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Biomedical subjects

I J Fidler

Publications and source records attributed to I J Fidler.

At least 19 recordsLinked to original sources
PubMed1999

Suppression of angiogenesis, tumorigenicity, and metastasis by human prostate cancer cells engineered to produce interferon-beta.

We determined whether the IFN-beta gene can be used to suppress angiogenesis, tumor growth, and metastasis of human prostate cancer cells growing in the prostate of nude mice. Highly metastatic PC-3M human prostate cancer cells were engineered to constitutively produce murine IFN-beta subsequent to infection with a retroviral vector containing murine IFN-beta cDNA. Parental (PC-3M-P), control vector-transduced (PC-3M-Neo), and IFN-beta-transduced (PC-3M-IFN-beta) cells were injected into the prostate (orthotopic) or subcutis (ectopic) of nude mice. PC-3M-P and PC-3M-Neo cells produced rapidly growing tumors and regional lymph node metastases, whereas PC-3M-IFN-beta cells did not. PC-3M-IFN-beta cells also suppressed the tumorigenicity of bystander nontransduced prostate cancer cells. PC-3M-IFN-beta cells produced small tumors (3-5 mm in diameter) in nude mice treated with anti-asialo GM1 antibodies and in severe combined immunodeficient/Beige mice. Immunohistochemical staining revealed that PC-3M-IFN-beta tumors were homogeneously infiltrated by macrophages, whereas control tumors contained fewer macrophages at their periphery. Most tumor cells in the control tumors were stained positive by an antibody to proliferative cell nuclear antigen; very few were positively stained by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling. In sharp contrast, PC-3M-IFN-beta tumors contained fewer proliferative cell nuclear antigen-positive cells and many terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling-positive cells. Staining with antibody against CD31 showed that control tumors contained more blood vessels than PC-3M-IFN-beta tumors. PC-3M-IFN-beta cells were more sensitive to lysis mediated by natural killer cells in vitro or to cytostasis mediated by macrophages than control transduced cells. Conditioned medium from PC-3M-IFN-beta cells augmented splenic cell-mediated cytolysis to control tumor cells, which could be neutralized by antibody against IFN-beta. Collectively, the data suggest that the suppression of tumorigenicity and metastasis of PC-3M-IFN-beta cells is due to inhibition of angiogenesis and activation of host effector cells.

Animals↗
PubMed1999

GM-CSF-transduced B16 melanoma cells are highly susceptible to lysis by normal murine macrophages and poorly tumorigenic in immune-compromised mice.

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-transduced B16-F10 murine melanoma cells had lower tumorigenicity in both syngeneic and nude mice than parental or LacZ-transduced (control) cells. The subcutaneous (s.c.) tumors producing GM-CSF were densely infiltrated with macrophages, whereas the control tumors were not. In vitro studies showed that GM-CSF-transduced B16 cells were susceptible to lysis mediated by nonactivated murine macrophages, whereas control B16 cells were not. Macrophage-mediated cytotoxicity against GM-CSF-transduced B16 cells was independent of the presence of NO, H2O2, O2-, tumor necrosis factor alpha, and matrix metalloproteinase. Coculture experiments using GM-CSF-producing and -nonproducing B16 cells demonstrated that GM-CSF produced by the transduced B16 cells activated macrophages to kill the bystander non-GM-CSF-producing tumor cells. The results suggest that GM-CSF released by tumor cells can induce macrophage-mediated cytotoxicity, which in turn can inhibit the in vivo growth of GM-CSF-transduced tumor cells.

Animals↗
PubMed1999

Progressive growth of infantile cutaneous hemangiomas is directly correlated with hyperplasia and angiogenesis of adjacent epidermis and inversely correlated with expression of the endogenous angiogenesis inhibitor, IFN-beta.

