Platelet-derived growth factor-B increases colon cancer cell growth in vivo by a paracrine effect

PDGF-B released from colon tumor cells regulated tumor growth in athymic mice in a paracrine manner by inducing blood vessel formation. A positive correlation was found between expression of PDGF B-chain in cells grown in vitro and the number of factor VIII-positive blood vessels in tumors induced by three classes of colon carcinoma cell lines. Elevated expression of PDGF-B was also correlated with tumor size. Each cell line had the same mutations in the colon cancer genes APC, DCC, and p53 and had wild type c-K-ras genes (Huang et al. [1994] Oncogene, 9:3701-3706.) eliminating the possibility that any differences in tumor blood vessel formation were due to mutations and/or deletions in these genes. Colon carcinoma cells released biologically active PDGF capable of stimulating the growth of NIH3T3 cells, which was inhibited by neutralizing antisera to PDGF-AB chains. An inverse correlation was found between induction of factor VIII-positive blood vessels and expression of vascular endothelial growth factor (VEGF), while no correlation was seen with expression of either TGF alpha or k-FGF. Basic fibroblast growth factor (FGF) expression was not detected in these tumor cells. TGF beta 1 was capable of inducing PDGF-B expression in the undifferentiated U9 colon carcinoma cell line, but this sensitivity was not seen in differentiated cells. In contrast, TGF beta 1 inhibited VEGF expression in both undifferentiated cells and differentiated colon cancer cells. Thus, TGF beta 1 has two roles in the growth of undifferentiated U9 colon carcinoma cells in vivo: direct stimulation of cell proliferation as we have showed in earlier studies, and an increase in angiogenesis by inducing PDGF-B.     

Significance of platelet-derived endothelial cell growth factor in the angiogenesis of human gastric cancer

Most patients with primary IgA nephropathy (IgAN) have a significantly higher memory repertoire of IgA1-producing B lymphocytes in their bone marrow together with high plasma levels of IgA1. The connection between the mucosal immune system and the bone marrow compartment is probably based on traffic of either antigen-presenting cells (APC) or antigen-specific lymphocytes. Cytokines play an important role in the proliferation and differentiation of lymphoid cells. In order to mimic the in vivo situation as much as possible, we assessed cytokine production profiles ex vivo in 23 IgAN patients and matched controls, using lipopolysaccharide (LPS)- or phytohaemagglutinin (PHA)-stimulated whole blood (WB) cultures. Interferon-gamma (IFN-gamma), IL-2, IL-6, IL-10 and tumour necrosis factor-alpha (TNF-alpha) production in culture supernatants were determined by cytokine-specific ELISAs. Compared with controls, PHA-stimulated cultures resulted in significantly higher IL-10 (P<0.001), IL-2 (P<0.005) and IFN-gamma (P<0.001) levels in IgAN patients, but no significant differences in TNF-alpha or IL-6 levels were found. In LPS-stimulated cultures, the only significant difference (P<0.001) between the two groups was the increased IL-10 production in IgAN patients. The enhanced cytokine production in stimulated WB cultures suggests altered monocyte-related T cell responses in patients with IgAN. Increased IL-10 production may eventually result in an increased number of IgA-producing B lymphocytes in the bone marrow. In addition, high levels of endogenous IL-10 may down-regulate the effector functions of monocytes, or possibly APC in general, and consequently the IgA response at the mucosal level.     

The molecular biology of breast cancer: accelerating clinical applications

Recent advances in basic science have led to a better understanding of the molecular events important in the pathogenesis of breast cancer. Very little of this new knowledge, however, has had a significant impact on improving the diagnosis and therapy of breast cancer. We review many of the molecular events important in the pathogenesis of breast cancer, including inherited abnormalities in BRCA-1 and BRCA-2, p53, ATM, and PTEN and sporadic alterations in growth factors and their receptors, signal transduction, cell cycle control, DNA repair, cell death, angiogenesis, and invasion and metastasis. We suggest ways to speed up clinical applications of the new molecular knowledge base through the use of preclinical disease models, development of high throughput sample analysis and infrastructure programs to facilitate translational research, implementation of practice guidelines, and development of regional oncology networks. Only through the implementation of such a deliberate, multifaceted strategy will the gap between the research laboratory and the clinic be closed.     

