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1.
Cancer Res ; 61(4): 1320-6, 2001 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-11245428

RESUMEN

Although growth factors and extracellular matrix (ECM) are recognized as important contributors to breast epithelial growth, morphogenesis, hormone responsiveness, and neoplastic progression, the influence of functional interactions between breast stromal and epithelial cells on these processes has not been defined. Using a novel three-dimensional cell-cell interaction model, we have compared the abilities of different mesenchymal cell types, including breast fibroblasts derived from reduction mammoplasty and tumor tissues, and human umbilical endothelial cells (HUVECs) to induce three-dimensional morphogenesis and growth of normal MCF10A and preneoplastic MCF10AT1-EIII8 (referred as EIII8) human breast epithelial cells. Our data demonstrate a requirement for organspecific fibroblasts in the induction of epithelial morphogenesis. Whereas inclusion of normal reduction mammoplasty fibroblasts inhibit or retard morphological conversion and growth of MCF10A and EIII8 cells, respectively, tumor-derived breast fibroblasts evoke ductal-alveolar morphogenesis of both MCF10A and EIII8 cells. The growth and morphogenesis inhibitory effects of normal fibroblasts remain even in the presence of estrogen because they are able to suppress the estrogen-induced growth of EIII8 cells, whereas tumor fibroblasts support and maintain estrogen responsiveness of EIII8 cells. The inductive morphogenic effects of tumor fibroblasts on EIII8 cells is further augmented by the inclusion of HUVECs because these cocultures undergo a dramatic increase in proliferation and branching ductal-alveolar morphogenesis that is accompanied by an increase in invasion, degradation of coincident ECM, and expression of MMP-9. Therefore, tumor fibroblasts confer morphogenic and mitogenic induction of epithelial cells, and further enhancement of growth and progression requires active angiogenesis. These data illustrate the importance of structural and functional interactions between breast stromal and epithelial cells in the regulation of breast epithelial growth and progression.


Asunto(s)
Neoplasias de la Mama/patología , Mama/citología , Comunicación Celular/fisiología , Mama/efectos de los fármacos , Comunicación Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , División Celular/efectos de los fármacos , División Celular/fisiología , Técnicas de Cocultivo , Inhibición de Contacto/efectos de los fármacos , Inhibición de Contacto/fisiología , Progresión de la Enfermedad , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Estradiol/farmacología , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Humanos , Células del Estroma/citología , Células del Estroma/efectos de los fármacos
2.
Cancer Res ; 60(2): 439-49, 2000 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-10667599

RESUMEN

Although there is experimental evidence supporting the involvement of angiogenesis in the pathogenesis of breast cancer, the exact nature and effects of interaction between human breast epithelial cells (HBECs) and endothelial cells (ECs) have not been described thus far. This approach requires an assay system that permits growth and differentiation of both epithelial and endothelial cells. Here, we report the development of a three-dimensional in vitro culture system that supports growth and functional differentiation of preneoplastic HBECs and ECs and recapitulates estrogen-induced in vivo effects on angiogenesis and the proliferative potential of MCF10AT xenografts. MCF10A and MCF10AT1-EIII8 (referred to as EIII8) cell lines used in this study are normal or produce preneoplastic lesions, respectively. When MCF10A or EIII8 cells are seeded on reconstituted basement membrane (Matrigel), both lines organize into a three-dimensional tubular network of cells; however, tubes produced by EIII8 cells appear multicellular in contrast to unicellular structures formed by MCF10A cells. However, when MCF10A or EIII8 cells are cocultured with human umbilical vein endothelial cells (HUVECs) on Matrigel, rather than interacting with extracellular matrix, the ECs exhibit preferential adherence to epithelial cells. Although both MCF10A and EIII8 cells provide preferential substrate for EC attachment, only EIII8 cells facilitate sustained proliferation of ECs for prolonged periods that are visualized as "endothelial cell enriched spots," which express factor VIII-related antigen. At regions of endothelial-enriched spots, preneoplastic HBECs undergo branching ductal-alveolar morphogenesis that produce mucin, express cytokeratins, and proliferating cell nuclear antigen. The presence of actively proliferating and functional endothelial cells is essential for ductal-alveolar morphogenesis of preneoplastic HBECs because without ECs, the epithelial cells formed only tubular structures. This ability to establish functional ECs and ductal-alveolar morphogenesis is facilitated only by preneoplastic HBECs because normal MCF10A cells fail to elicit similar effects. Thus, a cause-effect relationship that is mutually beneficial exists between EC and preneoplastic HBECs that is critical for generation of functional vascular networks and local proliferative ductal alveolar outgrowths with invasive potential. Both these processes are augmented by estrogen, whereas antiestrogens inhibit these processes. Induction and maintenance of angiogenic phenotype is associated with up-regulation in expression of interleukin 8 and matrix metalloproteinase-2 and estrogen-induced increases in vascular endothelial growth factor and vascular endothelial growth factor receptor 2. This three-dimensional culture model offers a unique opportunity to study endothelial- and epithelial cell-specific factors that are important for ductal-alveolar morphogenesis, angiogenesis, and progression to malignant phenotype.