Cutaneous infantile hemangioma progresses through proliferation and involution phases. Since treatment with interferon, a negative regulator of angiogenesis, accelerates the involution phase, we hypothesized that cutaneous infantile hemangioma is associated with an imbalance between endogenous positive and negative regulators of angiogenesis. We examined 30 specimens of cutaneous hemangioma [proliferative phase (n=15), involuting phase (n=8), and involuted phase (n=7)] and control human skin (n=17), fixed in formalin and embedded in paraffin. Routine histology, immunohistochemistry, and an mRNA in situ hybridization technique were used to measure expression of the positive angiogenic molecules basic fibroblast growth factor (bFGF) and vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), and an endogenous inhibitor of angiogenesis, interferon-beta (IFN-beta). Proliferative phase hemangiomas expressed high levels of bFGF and VEGF/VPF but not IFN-beta (mRNA and protein). The epidermis directly overlying proliferating hemangiomas was hyperplastic, contained numerous dividing cells, and expressed bFGF and VEGF/VPF but not IFN-beta. Epidermis from normal individuals and epidermis directly overlying involuted tumors or at sites distant to the proliferating hemangioma was not hyperplastic and expressed normal levels of bFGF, VEGF/VPF, and IFN-beta. These data suggest that the proliferation of cutaneous hemangiomas and adjacent epidermis is associated with an imbalance between positive and negative angiogenic factors expressed by the neoplasm and adjacent normal tissue.

Angiogenesis Inducing Agents↗
PubMed1999

Relative expression of E-cadherin and type IV collagenase genes predicts disease outcome in patients with resectable pancreatic carcinoma.

We examined the expression level of several genes that regulate distinct steps of metastasis in formalin-fixed, paraffin-embedded, archival specimens of primary human pancreatic carcinomas from patients undergoing curative surgery. The expression of epidermal growth factor receptor, E-cadherin, type IV collagenase [matrix metalloproteinase (MMP) 2 and MMP-9), basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor, and interleukin 8 was examined by a colorimetric in situ mRNA hybridization technique. Down-regulation of E-cadherin and up-regulation of type IV collagenase (MMP-9 and MMP-2) at the periphery of the neoplasms (P = 0.0167, 0.0102, and 0.0349, respectively) had significant prognostic value. The ratio of type IV collagenase expression (mean of the expression of MMP-2 and MMP-9) to E-cadherin expression (MMP:E-cadherin ratio) at the periphery of the tumors was significantly higher in patients with recurrent disease (4.7 +/- 2.1) than in patients who were disease free (2.3 +/- 1.7; P = 0.0008). Death from pancreatic cancer was significantly associated with a high MMP:E-cadherin ratio (>3.0) by overall survival analysis (P < 0.0002), whereas a low MMP:E-cadherin ratio (<3.0) was found in seven of eight patients alive 28-64 months after surgery. Multivariate analysis of overall survival showed that the MMP:E-cadherin ratio was a significant independent prognostic factor, whereas stage, nodal metastasis, and histological type were not. These data show that multiparametric analysis for several metastasis-related genes may allow physicians to assess the metastatic potential and hence predict the clinical outcome of individual patients with resectable pancreatic carcinoma.

Adenocarcinoma↗
PubMed1998

Therapy of human ovarian cancer by transfection with the murine interferon beta gene: role of macrophage-inducible nitric oxide synthase.

The purpose of this study was to determine whether the local sustained production of murine interferon beta (mIFN-beta) could inhibit the growth of human ovarian cancer cells in the peritoneal cavity of nude mice. Human ovarian tumor Hey-A8 cells transfected with mIFN-beta (Hey-beta) or a control neomycin resistance vector (Hey-Neo) grew well in culture. Tumor cells were injected into the peritoneal cavity or under the subcutis of nuce mice. Parental (wild-type) or control transfected cells produced large tumors, whereas mIFN-beta-transfected cells did not produce any tumors. The IFN-beta-transfected cells prevented the outgrowth of bystander parental, control-transfected cells, and another human ovarian tumor cell line, SKOV3i.p.1, in the peritoneal cavity of nude mice. The IFN-beta-transfected tumor cells stimulated a high level of nitric oxide (NO) production in murine macrophages under both in vitro and in vivo conditions, and only the NO-producing macrophages exhibited antitumor activity. Collectively, these results demonstrate that the local production of IFN-beta can inhibit the in vivo growth of human ovarian cancer cells by upregulating the expression of the inducible nitric oxide synthase (iNOS) gene in host macrophages.

Animals↗
PubMed1998

Angiostatin-mediated suppression of cancer metastases by primary neoplasms engineered to produce granulocyte/macrophage colony-stimulating factor.

