Dynamic interplay between breast cancer cells and normal endothelium mediates the expression of matrix macromolecules, proteasome activity and functional properties of endothelial cells

Background Breast cancer\u2013endothelium interactions provide regulatory signals facilitating tumor progression. The endothelial cells have so far been mainly viewed in the context of tumor perfusion and relatively little is known regarding the effects of such paracrine interactions on the expression of extracellular matrix (ECM), proteasome activity and properties of endothelial cells. Methods To address the effects of breast cancer cell (BCC) lines MDA-MB-231 and MCF-7 on the endothelial cells, two cell culture models were utilized; one involves endothelial cell culture in the presence of BCCs-derived conditioned media (CM) and the other co-culture of both cell populations in a Transwell system. Real-time PCR was utilized to evaluate gene expression, an immunofluorescence assay for proteasome activity, and functional assays (migration, adhesion and invasion) and immunofluorescence microscopy for cell integrity and properties. Results BCC-CM decreases the cell migration of HUVEC. Adhesion and invasion of BCCs are favored by HUVEC and HUVEC-CM. HA levels and the expression of CD44 and HA synthase-2 by HUVEC are substantially upregulated in both cell culture approaches. Adhesion molecules, ICAM-1 and VCAM-1, are also highly upregulated, whereas MT1-MMP and MMP-2 expressions are significantly downregulated in both culture systems. Notably, the expression and activity of the proteasome \u3b25 subunit are increased, especially by the action of MDA-MB-231-CM on HUVEC. Conclusions and general significance BCCs significantly alter the expression of matrix macromolecules, proteasome activity and functional properties of endothelial cells. Deep understanding of such paracrine interactions will help to design novel drugs targeting breast cancer at the ECM level. This article is part of a Special Issue entitled Matrix-mediated cell behavior and properties

Novel insights into matrix pathobiology regulatory mechanisms in health and disease

Matrix macromolecules exhibit leading roles in tissue properties, physiological processes, as well as the development and progression of several diseases. This thematic series covers emerging areas of research in the matrix macromolecule field and includes epigenetics, stem cells, microRNAs, as well as proteoglycan interactions with proteolytic enzymes. Current knowledge of these aspects will elucidate their regulatory mechanisms in pathophysiology and aid the design of novel pharmacological agents. Accompanied by a podcast, listen now. Or listen in iTunes

Determination and biological relevance of serum cross-linked type I collagen N-telopeptide and bone-specific alkaline phosphatase in breast metastatic cancer

Bone metastasis is a frequent complication of cancer disease. The metastatic spread of cancer to bone is common to many different malignancies, particularly breast (ca. 73%), prostate (ca. 68%) and lung (ca. 36%) cancers. Metastases to bone cause increased bone resorption both from direct effects of the tumor itself and thought osteoclastic activation. The diagnosis and follow-up of bone metastatic cancer patients usually relies on skeletal X-ray and bone scintigraphy. However, the development of biochemical markers, used as indicators of bone metabolism, provides data useful in the clinical practice. The most important markers for bone remodeling process, bone formation and resorption, are bone-specific alkaline phosphatase (BAP) and N-telopeptide of type I collagen (NTx), respectively. In this report, we applied two solid-phase immunoassays used for the determination of BAP and NTx in serum of breast cancer (BC) post-menopausal women with bone metastasis and healthy individuals. BAP level in patients was found to be 45.72±12.92U/l, while the normal range for healthy individuals was 14.2-42.7U/l. The respective level of serum NTx was 19.20±8.87nM bone collagen equivalents (BCE) for patients and 15.9±3.8nM BCE for healthy women. Correlation of the obtained data showed elevated levels for both markers indicating high rate of bone degradation in breast metastatic cancer. © 2003 Elsevier B.V. All rights reserved

Design and synthesis of new pyranoxanthenones bearing a nitro group or an aminosubstituted side chain on the pyran ring. Evaluation of their growth inhibitory activity in breast cancer cells

Some new 2,6-disubstituted pyrano- and 1,2-dihydropyrano[2,3-c]xanthen-7-ones have been synthesized and their antiproliferative activity has been evaluated against MDA-MB-231 breast cancer cells. The antiproliferative activity evaluation of the compounds provided evidence that a dimethylamino substituted side chain and the presence of 1,2 double bond play a key role in cell growth inhibition. Among the tested derivatives the 6-dimethylaminoethylamino-2-nitropyranoxanthenone analogue possessed a significant inhibitory effect in a wide range of concentrations. © 2006 Elsevier Masson SAS. All rights reserved

Design, synthesis and cell growth inhibitory activity of a series of novel aminosubstituted xantheno[1,2-d]imidazoles in breast cancer cells

A series of novel aminosubstituted xantheno[1,2-d]imidazole derivatives have been designed and synthesized and their antiproliferative activity has been evaluated against human breast MDA-MB-231 cell line. Among the tested compounds those bearing two basic side chains at 2- and 5-positions exhibited a strong dose-dependent antiproliferative activity. Increase of the size and basicity of the N-alkyl substituent resulted in amplification of the inhibitory activity. © 2007 Elsevier Ltd. All rights reserved

Design, synthesis, and evaluation of the antiproliferative activity of a series of novel fused xanthenone aminoderivatives in human breast cancer cells

Derivatives of two novel, structurally related heterocyclic ring systems, xantheno[3,4-d]imidazole and chromeno[4,3,2-c,d]imidazo[4,5-f]indazole, bearing aminoalkyl side chains, have been synthesized, and their antiproliferative activity has been studied against the aggressive human breast MDA-MB-231 cell line. The pyrazole-fused analogue 27a possesses a pronounced antiproliferative effect on the tested cell line, evident at 1 μM, and achieves an IC 50 of 6.5 μM. © 2007 American Chemical Society