Macrophage and Lymphocyte Potentiation of Syngeneic Tumor Cell and Host Fibroblast Collagenolytic Activity in Rats (original) (raw)
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Collagen production by macrophages in tumour encapsulation and dormancy
British Journal of Cancer, 1991
Dormant and regressing implants of C3H mammary carcinoma MC2 were always found to be surrounded by a cellular fibrous capsule where macrophages and T cells predominated as the cellular elements. Macrophages were always closely associated with the collagen deposition, and stained with anti-collagen type I immuno-peroxidase in tissue sections. The capacities of macrophages and T-lymphocytes to function in collagen formation was investigated with the use of Nuclepore chambers implanted i.p. in normal mice. The procollagen that entered the chambers via the pores, was assumed to have been produced by the packed layer of peritoneal macrophages that adhered firmly to the outside of washed chambers. The adherent cells all stained with Mac-I immuno-peroxidase, and phagocytosed yeast in short-term culture. The formation of collagen fibres in the chambers was enhanced if the chambers contained T lymphocytes. It appears that macrophages have the capacity to function as collagen producing cells in tumour encapsulation.
Clinical & Experimental Metastasis, 1995
Histological examination of the metastatic rat mammary adenocarcinoma line MTLn3 showed that macrophages and mast cells were frequently localized at the tumor periphery in the stromal tissues adjacent to the zones of tumor invasion. The interactions of these host cells with tumor cells and tumor-associated fibroblasts could be important in stimulating the production of extracellular matrix-degrading enzymes that facilitate tumor invasion and metastatic spread. Therefore, we examined the effects of isolated, activated macrophages and mast cells on the secretion of collagenolytic activities by normal fibroblasts, metastatic mammary adenocarcinoma cells and tumor-associated fibroblasts. Medium from activated macrophages or degranulated mast cells stimulated significant increases in production of collagenolytic activities by normal and tumor-associated fibroblasts and MTLn3 tumor cells. Medium from activated macrophages that had been pretreated with medium from degranulated mast cells, however, were less stimulatory to fibroblasts and tumor cell production of collagenolytic activities than medium from degranulated mast cells alone. We also examined the effects of two cytokines, interleukin-l~ and tumor necrosis factor-~ on activated macrophage-and degranulated mast cell-stimulation of fibroblast and tumor cell collagenolytic activities. The two cytokines alone or in combination stimulated increased production of collagenolytic activities by fibroblasts and tumor cells. Addition of the cytokines to degranulated mast cell products resulted in secretion of higher collagenolytic enzyme activities by normal fibroblasts (but not by tumor-derived fibroblasts or tumor cells) than with degranulated mast cell product-treatment of either target cell alone. Cytokines used in combination with macrophage-conditioned medium were less effective in stimulating fibroblast and tumor cell collagenase activities than cytokines alone. Thus normal infiltrating host cells such as macrophages and mast cells can have profound effects on the production of degradative enzymes by tumor cells and tumor-associated stromal fibroblasts.
