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F W Orr

Publications and source records attributed to F W Orr.

At least 37 records · Page 2Linked to original sources
PubMed1994

The relative roles of vitronectin receptor, E-selectin and alpha 4 beta 1 in cancer cell adhesion to interleukin-1-treated endothelial cells.

Adhesion of cancer cells to endothelium is thought to be a prerequisite to extravasation during the haematogenous phase of metastasis, and is enhanced after perturbation of the endothelium by interleukin-1 (IL-1). The inducible endothelial adhesion molecules, E-selectin, VCAM-1/alpha 4 beta 1 and vitronectin receptor have been reported to mediate attachment of cancer cells to IL-1-treated endothelial cells. We have examined the relative contribution of these molecules by quantifying the adhesion of a panel of 22 human, 125I-labelled cancer cells and the rat W256 tumour to untreated and IL-1-treated endothelial monolayers in the presence of relevant neutralising antibodies. Antibodies against E-selectin inhibited the adhesion of HL-60 leukaemia cells and two colon carcinomas. Anti-alpha 4 beta 1 antibodies blocked adhesion of four melanomas, five sarcomas and one lung carcinoma. Anti-vitronectin receptor antibodies inhibited adhesion of 14 of the 22 human cell lines to IL-1-treated endothelial cells. Adhesion of seven cell lines was inhibited by more than a single antibody. In contrast, adhesion of one of the cancer cell lines was unaffected by any of the antibodies, suggesting involvement of other IL-1-inducible endothelial adhesion molecules. Moreover, none of the antibodies altered the attachment of cancer cells to unstimulated endothelial monolayers. We conclude that the mechanisms of cancer cell adhesion to the endothelium are influenced by endothelial activation and by the adhesive repertoire of the cancer cell.

Animals↗
PubMed1994

Quantification and morphologic demonstration of reactive oxygen species produced by Walker 256 tumor cells in vitro and during metastasis in vivo.

BACKGROUND: Pulmonary endothelial damage can be caused by agents that generate oxidants, e.g., bleomycin, hyperoxia, neutrophils or x-irradiation. In animals with intravascular cancer cells, there is increased tumor cell arrest and the subsequent formation of metastatic tumors at the sites of such endothelial injury. We have previously shown that Walker 256 (W256) tumor cells, stimulated with phorbol esters (phorbol 12-myristate 13 acetate) or the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine, generate chemiluminescence that is inhibitable by catalase. Such activated cells can injure cultured endothelial monolayers. The purpose of the present study was to quantify and obtain morphological confirmation of the generation of reactive oxygen species by W256 cells in vitro, and to determine if this phenomenon could be morphologically detected in vivo during the metastatic process. EXPERIMENTAL DESIGN: The production of oxidants from W256 cells was quantitated in vitro by the scopoletin fluorescence assay, by a ferrithyiocyanate colorimetric assay (Thurman reaction), and confirmed morphologically, in vitro and in vivo, by the formation of cerium perhydroxide (Ce[OH]2OOH) deposits from cerium chloride (CeCl3). To demonstrate generation of reactive oxygen species in vivo, we examined W256 cells collected from the pulmonary circulation and at sites of spontaneous metastasis in the lung after intramuscular tumor transplantation, or cells arrested in the lungs after intravenous injection. The specificity of the CeCl3 reaction was confirmed by blocking in the presence of catalase. RESULTS: As measured by the loss in scopoletin fluorescence and by generation of ferrithiocyanate 5 x 10(6) activated W256 cells produced an equivalent of 18 nM of H2O2 per hour A. Ce-[OH]2OOH deposits were identified in vitro on the surface of W256 cells, and at points of attachment between W256 cells and cultured endothelial cell monolayers. In vivo, CeCl3-derived deposits were seen on circulating W256 cells and on W256 cells that had arrested in the lungs following the intravenous injection of activated or non-activated W256 cells, or in spontaneous pulmonary metastases which formed after intramuscular tumor inoculation. Pretreatment of tumor-bearing animals with phorbol 12-myristate 13 acetate increased the number of CeCl3-derived deposits more than 2 fold. Catalase inhibited the formation of the electron-dense deposits in vitro and in vivo. CONCLUSIONS: These data provide morphologic evidence that cancer cells can produce reactive oxygen species in vivo and suggest that free radicals might contribute to endothelial damage during the metastatic process.