Expression of p53 and vascular endothelial growth factor associated with tumor angiogenesis and prognosis in gastric cancer

We performed six immediate free flap reconstructions after tumor ablation in 5 children under the age of 15 years presenting with head and neck malignancy. One patient underwent free flap transfer on two separate occasions because of tumor recurrence. There were no flap losses nor were there any complications related to microvascular surgery. Although a pediatric head and neck malignant tumor is rare, surgical resection is the primary therapeutic role for those that are amenable to complete excision. Pediatric microsurgery provides a safe and reliable procedure for reconstruction of head and neck defects after extirpation of the tumor.     

The expression of thymidine phosphorylase/platelet-derived endothelial cell growth factor is correlated to angiogenesis in breast cancer

It has been shown that human thymidine phosphorylase (TP) is identical to platelet-derived endothelial cell growth factor and has angiogenic activity. In the present study, the expression of TP was examined in 139 mammary carcinomas and 35 benign mammary disorders using biochemical and immunohistochemical methods. Moreover, in order to evaluate the significance of TP expression in mammary carcinomas, the relationship between vascular density and various clinicopathological factors, including age and menopausal status of patients with a mammary carcinoma, were compared with the size, nodal status, expression of estrogen receptor (ER), progesterone receptor (PgR), c-erbB-2, p53 and TP of a mammary carcinoma. Thymidine phosphorylase expression increased in both the nuclei and cytoplasm of mammary carcinoma cells in comparison to mammary benign disorder cells. The number of microvessels in mammary carcinomas was generally correlated to the number of tumor cells with TP expression in cytoplasm. The number of cells with TP expression in cytoplasm was significantly large in tumors that measured 3-4 cm in diameter, compared with tumors measuring 1-2 and 5-6 cm in diameter. In mammary tumors of 1-4 cm diameter, TP expression and vessel density were significantly high in tumors negative for ER or positive for c-erbB2 and in tumors positive for TP or c-erbB2, respectively; whereas tumors of 5-6 cm in diameter were not modified by any clinicopathological factors. The results indicated that TP plays an important angiogenetic role in mammary carcinomas, especially tumors with a certain progression.     

Antisense estrogen receptor RNA expression increases epidermal growth factor receptor gene expression in breast cancer cells

In human breast cancer, progression to a more malignant phenotype is often accompanied by decreased expression of estrogen receptor (ER) and increased expression of epidermal growth factor receptor (EGFR). Higher levels of this receptor tyrosine kinase are found in tumors lacking ER, and a quantitative, inverse relationship exists between the level of ER and EGFR mRNA in human breast cell lines. Antisense ER (ASER) RNA was used to evaluate the consequence of decreased ER expression in breast cancer cells, specifically to determine whether ER is involved in the regulation of EGFR gene expression. ER-positive MCF-7 human breast cancer cells were transfected with ASER, and clones constitutively expressing ASER RNA had decreased ER and up to a 3-fold increase in the expression of EGFR mRNA. To confirm that this observation was a direct consequence of ASER expression, a metal-inducible ASER expression construct was transfected into MCF-7 cells, and transfected clones were isolated and characterized. Northern analysis revealed an induction of ASER RNA within 1 h of the addition of zinc, which was followed by a 4-fold increase in EGFR mRNA levels, maximal at 6-12 h. The basal level of expression of the glucocorticoid receptor is also inversely related to that of ER among breast cancer cell lines, but neither constitutive nor inducible expression of ASER affected the expression of glucocorticoid receptor. These data support the hypothesis that the level of expression of ER specifically influences the expression of EGFR in human breast cancer cells and provides a potential link between loss of steroid sensitivity and the acquisition of autonomous growth.     

