Tumoricidal Activity of Endothelial Cells

Carretero, Julián; Obrador, Elena; Esteve, Juan M.; Ortega, Ángel; Pellicer, José A.; Sempere, Francisco Vera; Estrela, José M.

doi:10.1074/jbc.m101148200

Cited by 48 publications

(63 citation statements)

References 59 publications

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“…We have shown that GSH protects circulating B16 cells against hepatic sinusoidal endothelium-induced cytotoxicity (11). By comparing B16 cells cultured to low versus high density, which have different GSH contents and different metastatic activities, we found that NO was particularly tumoricidal in the presence of H 2 O 2 (a mechanism involving formation of potent oxidants, probably ⅐ OH and -OONO, via a trace metal-dependent process) (10). A high percentage of tumor cells with high GSH content survived the combined nitrosative and oxidative attack and probably represent the main task force in the metastatic invasion (12).…”

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confidence: 99%

“…The B16-F10 line showed the highest metastatic activity and became a classical model widely used in metastasis research. Recent results identified the existence of a natural defense mechanism against cancer metastasis whereby the arrest of tumor cells in the liver induces endogenous NO and H 2 O 2 release, leading to sinusoidal tumor cell killing and reduced hepatic metastasis formation (3,10). We have shown that GSH protects circulating B16 cells against hepatic sinusoidal endothelium-induced cytotoxicity (11).…”

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Intertissue Flow of Glutathione (GSH) as a Tumor Growth-promoting Mechanism

Obrador

Benlloch

Pellicer

et al. 2011

Journal of Biological Chemistry

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B16 melanoma F10 (B16-F10) cells with high glutathione (GSH) content show high metastatic activity in vivo.An intertissue flow of GSH, where the liver is the main reservoir, can increase GSH content in metastatic cells and promote their growth. We have studied here possible tumor-derived molecular signals that could activate GSH release from hepatocytes. GSH efflux increases in hepatocytes isolated from mice bearing liver or lung metastases, thus suggesting a systemic mechanism. Fractionation of serum-free conditioned medium from cultured B16-F10 cells and monoclonal antibody-induced neutralization techniques facilitated identification of interleukin (IL)-6 as a tumor-derived molecule promoting GSH efflux in hepatocytes. IL-6 activates GSH release through a methionine-sensitive/organic anion transporter polypeptide 1-and multidrug resistance protein 1-independent channel located on the sinusoidal site of hepatocytes. Specific siRNAs were used to knock down key factors in the main signaling pathways activated by IL-6, which revealed a STAT3-dependent mechanism. Our results show that IL-6 (mainly of tumor origin in B16-F10-bearing mice) may facilitate GSH release from hepatocytes and its interorgan transport to metastatic growing foci.Glutathione (L-␥-glutamyl-L-cysteinyl-glycine; GSH), 2 the most prevalent non-protein thiol in mammalian cells, is involved in many cellular functions (1, 2). GSH in cancer cells is particularly relevant in the regulation of 1) carcinogenic mechanisms; 2) sensitivity against cytotoxic drugs, ionizing radiation, and some cytokines; 3) DNA synthesis; and 4) cell proliferation and death (3,4).Early studies on the organ distribution of metastatic cells showed that less than 0.1% of circulating cells survive to cause secondary metastatic growth (5). The liver is a common site for metastasis development, and, as previously shown, a high percentage of circulating cancer cells are mechanically trapped in the liver microvasculature (6). Interaction of metastatic cancer cells with the hepatic sinusoidal endothelium and Kupffer cells activates local release of proinflammatory cytokines, which then may act as molecular signals promoting cancer cell adhesion, invasion, and proliferation (3, 7). Direct in vitro lysis of metastatic tumor cells by cytokine-activated murine vascular endothelial cells has also been shown (8).From the original subcutaneous B16 melanoma tumor, spontaneously originated in C57BL/6J mice, and using sequential in vitro-in vivo growing cycles, I. J. Fidler (9) obtained 10 different cell variants (F1-F10) with increasing metastatic potentials. The B16-F10 line showed the highest metastatic activity and became a classical model widely used in metastasis research. Recent results identified the existence of a natural defense mechanism against cancer metastasis whereby the arrest of tumor cells in the liver induces endogenous NO and H 2 O 2 release, leading to sinusoidal tumor cell killing and reduced hepatic metastasis formation (3, 10). We have shown that GSH protects circulati...