Animals↗
PubMed1993

Increased growth rate and tumor burden of spontaneously metastatic Walker 256 cancer cells in the skeleton of bisphosphonate-treated rats.

We have studied the effect of 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD) on the morphology of rat bone and the metastatic behavior of Walker 256 (W256) cancer cells in the rat skeleton. Male Fischer rats (150-175 g) received s.c. injections for 7 days with APD (0.5 mg/kg body weight/day) (+ APD; n = 20) or with vehicle (-APD; n = 20). Subsequently, 10 + PD and 10 -APD rats received i.m. injections with W256 cells (+ W256), and the remaining rats received injections of vehicle (-W256). All rats were killed 14 days later. Trabecular bone volume was increased by 46 +/- 3% by APD treatment alone and was decreased by 56 +/- 7% (SEM) by W256 tumor burden alone. After 14 days of tumor burden, + APD/+ W256 rats had 3-fold more trabecular bone than did -APD/+W256 rats. Despite this bone-sparing effect, APD treatment of +W256 rats was associated with a 2.6-fold increase in skeletal tumor burden, while metastatic tumor burden in the liver, lungs, and kidneys was unaffected. The increased skeletal tumor burden in + APD/+ W256 rats was accompanied by an increase in the growth rate of W256 cells located in bone. Independent of APD treatment, W256 cells located adjacent to trabecular bone surfaces had greater growth rates than did W256 cells in the marrow, located > 50 microns from trabecular bone. In summary, the APD-induced increase in trabecular bone volume in rats is associated with a selective increase in skeletal tumor burden and an increased growth rate of W256 cells in the skeleton.

Acid Phosphatase↗
PubMed1993

Walker 256 tumor cell degradation of extracellular matrices involves a latent gelatinase activated by reactive oxygen species.

The invasion of blood vessel walls is a critical step in cancer metastasis, in which endothelial cells and their vascular basement membranes act as barriers to tumor cell passage. Here we report that Walker 256 carcinosarcoma (W256) cells degrade subendothelial matrices by a process involving both the generation of hydrogen peroxide and the secretion of a matrix metalloproteinase. As an assay of basement membrane degradation, [3H]proline-labeled subendothelial matrices were exposed to W256 cells in the presence or absence of the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). The release of [3H]proline, in the presence of 5 x 10(6) W256 cells, was increased from 49 +/- 2.5 to 64 +/- 2.2% by the addition of 10(-6) M fMLP. In the presence of fMLP-activated W256 cells, [3H]proline release was completely inhibited by the addition of 2000 units/ml catalase or by the metalloproteinase inhibitors 1,10-phenanthroline and EDTA at concentrations > or = 10 micrograms/ml. alpha 1-Antitrypsin or alpha 2-macroglobulin were without effect. Cell-free supernatants obtained from activated W256 cells were also able to promote basement membrane degradation. Electrophoresis of the cell-free supernatants from fMLP or PMA-activated W256 cells in gelatin-containing sodium dodecyl sulfate-polyacrylamide gels revealed a major band of gelatinolytic activity at 94 kDa. The 94-kDa band represented the activity of a latent gelatinase since incubation with 1 mM 4-aminophenylmercuric acetate (APMA; a known activator of latent metalloproteinases) resulted in the loss of gelatinolytic activity at 94 kDa and the appearance of five new bands of lower molecular weight (M(r) 86, 79, 74, 70, and 66 kDa). Two of these lower molecular weight bands (M(r) 86 and 66 kDa) were also detected in the absence of APMA, following 10-fold concentration of the cell-free supernatants. When the cell-free supernatants of phorbol myristate acetate-activated W256 cells (concentrated 10-fold) were incubated with increasing concentrations of hydrogen peroxide (35 to 70 mM), the band at 66 kDa demonstrated enhanced gelatinolytic activity. We suggest that W256 cells can secrete a latent metalloproteinase of molecular weight 94 kDa which, when activated by hydrogen peroxide, can degrade subendothelial matrices.

