Prognostic significance of TRAIL-R3 and CCR-2 expression in tumor epithelial cells of patients with early breast cancer

Tumor epithelial cells (TEpCs) and spindle-shaped stromal cells, not associated with the vasculature, of patients with early breast cancer express osteoprotegerin (OPG), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), receptor activator of nuclear factor kappa B ligand, stromal cell derived factor-1, interleukin-6, macrophage colony stimulating factor, chemokine (C-C motif) ligand-2 (CCL-2) and their receptors at significantly higher levels compared with non-neoplastic breast tissues. We evaluated the clinicopathological significance of these ligands and receptors in TEpC and spindle-shaped stromal cells, not associated with the vasculature, to determine their impact on prognosis of patients with early-stage breast cancer.Fil: Labovsky, Vivian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Martinez, Leandro Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Davies, Kevin Mauro. Hospital Italiano; ArgentinaFil: de Luján Calcagno, María. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: García Rivello, Hernán. Hospital Italiano; ArgentinaFil: Wernicke, Alejandra. Hospital Italiano; ArgentinaFil: Feldman, Leonardo. Fundación Favaloro; ArgentinaFil: Matas, Ayelen. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Giorello, María Belén. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Borzone, Francisco Raúl. Ministerio de Salud. Instituto Nacional del Cancer; ArgentinaFil: Choi, Hosoon. Central Texas Veterans Research Foundation; Estados UnidosFil: Howard, Scott C.. University of Tennessee; Estados UnidosFil: Chasseing, Norma Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Interleukin-6 receptor in spindle-shaped stromal cells, a prognostic determinant of early breast cancer

Spindle-shaped stromal cells, like carcinoma-associated fibroblasts and mesenchymal stem cells, influence tumor behavior and can serve as parameters in the clinical diagnosis, therapy, and prognosis of early breast cancer. Therefore, the aim of this study is to explore the clinicopathological significance of tumor necrosis factor-related apoptosis-induced ligand (TRAIL) receptors (Rs) 2 and 4 (TRAIL-R2 and R4), and interleukin-6 R (IL-6R) in spindle-shaped stromal cells, not associated with the vasculature, as prognostic determinants of early breast cancer patients. Receptors are able to trigger the migratory activity, among other functions, of these stromal cells. We conducted immunohistochemical analysis for the expression of these receptors in spindle-shaped stromal cells, not associated with the vasculature, of primary tumors from early invasive breast cancer patients, and analyzed their association with clinicopathological characteristics. Here, we demonstrate that the elevated levels of TRAIL-R2, TRAIL-R4, and IL-6R in these stromal cells were significantly associated with a higher risk of metastatic occurrence (p = 0.034, 0.026, and 0.006; respectively). Moreover, high expression of TRAIL-R4 was associated with shorter disease-free survival and metastasis-free survival (p = 0.013 and 0.019; respectively). Also, high expression of IL-6R was associated with shorter disease-free survival, metastasis-free survival, and overall survival (p = 0.003, 0.001, and 0.003; respectively). Multivariate analysis showed that IL-6R expression was an independent prognostic factor for disease-free survival and metastasis-free survival (p = 0.035). This study is the first to demonstrate that high levels of IL-6R expression in spindle-shaped stromal cells, not associated with the vasculature, could be used to identify early breast cancer patients with poor outcomes.Fil: Labovsky, Vivian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Martinez, Leandro Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Calcagno, María de Luján. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Davies, Kevin Mauro. Hospital Italiano; ArgentinaFil: Garcia Rivello, Hernan Jorge. Hospital Italiano; ArgentinaFil: Wernicke, Alejandra. Hospital Italiano; ArgentinaFil: Feldman, Leonardo. Fundación Favaloro; ArgentinaFil: Giorello, Maria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Matas, Ayelen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Borzone, Francisco Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Howard, Scott C.. University of Memphis; Estados UnidosFil: Chasseing, Norma Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

CD105 expression on CD34-negative spindle-shaped stromal cells of primary tumor is an unfavorable prognostic marker in early breast cancer patients

Several studies have confirmed that the breast tumor microenvironment drives cancer progression and metastatic development. The aim of our research was to investigate the prognostic significance of the breast tumor microenvironment in untreated early breast cancer patients. Therefore, we analyzed the association of the expression of α-SMA, FSP, CD105 and CD146 in CD34-negative spindle-shaped stromal cells, not associated with the vasculature, in primary breast tumors with classical prognostic marker levels, metastatic recurrence, local relapse, disease-free survival, metastasis-free survival and the overall survival of patients. In the same way, we evaluated the association of the amount of intra-tumor stroma, fibroblasts, collagen deposition, lymphocytic infiltration and myxoid changes in these samples with the clinical-pathological data previously described. This study is the first to demonstrate the high CD105 expression in this stromal cell type as a possible independent marker of unfavorable prognosis in early breast cancer patients. Our study suggests that this new finding can be useful prognostic marker in the clinical-pathological routine.Fil: Martinez, Leandro Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Labovsky, Vivian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Calcagno, María de Luján. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Davies, Kevin Mauro. Hospital Italiano de Buenos Aires; ArgentinaFil: García Rivello. Hernán. Hospital Italiano de Buenos Aires; ArgentinaFil: Bianchi, Maria Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Wernicke, Alejandra. Hospital Italiano de Buenos Aires; ArgentinaFil: Fernández Vallone, Valeria Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Chasseing, Norma Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentin

Association between of ligands and receptors related to the progression of early breast cancer in tumor epithelial and stromal cells

