Regulation of leukocyte binding to endothelial tissues by tumor-derived GM-CSF (original) (raw)
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Tumor angiogenesis factors reduce leukocyte adhesion in vivo
International Immunology, 2000
It is reported here that, in a tumorfree in vivo model, angiogenic factors can down-regulate leukocyte adhesion to endothelium. Slow releasing pellets were loaded with either basic fibroblast growth factor (bFGF), vascular endothelial cell growth factor (VEGF) or vehicle alone and were placed in the scrotum of mice. After 3 days, a single intrascrotal injection of 1 µg/kg IL-1β was given 4 h before vessels of the cremaster muscle were investigated for leukocyte rolling and adhesion by means of intravital microscopy. Exposure of normal tissue to either bFGF or VEGF resulted in markedly decreased levels of cytokine-induced leukocyte adhesion. Suppression of leukocyte rolling was not observed. Instead a moderate enhancement of rolling by VEGF was found. The observed differences could not be explained by differences in fluid dynamic parameters or systemic leukocyte counts. In conclusion, evidence is presented that, in vivo, angiogenic factors significantly reduce leukocyte adhesion, the final step preceding leukocyte infiltration. This observation may explain why tumors escape from immune surveillance.
Leukocyte trafficking in tumor microenvironment
Current opinion in pharmacology, 2017
The tumor microenvironment consists of both malignant and non-malignant cells and a plethora of soluble mediators. Different types of tumors have specific tumor microenvironments characterized by distinct chemokines and chemotactic factors that influence leukocyte recruitment. The immune cell infiltrate continuously interacts with stroma cells and influence tumor growth. Emerging evidence suggests that the regulation of the composition and the metabolic state of tumor-associated leukocytes may represent a new promising intervention strategy. Here we summarize the current knowledge on the role of tumor-associated immune cells in tumor growth and dissemination, with a specific focus on the nature of the chemotactic factors responsible for their accumulation and activation in tumors.
PubMed, 1995
Tumor necrosis factor alpha (TNF-alpha) can lead to tumor regression when injected locally or when used in an isolated limb perfusion, and it can enhance the tumoricidal effect of various therapies. TNF-alpha can also up-regulate adhesion molecules, and thus, facilitate the binding of leukocytes to normal vessels. The present study was designed to investigate the extent to which the host leukocytes roll and adhere to vessels of different tumors (MCaIV, a murine mammary adenocarcinoma; HGL21, a human malignant astrocytoma) at a given site or to the same tumor at different sites (dorsal skin and cranium), in different mouse strains [C3H and severe combined immunodeficient (SCID)], both with and without TNF-alpha-activation. There was no significant difference in hemodynamic parameters such as RBC velocity, diameter, or shear rate between PBS-treated control groups and corresponding TNF-alpha-treated groups. Under PBS control conditions, the leukocyte rolling count in MCaIV tumor vessels in the dorsal chamber in C3H and SCID mice and in the cranial window in C3H mice was significantly lower than that in normal vessels (P < 0.05), but stable cell adhesion was similar between normal and tumor vessels. TNF-alpha led to an increase (P < 0.05) in leukocyte-endothelial interaction in vessels in the following cases: normal tissue regardless of sites and strains, MCaIV tumor in the cranial window in C3H mice, and HGL21 tumor in the cranial window in SCID mice. However, the increase in rolling and adhesion in the MCaIV tumor in response to TNF-alpha was significantly lower than in the corresponding normal vessels (P < 0.05) in the dorsal chamber in C3H and SCID mice and in the cranial window in C3H mice. The HGL21 tumor in the cranial window in SCID mice showed leukocyte rolling and adhesion comparable to that in normal pial vessels. These findings suggest that (a) in general, basal leukocyte rolling is lower in tumor vessels than in normal vessels; (b) leukocyte rolling and adhesion in tumors can be enhanced by TNF-alpha-mediated activation; and (c) the TNF-alpha response is dependent on tumor type, transplantation site, and host strain. These results have significant implications in the gene therapy of cancer using TNF-alpha-gene-transfected cancer cells or lymphocytes.
Tumor blood vessels, a difficult hurdle for infiltrating leukocytes
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2007
In spite of a gradual improvement of its therapy, cancer is still a deadly disease for millions of patients. Immunotherapy is one of promising treatment strategies, but several mechanisms counteract the development of a proper anti-tumor immune response and the formation of an effective inflammatory infiltrate. One of the difficult hurdles is the hampered recruitment of leukocytes from the blood into the tumor site. It has been demonstrated that tumor cells evolved mechanisms to escape immunity, based on down regulation of endothelial adhesion molecules. This paper reviews the endothelial cell adhesion molecules that mediate leukocyte recruitment and the regulation of them during tumor development. In addition, an overview will be given of the translational development and clinical application of the specific composition of adhesion molecules on tumor endothelium, in diagnosis and therapy.
