Genetic dissection of tumor angiogenesis: are PlGF and VEGFR-1 novel anti-cancer targets?
(9/715)
Many proliferative diseases, most typically cancer, are driven by uncontrolled blood vessel growth. Genetic studies have been very helpful in unraveling the cellular and molecular players in pathological blood vessel formation and have provided opportunities to reduce tumor growth and metastasis. The fact that tumor vessels and normal blood vessels have distinct properties may help in designing more specific--and therefore safer--anti-angiogenic strategies. Such strategies may interfere with angiogenesis at the cellular or molecular level. Possible molecular targets include angiogenic growth factors and their receptors, proteinases, coagulation factors, junctional/adhesion molecules and extracellular matrix (ECM) components. Some anti-angiogenic drugs, i.e., vascular endothelial growth factor (VEGF) antibodies and VEGF receptor-2 (VEGFR-2) inhibitors, have progressed into clinical cancer trials. While the results of these trials support the potential of anti-angiogenic therapy to treat cancer, they also demonstrate the need for more effective and safer alternatives. Targeting placental growth factor (PlGF) or VEGFR-1 may constitute such an alternative since animal studies have proven their pleiotropic working mechanism and attractive safety profile. Together, these insights may bring anti-angiogenic drugs closer from bench to bedside. (+info)
Some scaling principles for the immune system.
(10/715)
Using recent progress in biological scaling, we explore the way in which the immune system of an animal scales with its mass (M). It is shown that the number of cells in a single clone of B cells should scale as M and that the B-cell repertoire scales as ln (cM), where c is a constant. The time that a B cell needs to circulate once through the organism is shown to scale as M(1/4)ln (cM). It is suggested that the scaling of other cell populations in the immune system could be derived from these scaling relations for B cells. (+info)
Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia.
(11/715)
Vascular endothelial growth factor-A (VEGF-A) expression is up-regulated in several inflammatory diseases including psoriasis, delayed-type hypersensitivity (DTH) reactions, and rheumatoid arthritis. To directly characterize the biologic function of VEGF-A in inflammation, we evaluated experimental DTH reactions induced in the ear skin of transgenic mice that overexpress VEGF-A specifically in the epidermis. VEGF-A transgenic mice underwent a significantly increased inflammatory response that persisted for more than 1 month, whereas inflammation returned to baseline levels within 7 days in wild-type mice. Inflammatory lesions in VEGF-A transgenic mice closely resembled human psoriasis and were characterized by epidermal hyperplasia, impaired epidermal differentiation, and accumulation of dermal CD4+ T-lymphocytes and epidermal CD8+ lymphocytes. Surprisingly, VEGF-A also promoted lymphatic vessel proliferation and enlargement, which might contribute to the increased inflammatory response, as lymphatic vessel enlargement was also detected in human psoriatic skin lesions. Combined systemic treatment with blocking antibodies against VEGF receptor-1 (VEGFR-1) and VEGFR-2 potently inhibited inflammation and also decreased lymphatic vessel size. Together, these findings reveal a central role of VEGF-A in promoting lymphatic enlargement, vascular hyperpermeability, and leukocyte recruitment, thereby leading to persistent chronic inflammation. They also indicate that inhibition of VEGF-A bioactivity might be a new approach to anti-inflammatory therapy. (+info)
Up-regulation of the chemokine CCL21 in the skin of subjects exposed to irritants.
(12/715)
BACKGROUND: Expression of murine CCL21 by dermal lymphatic endothelial cells (LEC) has been demonstrated to be one of the most important steps in Langerhans cell emigration from skin. Previously, our group and others have found that this chemokine is up-regulated in different human inflammatory skin diseases mediated by diverse specific immune responses. This study was carried out to investigate the involvement of CCL21 in human skin after challenge with irritant agents responsible for inducing Irritant Contact Dermatitis (ICD). RESULTS: Eleven normal individuals were challenged with different chemical or physical irritants. Two patients with Allergic Contact Dermatitis (ACD) were also challenged with the relevant antigen in order to have a positive control for CCL21 expression. Macroscopic as well as microscopic responses were evaluated. We observed typical ICD responses with mostly mononuclear cells in perivascular areas, but a predominance of polymorphonuclear cells away from the inflamed blood vessels and in the epidermis at 24 hours. Immunohistochemical studies showed up-regulation of CCL21 by lymphatic endothelial cells in all the biopsies taken from ICD and ACD lesions compared to normal skin. Kinetic study at 10, 48, 96 and 168 hours after contact with a classical irritant (sodium lauryl sulphate) showed that the expression of CCL21 was increased in lymphatic vessels at 10 hours, peaked at 48 hours, and then gradually declined. There was a strong correlation between CCL21 expression and the macroscopic response (r = 0.69; p = 0.0008), but not between CCL21 and the number of infiltrating cells in the lesions. CONCLUSIONS: These results provide new evidence for the role of CCL21 in inflammatory processes. Since the up-regulation of this chemokine was observed in ICD and ACD, it is tempting to speculate that this mechanism operates independently of the type of dermal insult, facilitating the emigration of CCR7+ cells. (+info)
Hypoplastic left heart syndrome with intact or highly restrictive atrial septum: outcome after neonatal transcatheter atrial septostomy.