Despite advances in the study of breast cancer (BC), it remains the second leading cause of mortality among women. BC is a heterogeneous system, mainly composed of tumor epithelial cells (TEpCs) and stromal cells (SCs); the interaction through the ligands and their receptors (Rs) plays a major role in BC progression. The aim of the present study was to evaluate the association between ligands, such as osteoprotegerin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), receptor activator of nuclear factor kappa B ligand (RANKL), stromal cell-derived factor (SDF)-1, interleukin (IL)-6, macrophage colony stimulating factor, chemokine (C-C motif) ligand-2 (CCL-2), and their Rs in TEpC and spindle-shaped SCs not closely associated with the vasculature.Fil: Labovsky, Vivian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Martinez, Leandro Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Davies, Kevin Mauro. Hospital Italiano de Buenos Aires; ArgentinaFil: García Rivello, Hernán. Hospital Italiano de Buenos Aires; ArgentinaFil: Calcagno, María de Luján. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Matas, Ayelen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Fernández Vallone, Valeria Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Wernicke, Alejandra. Hospital Italiano de Buenos Aires; ArgentinaFil: Choi, Hosoon. Institute for Regenerative Medicine at Scott & White. College of Medicine; Estados UnidosFil: Chasseing, Norma Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentin

CD1a- and CD83-positive dendritic cells as prognostic markers of metastasis development in early breast cancer patients

Dendritic cells (DCs) are the most potent antigen-presenting cells that play a major role in initiating the antitumor immune response in different types of cancer. However, the prognostic significance of the accumulation of these cells in human early breast tumors is not totally clear. The aim of this study is to evaluate the prognostic relevance of CD1a( +) and CD83( +) dendritic cells in early breast cancer patients.Fil: Giorello, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Matas, Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Marenco, Pablo. Instituto Universidad Escuela de Medicina del Hospital Italiano; ArgentinaFil: Davies, Kevin Mauro. Instituto Universidad Escuela de Medicina del Hospital Italiano; ArgentinaFil: Borzone, Francisco Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Calcagno, María de Luján. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: García-Rivello, Hernán. Hospital Italiano; ArgentinaFil: Wernicke, Alejandra. Hospital Italiano; ArgentinaFil: Martinez, Leandro Marcelo. Cornell University. Weil Cornell Medical College; Estados UnidosFil: Labovsky, Vivian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Chasseing, Norma Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Histological features of primary breast tumor stroma as determined by hematoxylin and eosin staining.

<p>This picture is an example of samples with a large amount and absent/scanty amount of stroma, fibroblasts, collagen deposition, lymphocytic infiltration and myxoid changes. The arrows show tumor fibroblasts (F), collagen deposition (C), lymphocytic infiltration (L) and myxoid changes (M C). Original magnification: 100×. The scale bars represent 200 μm.</p

Expression of CD34 in tumor stromal cells.

<p>Representative negative staining for CD34 in the evaluated spindle-shaped stromal cells, not associated with the vasculature, of primary tumor tissue from a breast cancer patient. The arrow shows an example of CD34-positive staining only in the endothelial cells (E). No staining was observed in the tissues when we incubated them with irrelevant mouse IgG1 as a negative isotype control. Nuclei were counterstained with hematoxylin (purple). Original magnification: 400×. The scale bar represents 50 μm.</p

Correlation of CD105 and FSP expression, as well as lymphocytic infiltration quantity with disease-free survival, metastasis-free survival and overall survival of 56 untreated early breast cancer patients.

<p><b>A</b> Kaplan-Meier curves show that high stromal cell expression of CD105 is associated with a shorter disease-free survival, metastasis-free survival and overall survival of our breast cancer patients. The difference is statistically significant [p = 0.0010 in all of cases by log-rank (Mantel-Cox)-test]. The adjusted p-value is 0.0327 (Benjamini-Hochberg correction) in all of cases. Moreover, positive FSP expression is significantly associated with a greater overall survival of these patients [p = 0.0400 by log-rank (Mantel-Cox) test]. Furthermore, a large amount of lymphocytic infiltration is significantly associated with a shorter overall survival of these patients [p = 0.0160, log-rank (Mantel-Cox) test]. After the Benjamini-Hochberg adjustment, these last associations were considered not significant (adjusted p = 0.4031 and 0.2096, respectively). <b>B</b> Photographs show a representative immunohistochemistry staining for tumor samples with high and negative/low stromal expression of CD105, as well as tumor samples with positive and negative FSP expression. The arrows show positive staining of evaluated stromal cells (S), endothelial cells (E) and tissue associated-macrophages (M) used as internal positive controls as previously described. Original magnification: 400×. The scale bars represent 50 μm.</p

Expression of α-SMA, FSP, CD105 and CD146 in malignant and non-malignant breast tissues.

<p><b>A</b> Representative immunohistochemistry staining for α-SMA, FSP, CD105 and CD146 in stromal cells of primary tumor tissues from breast cancer (BC) patients and non-malignant breast tissues. Reactions were evaluated in spindle-shaped stromal cells, not associated with the vasculature. The arrows show positive staining of evaluated stromal cells (S) and smooth muscle cells (S M), myoepithelial cells (MY), tissue-associated macrophages (M) and endothelial cells (E) used as internal positive controls as previously described. <b>B</b> No staining was observed in both types of tissues when we incubated them without primary antibodies and with irrelevant mouse IgG2a (for α-SMA), irrelevant mouse IgM (for FSP) or total normal goat IgG (for CD105 and CD146) as negative controls. Nuclei were counterstained with hematoxylin (purple). Original magnification A and B: 400×. The scale bars represent 50 μm.</p