Cancer research, 1990
Using an immunogenic nonmetastatic murine mammary adenocarcinoma (D1-DMBA-3) induced in BALB/c mice by dimethylbenzanthracene, we have previously shown that splenocytes from tumor bearers have depressed lymphocyte responses to mitogens and antigens, including tumor-associated antigens. In addition, they display decreased natural killer and T-cell cytotoxic activities. Macrophages from tumor-bearing mice appear to be responsible for the suppression of T- and B-cell responses to concanavalin A, lipopolysaccharide, and tumor-associated antigens observed in tumor bearers. The appearance of these macrophages in the spleen tightly parallels the progressive growth of the tumor and the concomitant immunosuppression. Simultaneously high levels of macrophage progenitors were observed in blood, bone marrow, lung, and liver. A significant increase of colony-stimulating activity of the granulocyte-macrophage lineage was detected in the sera from tumor-bearing mice. Higher levels of this colony-s...
Angiogenic Profile of Breast Carcinoma Determines Leukocyte Infiltration
Clinical Cancer Research, 2004
To study the relationship between the angiogenic profile and leukocyte infiltration of tumors, single cell suspensions of archival frozen medullary and ductal breast cancer tissues were analyzed by flow cytometry. The amount of leukocytes and endothelial cells was measured, as well as the expression of intercellular adhesion molecule-1 (ICAM-1) on the endothelial cell fraction. A significantly higher number (3.2-fold) of infiltrating leukocytes was observed in medullary carcinoma. The composition of this infiltrate was similar to that seen in ductal carcinomas. The more intense infiltrate was explained by the ϳ3-fold enhanced endothelial ICAM-1 expression in medullary carcinoma. The angiogenic profile of all tumors was assessed by quantitative real-time reverse transcription-PCR analysis. Vascular endothelial growth factor (VEGF)-C and VEGF-D, but not VEGF-A, basic fibroblast growth factor, placental growth factor, and angiopoietins 1, 2, and 3 showed a relatively higher level of expression in ductal carcinoma than in medullary carcinoma. In vitro, both VEGF-C and VEGF-D were found to decrease endothelial ICAM-1 expression in the presence of basic fibroblast growth factor. These data suggest that in vivo angiogenic stimuli prevent the formation of an effective leukocyte infiltrate in tumors by suppressing endothelial ICAM-1 expression.
Increased chemotaxis of leukocytes from mice bearing tumors
Cancer research, 1986
Increased chemotaxis toward activated serum was demonstrated by leukocytes from bone marrow, spleen, and peripheral blood of tumor-bearing mice as compared with those of normal mice. Increased chemotaxis was correlated with duration of tumor growth, which, in turn, was correlated with size of tumor. Upon surgical tumor removal, chemotaxis fell to normal levels unless metastasis had occurred, in which case, the extent of chemotaxis was correlated with the volume of the metastasis. Increased chemotaxis was seen in relation to the growth of a mammary adenocarcinoma as well as that of a chemically induced fibrosarcoma. The major chemotactant in serum was shown to be complement derived, and sera from tumor-bearing and normal animals were equally effective. The presence of a tumor resulted in an increase in the percentage of polymorphonuclear cells in the bone marrow. The numbers of cells which migrated were independent of the cellular composition of the bone marrow in normal mice. In con...
British journal of cancer, 1993
Leukocytosis sometimes accompanies malignant neoplasms in the absence of infection. It is thought that the production of colony-stimulating factor by neoplasms is the most potent cause of tumour-induced leukocytosis; several mechanisms have been suggested to explain this. We examined 155 human tumour xenografts established in nude mice, and found that 17 of the xenografts induced remarkable leukocytosis (> 15,000 microliters-1) in nude rats. We examined granulocyte colony-stimulating factor (G-CSF) production by the xenografts to study the mechanisms underlying this tumour-induced leukocytosis. Ten of the 17 xenografted human tumours appeared to express the G-CSF gene. Serum G-CSF increased, to concentrations of 179-37,218 pg ml-1, in host animals transplanted with the ten xenografts expressing the G-CSF gene transcripts. The biological activity of serum G-CSF also increased, to concentrations of 206-9,074 pg ml-1, in the host animals transplanted with the ten xenografts. Immunoh...
The Journal of Immunology
We have previously demonstrated that the murine colon adenocarcinoma C-26 cell line transduced with the human gene for the granulocyte CSF (G-CSF) loses tumorigenic activity through a mechanism that involved massive targeting of neutrophils at the site of tumor injection. The suppression of tumorigenicity by G-CSF was limited to the G-CSF-producing cells and was not transferred to nonproducing C-26 cells in a mixed tumor transplantation assay. We present direct evidence that neutrophils are involved in this phenomenon. We firstly examined, by electron microscopy (EM), the morphology of tumor infiltrates obtained 2, 5, and 10 days after s.c. injection of a mixture of G-CSF-producing and -nonproducing C-26 cells into syngeneic BALB/c mice. The EM analysis showed at 5, but not at 2 or 10 days, the presence of neutrophils in intimate contact with tumor cells. We then investigated whether neutrophils discriminate between G-CSF-producing and -nonproducing C-26 cells. To this aim, C-26 cel...