Animals↗
PubMed1993

Localization of 13-hydroxyoctadecadienoic acid and the vitronectin receptor in human endothelial cells and endothelial cell/platelet interactions in vitro.

Blood/vessel wall cell interactions depend, in part, on the expression of adhesion receptors on cell surfaces, such as expression of the vitronectin receptor (VnR) on the apical surface of endothelial cells (ECs) for platelet/EC adhesion. However, it is unclear how receptor expression is regulated from within cells. In previous studies, we found that ECs metabolize linoleic acid into the lipoxygenase monohydroxide, 13-hydroxyoctadecadienoic acid (13-HODE), and that the intracellular level of 13-HODE correlates inversely with VnR expression and platelet adhesion to the EC apical surface. In this study, we determined the physical associations of 13-HODE and VnR in unstimulated and stimulated ECs, ie, at times when ECs were and were not adhesive for specific ligands and platelets, using double antibody immunofluorescent staining techniques and binding assays. 13-HODE and the VnR were colocalized within unstimulated ECs. When ECs were stimulated, 13-HODE was no longer detectable, either in or outside the ECs, and the VnR was detected on the apical surface of the ECs. These changes were paralleled by increased vitronectin binding and increased platelet adhesion to the ECs. We suggest that colocalization of 13-HODE with VnR reflects a 13-HODE/VnR interaction, confining the VnR in a nonadhesive form inside unstimulated ECs, and, as a result, the ECs are nonadhesive. When the ECs are stimulated, 13-HODE and VnR dissociate, allowing the VnR to relocate on the EC surface, where the VnR undergoes a conformational change resulting in increased EC adhesivity.

Blood Platelets↗
PubMed1993

Interleukin 1-induced cancer cell/endothelial cell adhesion in vitro and its relationship to metastasis in vivo: role of vessel wall 13-HODE synthesis and integrin expression.

Previously, we have demonstrated that stimulation of endothelial cells (ECs) with interleukin-1 alpha (IL-1 alpha) enhances the synthesis and expression of the vitronectin receptor (VnR), promotes VnR-dependent adhesion of human A549 adenocarcinoma cells to ECs, and is associated with decreased EC 13-hydroxyoctadecadienoic acid (13-HODE) synthesis in vitro. To determine whether these observations are relevant in vivo, we examined the acute retention and subsequent metastasis of intravenously-injected B16F10 melanoma cells in murine lungs, in relation to vessel wall 13-HODE. In C57BL/6 mice pretreated with IL-1 alpha, vessel wall 13-HODE was decreased and B16F10 lung entrapment and metastasis were increased. The latter two events were blocked by pretreating the animals with the GRGDS peptide. These data suggest a relationship between vessel wall 13-HODE synthesis, adhesion molecule expression, and adhesion of B16F10 cells to the endothelium.

Animals↗
PubMed1993

Mechanisms involved in the metastasis of cancer to bone.

The metastasis of cancer to bone is a frequent outcome of common malignancies and is often associated with significant morbidity due to osteolysis. Bone metastasis is also selective in that a disproportionately small number of malignancies account for the majority of tumors which spread to bone. While the mechanisms of bone destruction have been studied, those responsible for the site-specific nature of bone metastasis are poorly understood. As a metastatic target, bone is unique in that it is continuously being remodelled under the influence of local and systemic growth factors, many of which are embedded in the bone matrix. This review summarizes evidence for the hypothesis that the formation of metastatic tumors in bone is the consequence of a unique microenvironment where metastatic cells can alter the metabolism of bone, thereby regulating the release of soluble bone-derived growth factors as a consequence of bone resorption. These, in turn, can modulate the malignant phenotypic properties of receptive cells. Transforming growth factor-beta is one factor which can promote the growth and motility of Walker 256 cells, a rat cell line with a propensity to metastasize spontaneously to bone.