We determined whether tumor cells consistently generating granulocyte/macrophage colony- stimulating factor (GM-CSF) can recruit and activate macrophages to generate angiostatin and, hence, inhibit the growth of distant metastasis. Two murine melanoma lines, B16-F10 (syngeneic to C57BL/6 mice) and K-1735 (syngeneic to C3H/HeN mice), were engineered to produce GM-CSF. High GM-CSF (>1 ng/10(6) cells)- and low GM-CSF (<10 pg/10(6) cells)-producing clones were identified. Parental, low, and high GM-CSF-producing cells were injected subcutaneously into syngeneic and into nude mice. Parental and low-producing cells produced rapidly growing tumors, whereas the high-producing cells produced slow-growing tumors. Macrophage density inversely correlated with tumorigenicity and directly correlated with steady state levels of macrophage metalloelastase (MME) mRNA. B16 and K-1735 subcutaneous (s.c.) tumors producing high levels of GM-CSF significantly suppressed lung metastasis of 3LL, UV-2237 fibrosarcoma, K-1735 M2, and B16-F10 cells, but parental or low-producing tumors did not. The level of angiostatin in the serum directly correlated with the production of GM-CSF by the s.c. tumors. Macrophages incubated with medium conditioned by GM-CSF- producing B16 or K-1735 cells had higher MME activity and generated fourfold more angiostatin than control counterparts. These data provide direct evidence that GM-CSF released from a primary tumor can upregulate angiostatin production and suppress growth of metastases.

Angiostatins↗
PubMed1998

Suppression of tumorigenicity and metastasis of human renal carcinoma cells by infection with retroviral vectors harboring the murine inducible nitric oxide synthase gene.

The purpose of this study was to determine whether retrovirus-mediated transfer of the murine macrophage inducible nitric oxide synthase (iNOS) gene can inhibit tumorigenicity and metastasis of human renal cancer cells. Retroviral vectors encoding murine macrophage iNOS were constructed in the pLXSN retroviral vector with the iNOS gene under the control of a long terminal repeat promoter and a neomycin resistance gene under the control of an internal simian virus 40 promoter. Highly metastatic human renal carcinoma SN12PM6 cells were infected with control or iNOS retrovirus. Expression of iNOS was confirmed by Northern and Western blot analyses, and expression of the functional iNOS protein, i.e., production of nitric oxide (NO), was determined by measuring nitrite accumulation in culture supernatants. Noninfected or control cells produced large orthotopic tumors in the kidney of nude mice and a larger number of experimental lung metastases, whereas iNOS-infected cells produced small tumors in the kidneys and few to no lung metastases. The data indicate that the infection of human renal cancer cells by retroviruses harboring the murine iNOS gene can induce the production of high levels of NO, which is associated with autocytotoxicity, suppression of tumorigenicity, and abrogation of metastasis.

Animals↗
PubMed1998

Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice.

BACKGROUND: By the time patients are diagnosed with ovarian carcinoma, peritoneal dissemination of the tumor often has occurred. The progressive growth and spread of ovarian carcinoma depend, in part, on the formation of an adequate blood supply. We determined whether the expression of genes that regulate distinct steps in angiogenesis (i.e., the formation of new blood vessels) was associated with the pattern and progressive growth of human ovarian carcinomas implanted in the peritoneal cavity of nude mice. METHODS: Five different human ovarian carcinomas were injected individually into the peritoneal cavity of female NCr-nu/nu nude mice. The expression of basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), interleukin 8 (IL-8), and collagenase type IV (MMP-2 [matrix metalloproteinase-2] and MMP-9) was determined by northern blot analysis, in situ hybridization of messenger RNA, and immunohistochemical analysis. Blood vessel distribution and density, macrophage infiltration pattern, and stromal reaction were determined by immunohistochemical analysis with specific antibodies. RESULTS: Three of the carcinomas produced both solid lesions and ascitic tumors, whereas the remaining two produced only solid lesions. Two of the carcinomas produced rapidly progressive disease, two produced slow disease, and one produced intermediate disease. The formation of ascites was directly associated with expression of VEGF/ VPF, and survival was inversely associated with expression of IL-8. In rapidly growing tumors, the number of blood vessels was high throughout the lesion; in contrast, in slow-growing tumors, most vessels (and infiltrating macrophages) were located at the periphery. CONCLUSIONS: The expression of various genes that regulate angiogenesis in human ovarian carcinomas is associated with the pattern of the disease and its progression. Therefore, targeting specific genes that regulate angiogenesis could offer new approaches to the treatment of ovarian cancer.

Animals↗
PubMed1998

Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic interferon-alpha administration.

