Metastatic Inefficiency

Weiss, Leonard

doi:10.1016/s0065-230x(08)60811-8

Cited by 421 publications

(238 citation statements)

References 173 publications

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“…Fig. 3 shows the mean percentages of observed cells that were in contact with or close to (within [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] ,um) arterioles, venules, or lymphatics at 24 h p.i. The percentages of cells at any particular category of vessel were not significantly different for the three cell types (0.32 < P < 0.83; Kruskal-Wallis analysis).…”

Section: Resultsmentioning

confidence: 99%

“…Mortality results from the direct anatomical and physiological effects of metastases on other organ systems (e.g., brain and liver) or sometimes from complications associated with treatment (1, 2). The metastatic process is thought to include the following steps: detachment of cancer cells from the primary tumor, invasion of surrounding tissue, entrance into blood or lymphatic vessels (intravasation), transport to new sites, escape from the microvasculature (extravasation), invasion of target tissue, and growth of metastatic tumors (3)(4)(5). Cancer cells also must evade the immune system throughout the metastatic process.…”

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confidence: 99%

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Independence of metastatic ability and extravasation: metastatic ras-transformed and control fibroblasts extravasate equally well.

Koop

Schmidt²,

Macdonald³

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Escape of cancer cells from the circulation (extravasation) is thought to be a major rate-limiting step in metastasis, with few cells being able to extravasate. Furthermore, highly metastatic cells are believed to extravasate more readily than poorly metastatic cells. We assessed in vivo the extravasation ability of highly metastatic ras-transformed NIH 3T3 cells (PAP2) versus control nontumorigenic nontransformed NIH 3T3 cells and primary mouse embryo fibroblasts. Fluorescently labeled cells were injected intravenously into chicken embryo chorioallantoic membrane and analyzed by intravital videomicroscopy. The chorioallantoic membrane is an appropriate model for studying extravasation, since, at the embryonic stage used, the microvasculature exhibits a continuous basement membrane and adult permeability properties. The kinetics of extravasation were assessed by determining whether individual cells (n = 1481) were intravascular, extravascular, or in the process of extravasation, at 3, 6, and 24 h after injection. Contrary to expectations, our results showed that all three cell types extravasated with the same kinetics. By 24 h after injection >89% of observed cells had completed extravasation from the capillary plexus. After extravasation, individual fibroblasts of all cell types demonstrated preferential migration within the mesenchymal layer toward arterioles, not to venules or lymphatics. Thus in this model and for these cells, extravasation is independent of metastatic ability. This suggests that the ability to extravasate in vivo is not necessarily predictive of subsequent metastasis formation, and that postextravasation events may be key determinants in metastasis.Metastasis, the spread of cancer cells from a primary tumor to distant sites, is the major cause of death from cancer. Mortality results from the direct anatomical and physiological effects of metastases on other organ systems (e.g., brain and liver) or sometimes from complications associated with treatment (1, 2). The metastatic process is thought to include the following steps: detachment of cancer cells from the primary tumor, invasion of surrounding tissue, entrance into blood or lymphatic vessels (intravasation), transport to new sites, escape from the microvasculature (extravasation), invasion of target tissue, and growth of metastatic tumors (3-5). Cancer cells also must evade the immune system throughout the metastatic process.Extravasation is thought to be a major rate-limiting step in metastasis, with only a few cancer cells capable of degrading the basement membrane and extracellular matrix to escape from microvessels. Moreover, poorly metastatic cells are believed to extravasate less readily than highly metastatic cells (4, 6-8). Our recent results from intravital videomicroscopy have raised questions about these views. Using in vivo assays with a variety of cell types (including melanoma and mammary carcinoma) in chicken embryo chorioallantoic membrane (CAM) and mouse liver, we found that the majority of observed cancer cells...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Independence of metastatic ability and extravasation: metastatic ras-transformed and control fibroblasts extravasate equally well.

Koop

Schmidt²,

Macdonald³

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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“…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).…”

mentioning

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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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%

“…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).…”

mentioning

confidence: 99%

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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Metastatic Inefficiency

Cited by 421 publications

References 173 publications

Independence of metastatic ability and extravasation: metastatic ras-transformed and control fibroblasts extravasate equally well.

Independence of metastatic ability and extravasation: metastatic ras-transformed and control fibroblasts extravasate equally well.

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

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

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