Animals↗
PubMed1993

Perichondrial arthroplasty in a canine elbow model: comparison of vascularized and nonvascularized techniques.

The purpose of this study was to use a canine model to compare the ability of vascularized and nonvascularized perichondrial grafts to resurface an experimental joint defect. In five adult mongrel dogs, a 3 x 2 cm segment of perichondrium, subtended by the intercostal-internal mammary vessels, was harvested and transplanted to a surgically created defect on the ulnar condyle of the humerus. A similar defect in the opposite elbow was repaired with a 3 x 2 cm standard perichondrial graft. Five untreated dogs acted as normal controls. The dogs were allowed to mobilize freely for a period of 6 months. At that time, angiography demonstrated that all microvascular anastomoses were patent. There was no statistical difference in the range of motion of the two elbows, in the radiographic appearance, or in bone density of the two groups of joints. Histologic assessment demonstrated that the vascularized perichondrium formed an articular cartilage with an average thickness of 21.8 microns as compared with 38.5 microns for the nonvascularized perichondrium (p < 0.05). The cartilage in both grafts was morphologically hyaline in type. There were degenerative changes in the grafts with partial separation of the graft from the underlying bone and formation of surface clefts or pits, villous projections, and synovial proliferation. Degenerative changes also were observed on the articular surface opposite the grafted humeral condyle. In two animals the grafts displaced from the recipient condyle, which instead became resurfaced by greater amounts of hyaline-type cartilage with lesser degrees of degeneration and subarticular fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1992

Up-regulated biosynthesis and expression of endothelial cell vitronectin receptor enhances cancer cell adhesion.

Extravasation of circulating cancer cells during metastasis is thought to involve adhesion to the vascular endothelium. To characterize this process, we measured the attachment of A549 human lung carcinoma cells to monolayers of cultured human umbilical vein endothelial cells. Pretreatment of the endothelial cells with 10 ng/ml interleukin 1 alpha (IL-1) for 4 h increased cancer cell attachment 2-5-fold. This increase was blocked by 100 microM glycyl-arginyl-glycyl-aspartyl-serine peptide and was decreased 60 +/- 10% (SD) by a vitronectin receptor polyclonal antiserum or 56 +/- 8% by a vitronectin receptor monoclonal antibody, LM609. Glycyl-arginyl-glycyl-aspartyl-serine or the vitronectin receptor antibodies did not inhibit cancer cell attachment to untreated endothelial cells. A fibronectin receptor antiserum had no effect on attachment to untreated or IL-1-treated endothelial cells. Pretreatment of endothelial cells with IL-1 increased their adhesion to fibronectin and vitronectin and increased the expression of vitronectin receptor and fibronectin receptor as detected by immunofluorescence flow cytometry, quantitative antibody binding, and immunoprecipitation of [35S]methionine-labeled cell extracts. IL-1 pretreatment also increased beta 1, beta 3, and alpha, integrin mRNA. The A549 cells did not express vitronectin receptor, since LM609 did not inhibit A549 adhesion to vitronectin or bind to A549 cells in flow cytometry, and vitronectin receptor antisera failed to immunoprecipitate vitronectin receptor from A549 cells. Furthermore, the beta 3 complementary DNA probe failed to hybridize to A549 RNA. A549 cells did express fibronectin receptor, which was increased by IL-1 treatment. We conclude that IL-1 induces the expression of both vitronectin receptor and fibronectin receptor on endothelial cells and that vitronectin receptor, in turn, facilitates A549 cell adhesion to endothelial cells.

Antibodies↗
PubMed1992

A quantitative model for spontaneous bone metastasis: evidence for a mitogenic effect of bone on Walker 256 cancer cells.