The purpose of these studies was to determine whether systemic administration of IFN-alpha can inhibit the expression of basic fibroblast growth factor (bFGF) in human transitional cell carcinoma, reduce its angiogenesis, and thus inhibit its growth in the bladder wall of nude mice. In vitro incubation of the highly metastatic 253J B-V cells and the IFN-alpha-resistant 253J B-V IFNR cells with noncytostatic concentrations of IFN-alpha down-regulated the steady-state mRNA transcripts and protein production of bFGF. IFN-alpha-insensitive and IFN-alpha-resistant cells were implanted in the bladder wall of nude mice. Systemic administration of IFN-alpha decreased the in vivo expression of bFGF, decreased blood vessel density in the tumors, and inhibited tumor growth of both IFN-alpha-insensitive and IFN-alpha-resistant cells. These data suggest that in addition to its well-documented antiproliferative effects, IFN-alpha can inhibit the growth of human bladder cancer cells by inhibition of angiogenesis.

Animals↗
PubMed1998

Activation of cytokine production, tumoricidal properties, and tyrosine phosphorylation of MAPKs in human monocytes by a new synthetic lipopeptide, JBT3002.

We investigated the expression of cytokine genes and tumoricidal properties in human blood monocytes in response to a new synthetic immunomodulating lipopeptide, JBT3002. Incubation of peripheral blood monocytes with free-form JBT3002 or JBT3002 encapsulated in multilamellar phospholipid vesicles (liposomes, MLV-JBT3002) induced tumoricidal properties in a dose-dependent manner. Both MLV-JBT3002 and free-form JBT3002 induced production of tumor necrosis factor alpha, interleukin-1beta, and interleukin-6 in a dose-dependent manner with similar kinetics. Treatment of monocytes with interferon-gamma did not significantly alter the expression of cytokine genes but increased the expression of cytokines induced by MLV-JBT3002 and free-form JBT3002. In contrast to monocyte activation by lipopolysaccharide (LPS), activation by JBT3002 was independent of serum and was not inhibited by CD14-neutralizing antibody. Incubation of monocytes with JBT3002 induced a rapid increase in tyrosine phosphorylation of proteins with apparent molecular masses of 42 and 38 kDa, a migration band shift of c-Jun NH2-terminal kinase 1 (JNK1), and activation of extracellular signaling regulated kinases. Consistent with its effect on cytokine expression, stimulation of these intracellular signaling pathways by JBT3002 was not inhibited in serum-free conditions. Collectively, the data indicate that the synthetic lipopeptide JBT3002 is a potent monocyte activator that modulates monocyte function by mechanisms similar to LPS but by a distinct receptor.

Adjuvants, Immunologic↗
PubMed1998

Suppression of tumorigenicity and metastasis in murine UV-2237 fibrosarcoma cells by infection with a retroviral vector harboring the interferon-beta gene.

In this study, we endeavored to determine the effectiveness of interferon beta (IFNbeta) gene therapy against highly metastatic murine UV-2237m fibrosarcoma cells. UV-2237m cells were engineered to produce murine IFNbeta constitutively following infection by a retroviral vector harboring the murine IFNbeta gene. Parental (UV-2237m-P), control-vector-transduced (UV-2237m-Neo), and IFNbeta-transduced (UV-2237m-IFNbeta) cells were injected subcutaneously (s.c.) or intravenously (i.v.) into syngeneic mice. Parental and control-transduced cells produced rapidly growing tumors, whereas IFNbeta-transduced cells did not. The tumorigenicity of IFNbeta-sensitive or -resistant parental cells was significantly suppressed when they were injected s.c. together with IFNbeta-transduced cells. The IFNbeta-transduced cells did not inhibit growth of parental cells injected s.c. at a distant site. UV-2237m-IFNbeta cells produced s.c. tumors in nude, SCID/Beige, and natural killer(NK)-cell-compromised syngeneic mice. The IFNbeta-transduced cells were more sensitive to in vitro splenic cell-mediated lysis than were the parental or control-transduced cells. Pretreatment of C3H/HeN mice with the NK-cell-selective antiserum (anti-asialoGM1) partially abrogated the cytotoxic activity of the cells. Cytotoxic activity was not observed in mixed culture of UV-2237m-IFNbeta cells and splenic cells from SCID/Beige mice. Significant cytotoxicity against UV-2237m-IFNbeta cells was mediated by macrophages activated by either IFNgamma, lipopolysaccharide, or a combination of both. Our data led us to conclude that the constitutive expression of IFNbeta can suppress tumorigenicity and metastasis of UV-2237m cells, which is due, in part, to activation of host effector cells.

Animals↗
PubMed1998

Therapy of cancer metastasis by tumoricidal activation of tissue macrophages using liposome-encapsulated immunomodulators.

