Agnese Mariotti

Vascular integrins: pleiotropic adhesion and signaling molecules in vascular homeostasis and angiogenesis.

Abstract: New blood vessel formation, a process referred to as angiogenesis, is essential for embryonic development and for many physiological and pathological processes during postnatal life, including cancer progression. Endothelial cell adhesion molecules of the integrin family have emerged as critical mediators and regulators of angiogenesis and vascular homeostasis. Integrins provide the physical interaction with the extracellular matrix necessary for cell adhesion, migration and positioning, and induction of signaling events essential for cell survival, proliferation and differentiation. Antagonists of integrin αVβ3 suppress angiogenesis in many experimental models and are currently tested in clinical trials for their therapeutic efficacy against angiogenesis-dependent diseases, including cancer. Furthermore, interfering with signaling pathways downstream of integrins results in suppression of angiogenesis and may have relevant therapeutic implications. In this article we review the role of integrins in endothelial cell function and angiogenesis. In the light of recent advances in the field, we will discuss their relevance as a therapeutic target to suppress tumor angiogenesis.

Induction of apoptosis by p75 neurotrophin receptor in human neuroblastoma cells.

The low-affinity nerve growth factor receptor p75NTR belongs to a membrane receptor superfamily whose members, in certain cell types, are able to transduce an apoptotic signal. To investigate the effect of p75NTR expression in neuroblastoma cells, we transfected the p75NTR cDNA into SK-N-BE cells, a neuroblastoma cell line that lacks expression of both p75NTR and TrkA. Cell clones expressing elevated levels of p75NTR showed a high degree of cell death by apoptosis, even in serum-supplemented medium. Moreover, the level of apoptosis correlated directly with the expression level of the receptor, indicating that p75NTR could activate the cell death program by itself. Clones expressing p75NTR showed a dramatic increase of cell death when switched into serum-free medium; these cultures rapidly extinguished. This apoptotic effect was greatly inhibited by NGF treatment. Our results support the hypothesis that p75NTR, when it is not bound by NGF, may play a role in neuronal selection during embryonic development and suggest that neuroblastomas may arise from immature neuroblasts that escape programmed cell death. Therefore, the loss of p75NTR expression in developing neural crest cells might be a primary event in the genesis of neuroblastoma.

Increased plasticity of the stiffness of melanoma cells correlates with their acquisition of metastatic properties.

UNLABELLED The stiffness of tumor cells varies during cancer progression. In particular, metastatic carcinoma cells analyzed by Atomic Force Microscopy (AFM) appear softer than non-invasive and normal cells. Here we examined by AFM how the stiffness of melanoma cells varies during progression from non-invasive Radial Growth Phase (RGP) to invasive Vertical Growth Phase (VGP) and to metastatic tumors. We show that transformation of melanocytes to RGP and to VGP cells is characterized by decreased cell stiffness. However, further progression to metastatic melanoma is accompanied by increased cell stiffness and the acquisition of higher plasticity by tumor cells, which is manifested by their ability to greatly augment or reduce their stiffness in response to diverse adhesion conditions. We conclude that increased plasticity, rather than decreased stiffness as suggested for other tumor types, is a marker of melanoma malignancy. These findings advise caution about the potential use of AFM for melanoma diagnosis. FROM THE CLINICAL EDITOR This study investigates the changes to cellular stiffness in metastatic melanoma cells examined via atomic force microscopy. The results demonstrate that increased plasticity is a marker of melanoma malignancy, as opposed to decreased stiffness.

MFG-E8/lactadherin regulates cyclins D1/D3 expression and enhances the tumorigenic potential of mammary epithelial cells

Milk fat globule-EGF factor 8 (MFG-E8) is a glycoprotein highly expressed in breast cancer that contributes to tumor progression through largely undefined mechanisms. By analyzing publicly available gene expression profiles of breast carcinomas, we found that MFG-E8 is highly expressed in primary and metastatic breast carcinomas, associated with absent estrogen receptor expression. Immunohistochemistry analysis of breast cancer biopsies revealed that MFG-E8 is expressed on the cell membrane as well as in the cytoplasm and nucleus. We also show that increased expression of MFG-E8 in mammary carcinoma cells increases their tumorigenicity in immunodeficient mice, and conversely, its downregulation reduces their in vivo growth. Moreover, expression of MFG-E8 in immortalized mammary epithelial cells promotes their growth and branching in three-dimensional collagen matrices and induces the expression of cyclins D1/D3 and N-cadherin. A mutant protein unable to bind integrins can in part exert these effects, indicating that MFG-E8 function is only partially dependent on integrin activation. We conclude that MFG-E8-dependent signaling stimulates cell proliferation and the acquisition of mesenchymal properties and contributes to mammary carcinoma development.

Omics meets hypothesis-driven research : Partnership for innovative discoveries in vascular biology and angiogenesis

The emergence of omics technologies allowing the global analysis of a given biological or molecular system, rather than the study of its individual components, has revolutionized biomedical research, including cardiovascular medicine research in the past decade. These developments raised the prospect that classical, hypothesis-driven, single gene-based approaches may soon become obsolete. The experience accumulated so far, however, indicates that omic technologies only represent tools similar to those classically used by scientists in the past and nowadays, to make hypothesis and build models, with the main difference that they generate large amounts of unbiased information. Thus, omics and classical hypothesis-driven research are rather complementary approaches with the potential to effectively synergize to boost research in many fields, including cardiovascular medicine. In this article we discuss some general aspects of omics approaches, and review contributions in three areas of vascular biology, thrombosis and haemostasis, atherosclerosis and angiogenesis, in which omics approaches have already been applied (vasculomics).

Breast cancer suppressor candidate-1 (BCSC-1) is a melanoma tumor suppressor that down regulates MITF

Understanding the molecular aberrations involved in the development and progression of metastatic melanoma (MM) is essential for a better diagnosis and targeted therapy. We identified breast cancer suppressor candidate‐1 (BCSC‐1) as a novel tumor suppressor in melanoma. BCSC‐1 expression is decreased in human MM, and its ectopic expression in MM–derived cell lines blocks tumor formation in vivo and melanoma cell proliferation in vitro while increasing cell migration. We demonstrate that BCSC‐1 binds to Sox10, which down regulates MITF, and results in a switch of melanoma cells from a proliferative to a migratory phenotype. In conclusion, we have identified BCSC‐1 as a tumor suppressor in melanoma and as a novel regulator of the MITF pathway.