A new model for the study of spontaneous bone metastasis has been developed which allows for the quantification of metastatic tumor burden and cancer cell growth rate, and which describes the progressive changes in bone morphology. Walker 256 (W256) cells or vehicle were injected into the left upper thigh muscle of male Fischer rats, which were killed 7, 10 or 14 days later. By day 7, metastases had appeared in the distal femur, in the glomeruli of the kidney, and diffusely throughout the liver and lungs. The extent of tumor burden in these organs increased over time. In the femur, 14 days of tumor burden was associated with a 53 +/- 10% decrease in trabecular bone content, a 61 +/- 15% increase in osteoclast surface, and a 95 +/- 10% decrease in osteoblast surface, as compared with non-tumor-bearing controls. By autoradiography, metastatic tumor cells in all organs were determined to have greater growth rates than did cells in the primary tumor. However, within the femur, W256 cells located adjacent to trabecular bone surfaces had a 33 +/- 7% greater growth rate than did W256 cells located > 50 microns from bone surfaces (P < 0.05), suggesting a mitogenic effect of bone.

Animals↗
PubMed1992

Stimulation of bone resorption results in a selective increase in the growth rate of spontaneously metastatic Walker 256 cancer cells in bone.

To test the hypothesis that bone metastasis is related to the rate of bone remodeling, we have examined the effect of enhanced bone resorption on the growth of spontaneously metastatic Walker 256 (W256) cancer cells. Bone resorption was stimulated in male Fischer rats by injecting Rice H-500 Leydig tumor cells subcutaneously. The resorptive response of the skeleton was confirmed in a pilot study by evaluating parameters of bone morphometry after 4, 7 and 10 days of tumor burden. The distal femoral epiphyses had 35 +/- 10% more osteoclast surface, 83 +/- 11% less osteoblast surface, and 46 +/- 5% less trabecular bone after 10 days of tumor burden, compared to non-tumor-bearing controls. To evaluate the effect of Leydig tumor-induced bone resorption on the growth response of W256 cells, 20 rats were injected intramuscularly with 2 x 10(7) W256 cells, and 20 rats were vehicle-injected. Two days later, 10 rats from each group were injected subcutaneously with Leydig tumor cells. Twelve days after W256/vehicle injection, rats were injected with [3H]thymidine, killed 2 h later, and their femurs, liver, lungs and kidneys were processed for histology. In rats injected with Leydig tumor cells only, enhanced bone resorption was confirmed by a 40 +/- 4% increase in serum calcium concentration, a 48 +/- 8% decrease in trabecular bone content, and a 72 +/- 15% decrease in osteoblast surface, compared with non-tumor-bearing rats. Metastatic W256 cells adjacent to trabecular bone in Leydig tumor-bearing rats had a 56 +/- 18% greater relative [3H]thymidine labeling index (TdR) than did W256 cells in the bones of non-Leydig tumor-bearing rats. The TdRs of W256 cells in the liver, lungs, and kidneys were not affected by Leydig tumor burden. In this model, enhanced bone resorption was associated with the selective growth promotion of metastatic W256 cells in bone, suggesting the existence of a bone-derived factor which is mitogenic to W256 cells.

Animals↗
PubMed1992

Cancer cell interactions with injured or activated endothelium.

Blood vessels and lymphatics are the most important pathways for dissemination of cancer cells but the entry and exit of these cells into and from the vasculature requires that they pass through barriers formed by the endothelium and its basement membrane. This review summarizes evidence that this step in metastasis can be regulated by microenvironmental influences which alter the properties of this barrier. These phenomena can be attributed to both 'passive' and 'active' responses of the endothelium. The microvasculature is susceptible to perturbation from environmental agents, host cells and cancer cells. There is clinical and experimental evidence that this can upregulate the metastatic process. Using established animal models of pulmonary microvascular injury it has been shown that endothelial damage promotes the localization and metastasis of circulating cancer cells to the lung and that this effect is lost after endothelial repair. Oxidative stress is an effector of vascular damage in several of the experimental models. While endothelial cells appear to be directly susceptible to free radical attack, basement membranes are not. However, oxidative injury of endothelial cells causes release of proteases which can then degrade the basement membrane. This event is associated with generation of tumor cell chemoattractants and enhances cancer cell invasion of vascular basement membranes in vitro. Vascular endothelial cells are also susceptible to stimulation by systemic mediators including cytokines, thrombin, or endotoxin which induce a series of active responses in the vessel wall. These perturbed endothelial cells synthesize and express cell surface adhesion molecules which can interact with cancer cells. They also release chemoattractants which stimulate cancer cell motility. We postulate that such responses endow the vessel wall with the potential to act as a determinant of metastatic rate.

