Regulation Of B16F1 melanoma cell metastasis by inducible functions of the hepatic microvasculature

Wang, H.H.; McIntosh, Alan R.; Hasinoff, Brian B.; MacNeil, Brian; Rector, Edward S.; Nance, Dwight M.; Orr, F. W.

doi:10.1016/s0959-8049(02)00039-4

Cited by 20 publications

(32 citation statements)

References 15 publications

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“…Previous experiments to stimulate iNOS in livers without cirrhosis have shown direct relationship between the expression of iNOS and increased tumor cell cytotoxicity at the site of iNOS expression. 22 We found a 7-to-9-fold increase in metastasis in livers with cirrhosis compared to controls. Because the increase was several orders of magnitude over the changes observed in the measured parameters (the number of arrested cells, NO release, tumor cell apoptosis, tumor growth) it seems likely that the endpoint differences are dependent upon the additive consequences of multiple variables rather than one effect.…”

Section: Discussionmentioning

confidence: 56%

“…19 These two adhesion molecules have been demonstrated to interact with counterreceptors on the melanoma cells. 8,22 To determine the impact of individual adhesion molecules in the cirrhotic models would require blocking them or using mice that are defective in their expression. However, it is unlikely that adhesive interactions between B16 melanoma cells and activated endothelium are mediated exclusively by ICAM-1 and VCAM-1 because there is considerable redundancy in the means by which these cancer cells can bind to endothelium and other adhesion molecules, e.g., ␣v␤3 and E-Selectin can also contribute to adhesion of these cells to endothelium in vitro or in vivo.…”

Section: Discussionmentioning

confidence: 99%

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Impact of cirrhosis on the development of experimental hepatic metastases by B16F1 melanoma cells in C57BL/6 mice

et al. 2004

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Metastases rarely occur in human livers with cirrhosis in clinical studies. We postulated that this phenomenon would also occur in experimental cirrhosis. Cirrhosis was established in C57BL/6 mice by carbon tetrachloride (CCl 4 ) gastrogavage. B16F1 melanoma cells were injected into the mesenteric vein to induce hepatic metastases. Contrary to our postulate, there was greater than 4-fold increase in metastasis in animals with cirrhosis compared to controls. Intravital videomicroscopy showed that the hepatic sinusoids were narrower and more tumor cells were retained in the terminal portal vein ( T he liver is a common site of metastatic tumor growth. Interestingly, the liver with cirrhosis has been reported to inhibit metastasis. 1 In clinical studies, colorectal cancers rarely metastasize to livers with cirrhosis. 2,3 Autopsy studies have shown that the rate of metastasis to such livers is lower than that to normal livers. 4,5 However, the mechanisms responsible for this result are not clear. Vanbockrijck and Kloppel suggested that the lower incidence of metastasis is due to a shorter life expectancy of patients with cirrhosis. 6 Seymour and Charnley considered that venovenous shunting in cirrhosis may prevent tumor cells from reaching the liver, and that changes in the architecture of cirrhotic sinusoids may reduce metastasis. 5 The activation of Kupffer cells in cirrhosis may also inhibit the formation of hepatic metastases. 7 Based on previous studies, the fate of metastatic cells in the liver is determined by the expression of hepatic microvasculature adhesion molecules and the release of endothelial-derived nitric oxide (NO). Specifically, the expression of inducible vascular adhesion molecules can cause tumor cell arrest in terminal portal vein (TPV) and increase metastasis. 8 Alternatively, tumor cell arrest in hepatic sinusoids can induce endothelial and hepatic NO release, causing tumor cell apoptosis and inhibiting metastasis. 9,10 We predicted these mechanisms would apply in a cirrhotic model. To examine this possibility, we established cirrhosis in C57BL/6 mice, using carbon tetrachloride (CCl 4 ) gastrogavage. Liver metastasis was induced by injecting B16F1 melanoma cells into the portal venous system. Surprisingly, we found a significant increase in metastasis of B16F1 melanoma cells in animals with cirrhosis. Our studies demonstrated that alterations

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Impact of cirrhosis on the development of experimental hepatic metastases by B16F1 melanoma cells in C57BL/6 mice

et al. 2004

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“…There is a large body of evidence that generation of NO, mediated by inducible NOS, can have cytotoxic effects on neoplastic cells and inhibit their potential for growth in vivo. [15][16][17][18][19][20][21][22][23][24] In addition to this mechanism, which generates NO throughout a sustained period of time, 24 we have shown here that tumor cell arrest can trigger the immediate release of NO via eNOS-dependent mechanisms and subsequently trigger apoptosis in these cells. Previous experiments in the liver have inferred a role for eNOS as an effector of B16 melanoma cytotoxicity on the basis that NO release occurred immediately (Ͻ5 minutes) after tumor cell arrest in the hepatic sinusoid.…”

Section: Discussionmentioning

confidence: 99%

Arrest of B16 Melanoma Cells in the Mouse Pulmonary Microcirculation Induces Endothelial Nitric Oxide Synthase-Dependent Nitric Oxide Release that Is Cytotoxic to the Tumor Cells