(13/715)
BACKGROUND: Hypoplastic left heart syndrome (HLHS) with intact or very restrictive atrial septum is a highly lethal combination. We review our 13-year institutional experience treating this high-risk subgroup of patients with emergent catheter therapy. METHODS AND RESULTS: Infants with HLHS requiring catheter septostomy within the first 2 days of life were compared with a matched control group with adequate interatrial communication. Preoperative, early postoperative, and medium-term survival were evaluated. Earlier experience was compared with recent results to assess the effect of changes in catheterization and surgical and intensive care unit management strategies over the study period. From 1990 to 2002, 33 newborns with HLHS (11% of newborns with HLHS managed during this period) underwent urgent/semiurgent catheterization to create or enlarge an interatrial communication before surgical palliation. Preoperative and early postoperative mortality were high (48%) compared with control HLHS patients, regardless of prenatal diagnosis and despite successful catheter-based atrial septostomy with clinical stabilization. Mortality trended down during the later part of the study period. Those who survived the neonatal period had late survival, pulmonary artery pressure, and resistance similar to those of control subjects. CONCLUSIONS: Neonatal mortality in the subgroup of HLHS patients with intact or highly restrictive atrial septum remains high despite successful urgent septostomy. Persistently poor outcomes for these patients have prompted efforts at our center to develop techniques for fetal intervention for this condition, in the hope that prenatal relief of left atrial and pulmonary venous hypertension may promote normal pulmonary vascular and parenchymal development and improve both short- and long-term outcomes. (+info)
Antitumor activity of a homing peptide that targets tumor lymphatics and tumor cells.
(14/715)
LyP-1 is a peptide selected from a phage-displayed peptide library that specifically binds to tumor and endothelial cells of tumor lymphatics in certain tumors. Fluorescein-conjugated LyP-1 and a related peptide, LyP-1b, strongly accumulated in primary MDA-MB-435 breast cancer xenografts and their metastases from i.v. peptide injections, allowing visualization of orthotopic tumors in intact mice. The LyP peptide accumulation coincided with hypoxic areas in tumors. LyP-1 induced cell death in cultured human breast carcinoma cells that bind and internalize the peptide. Melanoma cells that do not bind LyP-1 were unaffected. Systemic LyP-1 peptide treatment of mice with xenografted tumors induced with the breast cancer cells inhibited tumor growth. The treated tumors contained foci of apoptotic cells and were essentially devoid of lymphatics. These results reveal an unexpected antitumor effect by the LyP-1 peptide that seems to be dependent on a proapoptotic/cytotoxic activity of the peptide. As LyP-1 affects the poorly vascularized tumor compartment, it may complement treatments directed at tumor blood vessels. (+info)
Generation and characterization of telomerase-transfected human lymphatic endothelial cells with an extended life span.
(15/715)
The study of lymphatic endothelial cells and lymphangiogenesis has, in the past, been hampered by the lack of lymphatic endothelial-specific markers. The recent discovery of several such markers has permitted the isolation of lymphatic endothelial cells (LECs) from human skin. However, cell numbers are limited and purity is variable with the different isolation procedures. To overcome these problems, we have transfected human dermal microvascular endothelial cells (HDMVECs) with a retrovirus containing the coding region of human telomerase reverse transcriptase (hTERT), and have produced a cell line, hTERT-HDLEC, with an extended lifespan. hTERT-HDLEC exhibit a typical cobblestone morphology when grown in culture, are contact-inhibited, and express endothelial cell-specific markers. hTERT-HDLEC also express the recognized lymphatic markers, Prox-1, LYVE-1 and podoplanin, as well as integrin alpha9, but do not express CD34. They also form tube-like structures in three-dimensional collagen gels when stimulated with vascular endothelial growth factors -A and -C. Based on these currently recognized criteria, these cells are LEC. Surprisingly, we also found that the widely studied HMEC-1 cell line expresses recognized lymphatic markers; however, these cells are also CD34-positive. In summary, the ectopic expression of hTERT increases the life span of LECs and does not affect their capacity to form tube-like structures in a collagen matrix. The production and characterization of hTERT-HDLEC will facilitate the study of the properties of lymphatic endothelium in vitro. (+info)
Vascular endothelial growth factor (VEGF)-C is known to induce hyperplasia in normal murine lymphatics and in peritumor lymphatics. Here, we examine the function of these hyperplastic peritumor lymphatics. Microlymphangiography of B16F10 melanomas growing in the murine dorsal skinfold chamber showed that the number of functional, draining lymphatics in the peritumor tissue of VEGF-C-overexpressing tumors was significantly greater than that in mock-transduced tumors (9.5 +/- 1.0 versus 6.3 +/- 0.4; n = 6; P < 0.05). Forty percent of functional lymphatics associated with VEGF-C-overexpressing tumors contained proliferating lymphatic endothelial cells. Surprisingly, these new, functional lymphatic vessels displayed a retrograde draining pattern, which indicates possible dysfunction of the intraluminal valves of these vessels. (+info)