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confidence: 99%

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confidence: 99%

Intertissue Flow of Glutathione (GSH) as a Tumor Growth-promoting Mechanism

Obrador

Benlloch

Pellicer

et al. 2011

Journal of Biological Chemistry

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“…In fact, multidrug and/or radiation resistance, which are characteristic features of malignant tumors, frequently associate with high GSH content in the cancer cells (7). B16M-F10 cell resistance to the HSE-induced cytotoxicity is highly dependent on GSH and GSH peroxidase (4). However, B16M-F10 cells cultured to low density (LD), with high GSH content, were more resistant to NO and H 2 O 2 than B16M cultured to high density (with ϳ25% of the GSH content found in LD cells) (4).…”

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confidence: 99%

“…The B16 melanoma (B16M) 1 is a model widely used to study metastatic spread and tissue invasion (6). The liver is a common site for metastasis development, and we recently reported that GSH (␥-glutamylcysteinyl-glycine) protects B16M-F10 cells (with high metastatic potential) against nitrosative and oxidative stress in the hepatic microvasculature (4,6). In fact, multidrug and/or radiation resistance, which are characteristic features of malignant tumors, frequently associate with high GSH content in the cancer cells (7).…”

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“…This failure, termed "metastatic inefficiency" (1), is due to mechanical trauma produced by blood flow (2), the inability of cancer cells to withstand deformation (3), cytotoxicity of locally released reactive oxygen and nitrogen species (4), and the lytic action of lymphocytes and macrophages (5). The B16 melanoma (B16M) 1 is a model widely used to study metastatic spread and tissue invasion (6).…”

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Down-regulation of Glutathione and Bcl-2 Synthesis in Mouse B16 Melanoma Cells Avoids Their Survival during Interaction with the Vascular Endothelium

Ortega

Ferrer

Carretero

et al. 2003

Journal of Biological Chemistry

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B16 melanoma (B16M) cells with high GSH contentshow high metastatic activity. However, the molecular mechanisms linking GSH to metastatic cell survival are unclear. The possible relationship between GSH and the ability of Bcl-2 to prevent cell death was studied in B16M cells with high (F10) and low (F1) metastatic potential. Analysis of a Bcl-2 family of genes revealed that B16M-F10 cells, as compared with B16M-F1 cells, overexpressed preferentially Bcl-2 (ϳ5.7-fold). Hepatic sinusoidal endothelium-induced B16M-F10 cytotoxicity in vitro increased from ϳ19% (controls) to ϳ97% in GSH-depleted B16M-F10 cells treated with an antisense Bcl-2 oligodeoxynucleotide (Bcl-2-AS). L-Buthionine (S,R)-sulfoximine-induced GSH depletion or Bcl-2-AS decreased the metastatic growth of B16M-F10 cells in the liver. However, the combination of L-buthionine (S,R)-sulfoximine and Bcl-2-AS abolished metastatic invasion. Bcl-2-overexpressing B16M-F1/Tet-Bcl-2 and B16M-F10/TetBcl-2 cells, as compared with controls, showed an increase in GSH content, no change in the rate of GSH synthesis, and a decrease in GSH efflux. Thus, Bcl-2 overexpression may increase metastatic cell resistance against oxidative/nitrosative stress by inhibiting release of GSH. In addition, Bcl-2 availability regulates the mitochondrial GSH (mtGSH)-dependent opening of the permeability transition pore complex. Death in B16M-F10 cells was sharply activated at mtGSH levels below 30% of controls values. However, this critical threshold increased to ϳ60% of control values in Bcl-2-AS-treated B16M-F10 cells. GSH ester-induced replenishment of mtGSH levels (even under conditions of cytosolic GSH depletion) prevented cell death. Our results indicate that survival of B16M cells with high metastatic potential can be challenged by inhibiting their GSH and Bcl-2 synthesis.The majority of metastatic cells entering microvascular beds are killed within the first hours and do not generate colonies. This failure, termed "metastatic inefficiency" (1), is due to mechanical trauma produced by blood flow (2), the inability of cancer cells to withstand deformation (3), cytotoxicity of locally released reactive oxygen and nitrogen species (4), and the lytic action of lymphocytes and macrophages (5). The B16 melanoma (B16M) 1 is a model widely used to study metastatic spread and tissue invasion (6). The liver is a common site for metastasis development, and we recently reported that GSH (␥-glutamylcysteinyl-glycine) protects B16M-F10 cells (with high metastatic potential) against nitrosative and oxidative stress in the hepatic microvasculature (4, 6). In fact, multidrug and/or radiation resistance, which are characteristic features of malignant tumors, frequently associate with high GSH content in the cancer cells (7). B16M-F10 cell resistance to the HSE-induced cytotoxicity is highly dependent on GSH and GSH peroxidase (4). However, B16M-F10 cells cultured to low density (LD), with high GSH content, were more resistant to NO and H 2 O 2 than B16M cultured to high density (with ϳ25% of th...

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