Animals↗
PubMed1992

Endothelial injury causes degradation of adjacent basement membranes and promotes their invasion by A549 carcinoma cells.

Experiments in vivo have demonstrated that endothelial cell injury promotes the local arrest of circulating, intravascular cancer cells and the subsequent formation of metastatic tumors. The experiments described here were performed to test the hypothesis that injury of the endothelium also causes damage to the adjacent vascular basement membrane, which in turn facilitates the passage of cancer cells across the vessel wall. Confluent monolayers of bovine pulmonary artery endothelial cells were incubated with 3H-2-deoxyglucose or 3H-proline to label the endothelial cells or the basement membrane, respectively. After adding H2O2 to these cultures, damage of the endothelium and basement membrane was detected by release of the isotopes into the culture medium. The kinetics and magnitude of basement membrane degradation correlated with the damage to the endothelial cells. Evidence for involvement of endothelial proteases in basement membrane injury included identification of a 63-kD gelatinase in the culture medium, inhibition of injury by protease inhibitors and the inability of H2O2 to cause 3H-proline release when applied directly to basement membranes. Scanning electron microscopy demonstrated that a greater number of A549 lung adenocarcinoma cells attached to the basement membrane and endothelium at points of endothelial retraction. However, this was not due to an increase in the adhesive properties of the basement membrane. The media from injured endothelial cultures stimulated the motility of A549 cells in a Boyden chamber assay. Furthermore, in a 24-hour invasion assay, a greater number of A549 cells migrated through injured basement membranes than through control membranes. We conclude that endothelial cell injury can cause enzymatic damage to the underlying basement membrane and postulate that this can facilitate the transvascular passage of cancer cells in vivo.

Animals↗
PubMed1991

Endothelial cell damage by Walker carcinosarcoma cells is dependent on vitronectin receptor-mediated tumor cell adhesion.

The transport of cancer cells from blood vessels to extravascular tissue is a critical step in metastasis, where endothelial cells and the vascular basement membrane act as barriers to cell traffic. Because endothelial injury can facilitate the metastasis of intravascular cancer cells in vivo, the authors have studied in vitro the free-radical-mediated endothelial damage caused by the rat Walker 256 carcinosarcoma (W256) cell after stimulation with 10(-6) mol/l (molar) phorbol ester. Here the authors have examined the hypothesis that W256 cell-mediated endothelial injury is dependent on adhesion between the effector and target cells. Attachment of phorbol 12-myristate, 13-acetate (PMA)-stimulated W256 cells to endothelial monolayers was increased 1.8 +/- 0.1-fold and damage (3H-2-deoxyglucose release from labeled endothelium) 1.4 +/- 0.1-fold after 4-hour pretreatment of the endothelium with 10 ng/ml recombinant human interleukin-1 alpha (rIL-1 alpha). Under various assay conditions, the release of 3H-2-deoxyglucose correlated directly with tumor cell adhesion (r = 0.98, P less than 0.005). In the presence of a polyclonal anti-vitronectin receptor antiserum, adhesion of stimulated W256 cells to rIL-1 alpha-treated monolayers was inhibited by 39% +/- 2%, and 3H-2-deoxyglucose release was inhibited by 53% +/- 13%. Immunoblot analysis and immunofluorescence flow cytometry demonstrated that the endothelial cells but not the W256 cells expressed vitronectin receptor (VnR) on their cell surface. The surface expression of VnR by endothelial cells was increased 1.9 +/- 0.1-fold after 4 hours' incubation with rIL-1 alpha. The authors conclude that W256 cell-mediated endothelial damage is dependent on cell adhesion, which, in turn, is partly regulated by the expression of VnR on the endothelial cell surface.