The therapy of cancer requires strategies that can eradicate metastatic disease. Metastases consist of unique subpopulations of tumor cells that are able to colonize distant organs and become autonomous from homeostatic mechanisms. Conventional therapies generally have been unsuccessful due to biological heterogeneity in metastatic tumors. It is possible to circumvent this heterogeneity by the tumoricidal activation of tissue macrophages. Activation can be achieved by encapsulation of immunomodulators, e.g., muramyl tripeptide analogues, into liposomes, and this form of immunomodulation leads to eradication of established tumor metastases in numerous animal tumor models. Modulation of the tumor microenvironment by activated macrophages may prove to be an additional modality in therapy that combines the use of biological response modifiers with conventional therapies.

Adjuvants, Immunologic↗
PubMed1998

Expression of metastasis-related genes in surgical specimens of human gastric cancer can predict disease recurrence.

It was determined whether the expression level of several genes that regulate different steps of metastasis in formalin-fixed paraffin-embedded archival specimens of human gastric cancers correlated with disease recurrence and metastasis. The steady-state mRNA expression level for epidermal growth factor receptor (EGF-R), basic fibroblast growth factor (bFGF), E-cadherin, type IV collagenase and multidrug resistance (MDR-1) were examined by a colorimetric in situ hybridisation (ISH) technique, concentrating on reactivity at the periphery of the lesions. All patients were operated on for cure. 15 cases were disease-free and 10 had disease recurrence by 4.5 years after resection of the primary tumours. The expression of EGF-R and bFGF type IV collagenase was higher and expression of E-cadherin was lower in the disease-recurrence cases than in the disease-free cases. The ratio between the expression level of collagenase type IV and E-cadherin at the periphery of the surgical specimens differed significantly between the disease-free cases and the recurrent-metastatic cases. These data show that multiparametric ISH analysis for several metastasis-related genes may allow prediction of disease recurrence of gastric cancer.

Cadherins↗
PubMed1998

Therapy of cancer metastasis by activation of the inducible nitric oxide synthase.

The process of cancer metastasis consists of multiple sequential and highly selective steps. The vast majority of tumor cells that enter the circulation die rapidly; only a few survive to produce metastases. This survival is not random. Metastases are clonal in origin and are produced by specialized subpopulations of cells that preexist in a heterogeneous primary tumor. Experimental studies concluded that metastatic cells survive in the circulation whereas nonmetastatic cells do not. In part, this difference is due to an inverse correlation between expression of endogenous inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO) and metastatic potential. Direct evidence for the role of iNOS in metastasis has been provided by our data on transfection of highly metastatic murine K-1735 clone 4 (C4.P) cells which express low levels of iNOS, with a functional iNOS (C4.L8), inactive mutated iNOS (C4.S2), or neomycin resistance (C4.Neo) genes in medium containing 3 mM of the specific iNOS inhibitor NG-L-methyl arginine (NMA). C4.P, C4.Neo, and C4.S2 cells were highly metastatic, whereas C4.L8 cells were not. Moreover, C4.L8 cells produced slow-growing subcutaneous tumors in nude mice, whereas the other 3 cell lines produced fast-growing tumors. In vitro studies indicated that the expression of iNOS in C4.L8.5 cells was associated with either cytostasis or cytolysis via apoptosis, depending upon NO output. The tumor cells producing high levels of NO underwent autocytolysis and produced cytolysis of bystander cells under both in vitro and in vivo conditions. Multiple i.v. injections of liposomes containing a synthetic lipopeptide upregulated iNOS expression in murine M5076 reticulum sarcoma cells growing as hepatic metastases. The induction of iNOS was associated with the complete regression of the lesions. Transfection of interferon-beta suppressed tumor formation and eradicated metastases, which was apparently linked to iNOS expression and NO production in host cells such as macrophage. Besides mediating cell death, NO produced tumor suppression by regulating expression of genes related to metastasis, e.g., survival, invasion, and angiogenesis. Suppression of metastasis can be achieved through use of immunomodulators that induce iNOS expression in tumor lesions or by the direct delivery of the iNOS gene to tumor cells or host cells through liposome and/or viral vectors.

Animals↗
PubMed1998

Molecular regulation of UVB-induced cutaneous angiogenesis.