Asunto(s)
Neoplasias de la Mama/patología , Mama/patología , Endotelio Vascular/citología , Células Epiteliales/patología , Estrógenos/farmacología , Lesiones Precancerosas/patología , Membrana Basal , Mama/fisiopatología , Neoplasias de la Mama/fisiopatología , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Colágeno , Medios de Cultivo Condicionados , Combinación de Medicamentos , Factores de Crecimiento Endotelial/biosíntesis , Endotelio Vascular/fisiología , Células Epiteliales/fisiología , Femenino , Humanos , Hiperplasia , Interleucina-8/biosíntesis , Queratinas/análisis , Laminina , Linfocinas/biosíntesis , Metaloproteinasa 2 de la Matriz/biosíntesis , Mucinas/análisis , Lesiones Precancerosas/fisiopatología , Antígeno Nuclear de Célula en Proliferación/análisis , Proteoglicanos , Proteínas Tirosina Quinasas Receptoras/biosíntesis , Receptores de Factores de Crecimiento/biosíntesis , Receptores de Factores de Crecimiento Endotelial Vascular , Venas Umbilicales , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
3.
Am J Pathol ; 152(5): 1129-32, 1998 May.
Artículo en Inglés | MEDLINE | ID: mdl-9588879

RESUMEN

We have used the MCF10AT xenograft model of human proliferative breast disease to examine the early effects of estradiol exposure on morphological progression of preneoplastic lesions and to define the step(s) in the morphological sequence at which estrogen may act. The effects of estradiol on neoplastic progression of estrogen-receptor-positive MCF10AT cells in the orthotopic site were examined in ovariectomized female nude mice that received subcutaneous administration of implants of 17beta-estradiol or placebo pellets. At 10 weeks, histological analysis of the lesions derived from the estrogen-supplemented group revealed that 92% of lesions displayed histological features of atypical hyperplasia, carcinoma in situ, or invasive carcinoma, and the remaining 8% exhibited histological features of moderate hyperplasia. These highly proliferative lesions are in marked contrast to the control group in which 60% of samples displayed no evidence of hyperplasia. In contrast with control xenografts, estrogen-exposed xenografts demonstrated extensive areas of papillary growth, adenosis-like areas, prominent host inflammatory infiltration, and angiogenesis. Our results suggest that estrogen exerts a growth-promoting effect on benign or premalignant ductal epithelium by enhancing 1) the frequency of lesion formation, 2) the size of lesions, 3) the speed of transformation from normal/mild hyperplasia to those with atypia, 4) the degree of dysplasia, and 5) angiogenesis.


Asunto(s)
Mama/patología , Carcinoma in Situ/patología , Transformación Celular Neoplásica/patología , Estradiol/farmacología , Neoplasias Mamarias Experimentales/patología , Lesiones Precancerosas/patología , Animales , Carcinoma in Situ/inducido químicamente , Línea Celular , Transformación Celular Neoplásica/inducido químicamente , Progresión de la Enfermedad , Femenino , Humanos , Hiperplasia/inducido químicamente , Hiperplasia/patología , Neoplasias Mamarias Experimentales/inducido químicamente , Ratones , Ratones Desnudos , Invasividad Neoplásica , Ovariectomía , Lesiones Precancerosas/inducido químicamente , Trasplante Heterólogo
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