title: CD68+, but not stabilin-1+ tumor associated macrophages in gaps of ductal tumor structures negatively correlate with the lymphatic metastasis in human breast cancer.
abstract: Tumor associated macrophages (TAM) support tumor growth and metastasis in several animal models of breast cancer, and TAM amount is predictive for efficient tumor growth and metastatic spread via blood circulation. However, limited information is available about intratumoral TAM heterogeneity and functional role of TAM subpopulations in tumor progression. The aim of our study was to examine correlation of TAM presence in various morphological segments of human breast cancer with clinical parameters. Thirty six female patients with nonspecific invasive breast cancer T1-4N0-3M0 were included in the study. Morphological examination was performed using Carl Zeiss Axio Lab.A1 and MiraxMidiZeiss. Immunohistochemical and immunofluorescence/confocal microcopy analysis was used to detect CD68 and stabilin-1 in 5 different tumor segments: (1) areas with soft fibrous stroma; (2) areas with coarse fibrous stroma; (3) areas of maximum stromal-and-parenchymal relationship; (4) parenchymal elements; (5) gaps of ductal tumor structures. The highest expression of CD68 was in areas with soft fibrous stroma or areas of maximum stromal-and-parenchymal relationship (79%). The lowest expression of CD68 was in areas with coarse fiber stroma (23%). Inverse correlation of tumor size and expression of CD68 in gaps of tubular tumor structures was found (R=-0.67; p=0.02). In case of the lymph node metastases the average score of CD68 expression in ductal gaps tumor structures was lower (1.4±0.5) compared to negative lymph nodes case (3.1±1.0; F=10.9; p=0.007). Confocal microscopy identified 3 phenotypes of TAM: CD68+/stabilin-1-; CD68+/stabilin-1+(over 50%); and CD68-/stabilin-1+. However, expression of stabilin-1 did not correlate with lymph node metastasis. We concluded, that increased amount of CD68+TAM in gaps of ductal tumor structures is protective against metastatic spread in regional lymph nodes.
authors.affiliation: Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Pr. Lenina, 36, 634050 Tomsk, Russia; Tomsk Cancer Research Institute, Per. Kooperativny, 5, 634050 Tomsk, Russia.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Buldakov
authors.affiliation: Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Pr. Lenina, 36, 634050 Tomsk, Russia; Tomsk Cancer Research Institute, Per. Kooperativny, 5, 634050 Tomsk, Russia; Siberian State Medical University, Moskovskiy Trakt, 2, 634050 Tomsk, Russia.
authors.forename: Marina
authors.initials: M
authors.lastname: Zavyalova
authors.affiliation: Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Pr. Lenina, 36, 634050 Tomsk, Russia; Siberian State Medical University, Moskovskiy Trakt, 2, 634050 Tomsk, Russia.
authors.forename: Nadezhda
authors.initials: N
authors.lastname: Krakhmal
authors.affiliation: Siberian State Medical University, Moskovskiy Trakt, 2, 634050 Tomsk, Russia.
authors.forename: Nadezhda
authors.initials: N
authors.lastname: Telegina
authors.affiliation: Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Pr. Lenina, 36, 634050 Tomsk, Russia; Siberian State Medical University, Moskovskiy Trakt, 2, 634050 Tomsk, Russia.
authors.forename: Sergei
authors.initials: S
authors.lastname: Vtorushin
authors.affiliation: Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Pr. Lenina, 36, 634050 Tomsk, Russia.
authors.forename: Irina
authors.initials: I
authors.lastname: Mitrofanova
authors.affiliation: Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Pr. Lenina, 36, 634050 Tomsk, Russia; Department of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Riabov
authors.affiliation: Department of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
authors.forename: Shuiping
authors.initials: S
authors.lastname: Yin
authors.affiliation: Department of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
authors.forename: Bin
authors.initials: B
authors.lastname: Song
authors.affiliation: Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Pr. Lenina, 36, 634050 Tomsk, Russia; Tomsk Cancer Research Institute, Per. Kooperativny, 5, 634050 Tomsk, Russia.
authors.forename: Nadezhda
authors.initials: N
authors.lastname: Cherdyntseva
authors.affiliation: Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Pr. Lenina, 36, 634050 Tomsk, Russia; Department of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; German Red Cross Blood Service Baden-Württemberg-Hessen, Friedrich-Ebert Strasse 107, 68167 Mannheim, Germany. Electronic address: julia.kzhyshkowska@medma.uni-heidelberg.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Kzhyshkowska
mesh_terms: D000368:Aged; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D016201:Receptors, Lymphocyte Homing / Q000235:genetics / Q000378:metabolism*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D015816:Cell Adhesion Molecules, Neuronal; D016201:Receptors, Lymphocyte Homing; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C449926:STAB1 protein, human
keywords: Breast cancer; CD68; Intratumoral heterogeneity; Lymphatic metastasis; Stabilin-1; Tumor-associated macrophages