We determined whether cutaneous angiogenesis induced by exposure of mice to ultraviolet-B (UVB) radiation is associated with an imbalance between positive and negative angiogenesis-regulating molecules. Unshaved C3H/HeN mice were exposed to a single dose (15 kJ per m2) of UVB. At various times, the mice were killed, and their external ears were processed for routine histology and immunohistochemistry. Antibodies against proliferating cell nuclear antigen and bromodeoxyuridine identified dividing cells. Antibodies against CD31/ PECAM-1 identified endothelial cells, and antibodies against basic fibroblast growth factor (bFGF), vascular endothelial growth factor/vascular permeability factor, and interferon-beta (IFN-beta) identified angiogenesis-regulating molecules. Epidermal hyperplasia was documented by 48 h and reached a maximum on day 7 after exposure to UVB. The expression of bFGF increased by 24 h, whereas the expression of IFN-beta decreased by 72 h after exposure to UVB. The expression of vascular endothelial growth factor/vascular permeability factor increased slightly after irradiation. The altered balance between bFGF and IFN-beta was associated with increased endothelial cell proliferation (bromodeoxyuridine + CD31 + cells) within existing blood vessels, leading to telangiectasia and new blood vessels. UV-induced epidermal hyperplasia and cutaneous angiogenesis were highest in IFN-alpha/beta receptor knockout mice. These results demonstrate that in response to UVB radiation, dividing keratinocytes produce a positive angiogenic molecule (bFGF) but not a negative angiogenic molecule (IFN-beta), and that this altered balance is associated with enhanced cutaneous angiogenesis.

Animals↗
PubMed1998

Induction of nitric oxide production and tumoricidal properties in murine macrophages by a new synthetic lipopeptide JBT3002 encapsulated in liposomes.

We studied activation to the tumoricidal state of murine peritoneal macrophages by liposomes containing a new synthetic analogue, JBT3002, of a lipoprotein from the outer wall of a gram-negative bacterium. The liposomes containing JBT3002 or CGP31362 were superior to liposomes containing muramyl tripeptide phosphatidylethanolamine (MTP-PE) for tumoricidal activation in three ways. First, efficient macrophage activation required lower concentrations of JBT3002 or CGP31362 than MTP-PE. Second, macrophage activation by JBT3002 was less dependent on priming by interferon-gamma. Third, MLV-JBT3002 activated tumoricidal properties in both lipopolysaccharide (LPS)-responsive and LPS-nonresponsive macrophages. The activation of tumoricidal properties by MLV-JBP3002 depended on protein tyrosine kinase (PTK) activity associated with phosphorylation of tyrosine. The major mechanism for tumoricidal activity in macrophages incubated with MLV-JBT3002 was due to increased activity of inducible nitric oxide synthase (iNOS) and, hence, production of nitric oxide (NO). We base this conclusion on the results of several experiments. First, MLV-JBT3002 was not directly toxic to tumor target cells. Second, the specific iNOS inhibitor NG-monomethyl-L-arginine abrogated tumor cell lysis by MLV-JBT3002-treated macrophages. Third, macrophages from iNOS knockout mice did not lyse tumor cells, even after incubation with high concentrations of MLV-JBT3002. These data suggest that liposomes containing the synthetic bacterial lipopeptide JBT3002 are potent activators of macrophage tumoricidal properties.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1998

Regulation of distinct steps of angiogenesis by different angiogenic molecules.

This study was designed to determine the relative activity of basic fibroblast growth factor (bFGF), vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), platelet-derived growth factor (PDGF), platelet-derived endothelial cell growth factor (PD-ECGF), hepatocyte growth factor (HGF), and interleukin-8 (IL-8) in regulating endothelial cell division, migration, degradation of the extracellular matrix (ECM), morphogenesis, and survival. Human umbilical vein endothelial cells (HUVEC) were treated with different concentrations of the six cytokines. bFGF was the most potent mitogen followed by VEGF/VPF and PD-ECGF. VEGF/VPF and bFGF also enhanced the survival of the endothelial cells in serum-free medium. Interstitial collagenase (MMP-1) and urokinase plasminogen activator (uPA) were significantly upregulated only by bFGF. HGF, bFGF, and VEGF/VPF induced chemotactic migration of the endothelial cells, but only HGF (scatter factor) enhanced nondirectional motility. The organization of endothelial cells to form tubes on Matrigel was induced by bFGF and, to a lesser extent, by VEGF/VPF and IL-8. Permeability across endothelial cell monolayers was induced only by VEGF/VPF. These data demonstrate that different angiogenic molecules differentially regulate distinct steps in the process of angiogenesis, suggesting that any given molecule may be necessary but in itself insufficient for establishment of a viable vasculature.

Angiogenesis Inducing Agents↗