Breast Cancer Research, 2012
Introduction: Tumor-associated macrophages, which are derived from the infiltration of circulating bone marrowderived monocytes, consist primarily of a polarized M2 macrophage (M2-M) population and are associated with poor prognosis in various cancers. In the present study, we attempted to assess whether M2-M s derived from bone marrow stimulate the promotion and progression of mammary tumors. Methods: 4T1 murine mammary carcinoma cells were injected either alone or coupled with M2-M s into the mammary fat pads of syngeneic female Balb/C mice. M2-M s were prepared by treating monocytes isolated from female Balb/C mouse bone marrow with IL-4. Tumor cell growth was determined using an in vivo imaging system and the expression of cell proliferation-related, angiogenesis-related, and lymphangiogenesis-related proteins in tumor tissues was immunohistochemically analyzed. To evaluate the effects of the crosstalk between 4T1 cells and M2-M s on the secretion and mRNA expression of cytokines and the migration of monocytes, 4T1 cells and M2-M s were co-cultured and cytokine antibody array, real-time RT-PCR, and trans-well migration assays were conducted. Results: The co-injection of M2-M s into the mammary fat pads of mice increased solid tumor growth and lung metastasis of 4T1 cells as well as the infiltration of CD45 + leukocytes into tumor tissues. The proportions of Ki-67 + proliferating cells and the expression of hypoxia inducible factor-1α, vascular endothelial cell growth factor A, CD31, vascular endothelial cell growth factor C, and lymphatic vessel endothelial receptor-1 were increased significantly in the tumor tissues of mice co-injected with 4T1 cells and M2-M s. The in vitro results revealed that the proliferation of 4T1 cells, the migration of monocytes, and the secretion of granulocyte colony-stimulating factor, IFNγ, IL-1α, IL-2, IL-16, IFNγ-induced protein-10, keratinocyte-derived chemokine, macrophage colonystimulating factor, monocyte chemotactic protein-1, macrophage inflammatory protein-1α, and RANTES were increased when 4T1 cells were co-cultured with M2-M s, as compared with when the 4T1 cells were cultured alone. Conclusion: The crosstalk between 4T1 cells and M2-M s increased the production of cytokines, which may have induced immune cell infiltration into tumor tissues, tumor cell proliferation, angiogenesis, and lymph angiogenesis, thereby increasing solid tumor growth and lung metastasis.
Enhancement of tumor growth in mice: Evidence for the involvement of host macrophages
Cellular Immunology, 1984
Intratumor host cells of methylcholanthrene-induced fibrosarcoma(s) were shown to enhance the in vivo outgrowth of syngeneic homologous tumors (MClA, Mc2A, Mc2B) but not two heterologous T-lymphomas (EL4 and TLX9) in the Winn adoptive transfer assay. This enhancing activity was not restricted only to the latent period of tumor growth but was also observed during the period of active in vivo tumor proliferation. Tumor enhancement was mediated by a population of cells adherent to nylon wool and glass and insensitive to irradiation (with 850 tads) or to treatment with anti-Thy 1.2 serum and complement. Macrophages from peritoneal exudates of normal mice, used as control host cell population, showed similar tumor-enhancing activity. These findings suggest that tumor infiltrating host cells, predominantly macrophages appear to be the cell type responsible for tumor enhancement and active promotion of tumor growth (in vivo).
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...
Virchows Archiv. B, Cell pathology including molecular pathology, 1986
An ascites subline (AA) of the murine sarcoma MC1M grows in vivo in the peritoneal cavity but dies in vitro when cultured on glass or collagen. The viability of AA cells in vitro is not influenced in cocultures with fibroblast cell line L929, and is diminished in cocultures supplemented with macrophage culture supernatant or in cocultures with non-adherent peritoneal cells. However, AA cells proliferate in vitro on glass or collagen when cocultured with syngeneic, semisyngeneic, and allogeneic peritoneal macrophages. This was demonstrated by tritiated thymidine incorporation assay, by AA cell number counting, and by measuring AA cell protein content. Proliferation also occurs when AA cells are separated from the macrophage monolayer by millipore filters.
