement A. ; Kimler, Victoria A. ; Taylor, John D. ; Marnett, Lawrence J. / Tumor cell-derived 12(S)-hydroxyeicosatetraenoic acid induces microvascular endothelial cell retraction. In: Cancer Research. 1994 ; Vol. 54, No. 2. pp. 565-574.
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abstract = "Our previous work demonstrated that the 12-lipoxygenase metabolite of arachidonic acid, 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] induced a nondestructive and reversible retraction of cultured endothelial cells. In the current study we tested the hypothesis that tumor cells produce 12(S)- HETE during their interactions with endothelial cells which in turn induces endothelial cell retraction. Coincubation of Lewis lung carcinoma cells or elutriated B16 amelanotic melanoma (B16a) cells but not 3T3 fibroblasts with microvascular endothelial cells (CD3) resulted in a time- and concentration- dependent retraction of the CD3 monolayers as revealed by quantitative binding assays and phase contrast microscopy. Lewis lung carcinoma cell- induced endothelial cell retraction was blocked by specific lipoxygenase inhibitors but not by cyclooxygenase inhibitors, suggesting the involvement of a lipoxygenase metabolite(s). Radioimmunoassay and high-performance liquid chromatography analysis of tumor cell extracts identified 12(S)-HETE as the major lipoxygenase metabolite of arachidonic acid and tumor cell generation of 12(S)-HETE was specifically blocked by a select 12-lipoxygenase inhibitor N-benzyl-N-hydroxy-5-phenyl-pentamide. The identity and stereochemistry of tumor cell-derived 12-HETE was substantiated by gas chromatography-mass spectrometry analysis and chiral phase high-performance liquid chromatography, respectively. Lewis lung carcinoma cell adhesion to CD3 monolayers was accompanied by an enhanced 12(S)-HETE biosynthesis by tumor cells, which paralleled the tumor cell-induced endothelial cell retraction in a cell number-dependent manner. Pretreatment of tumor cells with N-benzyl-N- hydroxy-5-phenylpentamide inhibited both increased 12-(S)-HETE biosynthesis and tumor cell-induced endothelial cell retraction. Highly metastatic variants of elutriated B16a cells which had been shown to produce large quantities of 12(S)-HETE induced significant CD3 cell retraction, while low metastatic subpopulations of B16a cells which synthesized no or little 12(S)- HETE did not induce endothelial cell retraction. These results suggest that 12(S)-HETE synthesis during tumor cell-endothelial cell interactions may represent a key contributory factor in cancer metastasis.",
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