Animals↗
PubMed1991

Effects of endothelial cell treatment on 13-HODE and prostacyclin synthesis and its correlation with tumor cell-vascular endothelial cell adhesion.

Adhesion of tumor cells to vascular endothelial surfaces is one of the key steps in metastatic dissemination. Several factors are believed to be implicated in the regulation of the adhesive properties of tumor cells. We show that the adhesion of five different tumor cell lines, all of them of human origin, to human umbilical vascular endothelial cells (ECs) significantly increases following pretreatment of ECs with the cytokines interleukin-1 and tumor necrosis factor, whereas tumor cell/EC interactions remained unchanged after incubation with interferon-gamma. Significant augmentation in tumor cell adhesion was also observed when ECs were treated with the lipoxygenase inhibitors salicylate and the compound BW755C. In all cases, increased tumor cell adhesion was concomitant with significant decreases in the EC levels of linoleic acid, lipoxygenase-derived metabolite 13-hydroxy-octadecadienoic acid (13-HODE). On the contrary, pretreatment of the EC monolayers with aspirin did not result in any changes towards tumor cell adhesion. These results suggest that tumor cell/EC interaction is modulated, at least in part, by intracellular levels of 13-HODE and is independent of prostacyclin (PGI2) production by the ECs.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Effect of blood transfusions on experimental pulmonary metastases in mice.

We examined the effect of allogeneic blood transfusions (BT) on pulmonary metastases in a mouse model. Recipient (C57B1/6J) mice were transfused with either saline, syngeneic blood or allogeneic (Balb/c) blood on two occasions, days 0 and 3. One week after the last transfusion, recipient mice were injected intravenously with varying numbers of methylcholanthrene-induced fibrosarcoma cells. Twenty days later the number of pleural nodules was counted as an index of pulmonary metastasis. The data demonstrate that the inoculation of 2.5 x 10(5) or 1 x 10(5) tumor cells resulted in significantly higher numbers of pulmonary metastases in mice that received allogeneic BT than the mice that received syngeneic blood or saline. In contrast, allogeneic BT caused significant inhibition of pulmonary metastases in mice that received 3.5 x 10(5) tumor cells. The data suggest that the immunomodulatory (stimulatory or inhibitory) effect of BT is dependent on the numbers of tumor cells inoculated. It is likely that the conflicting reports in the literature on the effects of BT on tumor growth may be due to inoculation of different numbers of tumor cells. These results have an important bearing in understanding the effect of allogeneic BT on tumor growth both in experimental animals and in cancer patients.

Animals↗
PubMed1990

Effects of systemic complement activation and neutrophil-mediated pulmonary injury on the retention and metastasis of circulating cancer cells in mouse lungs.

Vascular pathways are major transit routes for the dissemination of malignant neoplasms and are also regulators of cancer metastasis, in part because the endothelium and vascular basement membrane are barriers to the entry and exit of tumor cells. In this study, we have examined the hypothesis that host cell-mediated damage to the pulmonary microvasculature facilitates the experimental metastasis of a syngeneic fibrosarcoma in the C57BL/6J mouse. Intravenous injection of purified cobra venom factor was followed in 30 minutes by complement activation, neutropenia with sequestration of neutrophils in the lung, and increased pulmonary vasopermeability. When syngeneic fibrosarcoma cells were injected simultaneously with cobra venom factor, there was a 3 fold increase in cancer cell retention in the lungs after 24 hours and a 3- to 20-fold increase in metastatic tumor burden after 14 days. Enhanced cancer cell retention after cobra venom factor was not seen in mice deficient in complement component C5 and was diminished by pretreatment of animals with antineutrophil antibodies, catalase, inhibitors of lipoxygenase, thromboxane synthetase, and lipid peroxidation (oxygen radical scavenger). We conclude that neutrophil-mediated microvascular injury can promote the organ localization and metastasis of circulating cancer cells.

Animals↗