In Vitro Cellular & Developmental Biology - Animal, 1993
Breast carcinomas commonly contain varying amounts of fibrous stroma and infiltrates of lymphoid cells. Dickson and Lippman (Endocrine Rev., 8,29, 1987) have proposed a model of growth regulation in breast cancer involving interactions between stroma and carcinoma cells. This model is based on results obtained with established cell lines. In an effort to bring experimentation closer to the clinical situation we have used short-term primary cultures from human breast cancer in co-cultures with lymphocytes and fibroblasts. Cultures were established in a chemically defined serum-free medium (CDM3). Cell types were characterized on the basis of live morphology and expression of vimentin and keratin 18. A semi-quantitative system was developed for measuring growth of epithelial cells, thus defining two indices: maximal growth index (GI-max) and growth rate (GR). Moderate-to-good growth was obtained from 34 out of 46 carcinoma samples (74%) and 30 out of 38 parallel samples of non-cancerous tissue (79%). Success in culture was negatively correlated with the amount of hard stroma but unrelated to age of patient or clinical status. Malignant epithelium was clearly identified in 12 out of 34 (35%) carcinoma samples. For the evaluation of responses of epithelial cells in co-cultures, the cultures from each sample were ranked according to GI-max. From 20 co-culture experiments using carcinoma samples, the following results were obtained: the highest GI-max was found in 11 of the co-cuhures with lymphocytes; in six of the co-cultures with fibroblasts; in one case in the control culture without partner cells; and in two experiments there was no difference between controls and co-cultures. The corresponding values for non-cancerous samples were: 5 out of 17, 2/17, 2/17, and 8/17. Control experiments performed without partner cells confirmed that these differences in GI-max between cultures were beyond random variations. Four samples displayed particularly vigorous responses to lymphocytes, and two samples responded extensively to fibroblasts. In four of these six samples cancer ceils proliferated. We conclude that it is feasible to use primary cultures of breast carcinomas for experimentation. Fibroblasts did not have very marked effects on epithelial cell growth, but, contrary to expectation, there was a clear tendency for lymphocytes to stimulate growth.
International Journal of Cancer, 1975
Murine solid tumors were shown to contain 9-54 % medium to large non-malignant cells bearing receptors .for immunoglobulin Fc. These cells rapidly adhered to plastic surfaces, were trypsin-resistant, were capable of phagocytosis of latex particles and were sensitive to the lytic efects of anti-macrophage serum and complement. PuriJied Fc-receptor-positive cells failed to produce tumors, which strongly suggested that they were macrophages. When tumor-cell suspensions, depleted of macrophages by adherence to plastic surfaces, were injected subcutaneously into normal syngeneic mice, the tumors displayed an increased potential for metastasis. By contrast, control animals which received tumor-cell suspensions containing their normal complement of macrophages invariably developed progressive localized tumors. The survival times of mice injected with macrophage-depleted tumor-cell suspensions were significantly shorter (p tO.05) than those for animals inoculated with intact tumor-cell suspensions. These studies confirm the existence of a substantial number of macrophages within progressing syngeneic murine solid tumors and strongly suggest a regulatory role for the macrophages in the growth and metastasis ofthe tumor.
Cellular Immunology, 2019
Here we used three different murine mammary carcinomas to study the immune environment associated with early tumor sites. While it was not surprising that the early immune response was predominated by macrophages and neutrophils, there were some novel findings at this early stage of disease. For instance, the macrophages and neutrophils expressed a mixed cytokine profile with TNF- and TGF- both produced at appreciable levels. Moreover, while the cells retained their phagocytic capacity, production of reactive oxygen species by the macrophages and neutrophils was in decline. Alterations in the metabolic profile of the tumor associated macrophages were also evident with a decrease in the ATP production rate, and a higher dependence on oxidative phosphorylation for ATP production. Collectively, these data indicate a mixed phenotype of tumor-associated macrophages and neutrophils evident within hours of murine mammary carcinoma delivery.
Resistance of tumour cells to macrophages
Cancer Immunology Immunotherapy, 1980
The concept of specific immune surveillance in neoplastic disease has exercised considerable intellectual appeal during the last two decades, and attempts to substantiate the concept by experimentation have been proportionately intense. Unfortunately the results of this effort have been often disappointing, particularly With regard to human tumours. Studies of the relationship between macrophages and tumours have seemed, by comparison, reasonably free of specific expectations. Certainly there existed no particular obligation to show that tumours exert a suppressive influence on the function of macrophages. All the more interesting then were the initial observations, made independently in a number of laboratories, that macrophage function is defective in tumour hosts and that soluble tumour-derived material influences macrophage function in vitro. The case for macrophages as major effectors in anti-tumour host defence ~as been persuasively argued elsewhere . Although the elaboration of factors suppressing macrophage function could be a chance consequence of tumour development, the probability that such mechanisms represent an evolved means of tumour resistance, emerging under the selective pressure of macrophage-mediated host defence, is likely to be directly proportional to their proficiency, their selectivity, and the consistency with which they are encountered.