Qiu

Orr

Jensen

et al. 2003

The American Journal of Pathology

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Metastatic cancer cells seed the lung via blood vessels. Because endothelial cells generate nitric oxide (NO) in response to shear stress, we postulated that the arrest of cancer cells in the pulmonary microcirculation causes the release of NO in the lung. After intravenous injection of B16F1 melanoma cells, pulmonary NO increased sevenfold throughout 20 minutes and approached basal levels by 4 hours. NO induction was blocked by N G -nitro-L-arginine methyl ester (L-NAME) and was not observed in endothelial nitric oxide synthase (eNOS)-deficient mice. NO production, visualized ex vivo with the fluorescent NO probe diaminofluorescein diacetate, increased rapidly at the site of tumor cell arrest, and continued to increase throughout 20 minutes. Arrested tumor cells underwent apoptosis with apoptotic counts more than threefold over baseline at 8 and 48 hours. Neither the NO signals nor increased apoptosis were seen in eNOS knockout mice or mice pretreated with L-NAME. At 48 hours, 83% of the arrested cells had cleared from the lungs of wild-type mice but only ϳ55% of the cells cleared from eNOS-deficient or L-NAME pretreated mice. eNOS knockout and L-NAME-treated mice had twofold to fivefold more metastases than wild-type mice, measured by the number of surface nodules or by histomorphometry. We conclude that tumor cell arrest in the pulmonary microcirculation induces eNOS-dependent NO release by the endothelium adjacent to the arrested tumor cells and that NO is one factor that causes tumor cell apoptosis, clearance from the lung, and inhibition of metastasis. In the lung, metastatic neoplasms are the most common malignant tumors. Their formation usually involves hematogenous seeding of metastatic cancer cells into the lung from remote primary tumors. Interactions between intravascular cancer cells and the endothelium are important determinants of metastatic outcome. 1,2 For example, the expression of constitutive and inducible microvascular adhesion molecules, and the release of reactive oxygen species (NO, O 2 Ϫ , and H 2 O 2 ) by endothelial cells or cancer cells can regulate the mechanisms that govern the metastatic process, including cancer cell adhesion and arrest, 3 the production of endothelial matrix metalloproteinases, 4 and cancer cell apoptosis. 5 Evidence from in vitro and in vivo studies has shown that reactive oxygen and nitrogen species can be cytotoxic to neoplastic cells 6 -9 and reduced their adhesion to postcapillary venules. 10 In vivo, we have recently demonstrated that the arrest of intravascular B16F1 melanoma cells in the liver induces the rapid local release of nitric oxide (NO) that causes apoptosis of the melanoma cells and inhibits their subsequent development into hepatic metastases. 5 Because pulmonary endothelial cells generate NO in response to shear stress, 11 we have postulated that there is a comparable cytotoxic mechanism in the lung.Here we provide data showing that the arrest of B16F1 melanoma cells in the pulmonary circulation of wild-type C57B1/6 mice (WT mice) induces the ...

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“…In other studies, it has been shown that the i.p. administration of recombinant TNF-a in mice led to a significant increase in the number of liver metastases, in several models including metastatic lymphoma (16) and solid tumors (17)(18)(19). This effect may be mediated through several mechanisms including TNF-a-induced tumor cell motility and increased production of metalloproteinases, resulting in enhanced invasion and angiogenesis (13,20).…”

Section: Introductionmentioning

confidence: 99%

The Secretory Leukocyte Protease Inhibitor Is a Type 1 Insulin-Like Growth Factor Receptor–Regulated Protein that Protects against Liver Metastasis by Attenuating the Host Proinflammatory Response

Wang

Thuraisingam²,

Fallavollita

et al. 2006

Cancer Research

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The secretory leukocyte protease inhibitor (SLPI) can attenuate the host proinflammatory response by blocking nuclear factor KB (NF-KB)-mediated tumor necrosis factor A (TNF-A) production in macrophages. We have previously shown that highly metastatic human and mouse carcinoma cells, on their entry into the hepatic microcirculation, trigger a rapid host proinflammatory response by inducing TNF-A production in resident Kupffer cells. Using GeneChip microarray analysis, we found that in mouse Lewis lung carcinoma subclones, SLPI expression was inversely correlated with tumor cell ability to induce a proinflammatory response and metastasize to the liver and with type 1 insulin-like growth factor receptor expression levels. To establish a causal relationship between SLPI expression and the metastatic phenotype, we generated, by transfection, multiple clones of the highly metastatic subline (H-59) that overexpress SLPI. We show here that the ability of these cells to elicit a host proinflammatory response in the liver was markedly decreased, as evidenced by reduced TNF-A production and vascular E-selectin expression, relative to controls. Moreover, these cells formed significantly fewer hepatic metastases (up to 80% reduction) as compared with mock-transfected controls. Our findings show that SLPI can decrease the liver-metastasizing potential of carcinoma cells and that this protective effect correlates with a decrease in the production of hepatic TNF-A and E-selectin. They suggest that factors that attenuate the host proinflammatory response may have a therapeutic potential in the prevention of liver metastasis. (Cancer Res 2006; 66(6): 3062-70)

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Regulation Of B16F1 melanoma cell metastasis by inducible functions of the hepatic microvasculature

Cited by 20 publications

References 15 publications

Impact of cirrhosis on the development of experimental hepatic metastases by B16F1 melanoma cells in C57BL/6 mice

Impact of cirrhosis on the development of experimental hepatic metastases by B16F1 melanoma cells in C57BL/6 mice

Arrest of B16 Melanoma Cells in the Mouse Pulmonary Microcirculation Induces Endothelial Nitric Oxide Synthase-Dependent Nitric Oxide Release that Is Cytotoxic to the Tumor Cells

The Secretory Leukocyte Protease Inhibitor Is a Type 1 Insulin-Like Growth Factor Receptor–Regulated Protein that Protects against Liver Metastasis by Attenuating the Host Proinflammatory Response

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