ABSTRACT
Galectins, beta-galactoside binding proteins, expressed selectively in human breast carcinoma are attractive targets to employ lectin-aimed therapeutics. We examined beta-galactoside binding potency of neoplastic cells using fluorescein-labelled synthetic glycoconjugates as probes for flow cytometry. As a result, surface beta-galactoside binding proteins/galectins were discovered on mouse mammary carcinoma cells in vitro and in vivo unlike non-malignant cells from the several tissues; and asialo-GM1 ganglioside carbohydrate part--containing probe was the most specific one. However, in liver and lung metastatic cells galectins seem to be expressed within cytoplasm and/or nuclei. Galectin expression correlated directly with aggressive tumour potential in the A/Sn transplantable model similar to findings in several human breast carcinoma cell lines. However, galectin expression was reduced during tumour progression in more aggressive forms of spontaneous BLRB mammary carcinomas like it was shown for human breast carcinoma specimens. Analysis of the histopathological data led, however, to the conclusion that galectin expression hardly might be a suitable marker of aggressiveness of heterogeneous mammary carcinomas as the observed level of galectin expression is influenced by the amount of the stroma in a tumour sample and/or probably, galectin expression inversely correlates with tumour aggressiveness during the initial and advanced steps of mammary tumour progression. We conclude that surface beta-galactoside binding proteins/galectins that are selectively expressed during mouse mammary carcinoma progression, similarly to human breast carcinomas, seem to be proper targets for asialo-GM1-vectored cytotoxics and our mouse model system might be a relevant instrument to further test novel modes of anti-breast cancer therapy.
Subject(s)
Biomarkers, Tumor/metabolism , G(M1) Ganglioside/metabolism , Galactosides/metabolism , Galectins/metabolism , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/therapy , Animals , Cell Membrane/metabolism , Cell Nucleus/metabolism , Cytoplasm/metabolism , Disease Progression , Female , Glycoconjugates , In Vitro Techniques , Liver Neoplasms/metabolism , Liver Neoplasms/secondary , Male , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred Strains , Stromal Cells/metabolism , Stromal Cells/pathology , Tumor Cells, Cultured/transplantationABSTRACT
We have compared the effect of one and up to four local IL-2 treatments of transplanted MC38 colon carcinoma. A single IL-2 treatment prolonged the survival time ( p=0.015), but no cure was obtained. One local IL-2 treatment inhibited tumor growth for about 1 week. After the start of tumor regrowth, a further IL-2 injection was given. After four IL-2 injections 6 out of 13 mice were cured. Histological studies show that IL-2 induced a local vascular leakage syndrome leading to massive peritumoral edema and subsequent necrosis of tumor tissue. IL-2 also attracted infiltrating cells, mainly macrophages. Subsequent IL-2 injections led to complete tumor regression. We believe that the combination of necrotic tumor debris and the IL-2-induced macrophage reaction enhanced a tumor-specific immune response. This local IL-2 application was not toxic.
Subject(s)
Colonic Neoplasms/drug therapy , Interleukin-2/administration & dosage , Neoplasms, Experimental/drug therapy , Animals , Colonic Neoplasms/pathology , Dose-Response Relationship, Drug , Female , Interleukin-2/pharmacology , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Neoplasms, Experimental/pathology , Nitric Oxide/metabolism , Tumor Cells, Cultured/transplantationABSTRACT
Interleukin-2 therapy is not clearly effective against breast cancer both in mouse models and in human patients. However, the study of IL-2 therapy of breast cancer remains important, as 3,700 women died from this malignancy in the Netherlands in 2000. Previously we have shown the therapeutical efficacy of a single peritumoural IL-2 application in different experimental models and in veterinary patients. Here we apply this mode of IL-2 therapy to advanced mouse mammary carcinoma models, i.e., severe metastasised tumours in A/Sn mice and non-metastasised carcinomas in BALB/c mice. Mice with advanced transplanted mammary carcinomas were given a single peritumoural treatment with 2.5 x 10(6) IU IL-2 at days 10-14 after i.p. or s.c. inoculation of 10(6) carcinoma cells. Within each experiment it was always possible to distinguish relatively slowly and fast growing tumours which allows the therapeutical effect of IL-2 in tumours with different growth rates to be studied. A new approach to analyse results enabled us to show that survival of mice with transplanted, advanced metastasised breast cancer can be significantly improved after a single local treatment with IL-2. Advanced relatively fast i.p and s.c. growing mammary carcinomas seem to be more sensitive to a single IL-2 treatment than relatively slowly growing tumours. IL-2 was most effective against non-metastasised mouse breast cancer.