Breast cancer screening in Navarra: interpretation of a high detection rate at the first screening round and a low rate at the second round

Endothelial cells and pericytes are closely associated in brain capillaries. Together with astrocytic foot processes, they form the blood-brain barrier. Capillaries were isolated from bovine brain cortex. Pure populations of endothelial cells and pericytes were isolated and cultured in vitro. Polarized monolayers of endothelial cells preferentially secreted immunoreactive endothelin-1 (Et-1) at their abluminal (brain-facing) membrane. They did not express receptors for Et-1. Pericytes expressed BQ-123-sensitive ETA receptors for endothelins as evidenced by 125I-Et-1 binding experiments. These receptors were coupled to phospholipase C as demonstrated by intracellular calcium measurements using indo-1-loaded cells. Addition of Et-1 to pericytes induced marked changes in the cell morphology that were associated with a reorganization of F-actin and intermediate filaments. It is concluded that Et-1 is a paracrine mediator at the bovine blood-brain barrier and that capillary pericytes are target cells for endothelium-derived Et-1.     

Vascular endothelial growth factor, wild-type p53, and angiogenesis in early operable non-small cell lung cancer

Vascular endothelial growth factor (VEGF) is a cytokine that is involved in tumor angiogenesis. Wild-type p53 (wt-p53) protein has been shown in cell lines to suppress angiogenesis through thrombospondin regulation. In this study, we immunohistochemically examined the expression of VEGF, nuclear and wild-type cytoplasmic p53, bcl-2, epidermal growth factor receptor, and c-erbB-2 oncoprotein; vascular grade; proliferation index; and extent of necrosis in non-small cell lung cancer (NSCLC). We analyzed 120 cases of early-stage NSCLCs (81 squamous cell carcinomas and 39 adenocarcinomas) treated with surgery alone (median follow-up, 63 months; range, 45-74 months). VEGF expression showed a positive association with high vascular grade (microvessel score of >75 per x250 field; P = 0.008), although about half of the LVG cases also expressed VEGF. None of the p53 antibodies examined correlated with angiogenesis. However, wt-p53 expression was inversely associated with VEGF expression, suggesting that wt-p53 is involved in the suppression of the VEGF gene. Combined analysis of VEGF, wt-p53, and microvessel counting showed that, although wt-p53 loss associates with VEGF switch-on, p53 protein may not be involved in the regulation of the angiogenic events downstream of VEGF expression. Moreover, no significant association of bcl-2 and c-erbB-2 oncoprotein expression with VEGF expression was observed. T/N stage, grade, Ki67 proliferation index, and extent of necrosis were not correlated with VEGF expression. Survival analysis showed that VEGF correlated with poor survival (P = 0.04) and was significant in node-negative cases (P = 0.03). We conclude that VEGF is an important angiogenic factor in NSCLC, its expression being dependent on wt-p53 loss.     

Breast cancer detection by daughters of women with breast cancer

The preferred therapy for genuine stress incontinence is surgery. The Burch procedure is considered by many to be the gold standard for surgical treatment of genuine stress incontinence. The Burch procedure requires the elevation of the anterior wall of the vagina to the level of the origin of the paravaginal fascia by suspension from Cooper's ligaments. The laparoscopic performance of the Burch procedure by suturing or by endoscopic stapler mesh technique results in a decrease in the length of hospital stay, faster recovery, much shorter catheterization and less scarring due to the smaller incisions. The laparoscopic procedure provides results similar to the open operation if a meticulous technique is used. Long-term follow-up will be necessary before these procedures can be generally offered as a therapeutic alternative.     

Latent growth curve analyses of accelerating decline in cognitive abilities in late adulthood.

Latent growth models were applied to data from the Swedish Adoption/Twin Study of Aging to discover if the rate of change in cognitive performance increased from middle age to later adulthood. The sample included 590 participants aged 44 to 88 years at first measurement. Data were gathered at 2 follow-up occasions at intervals of 3 years. Cognitive ability was assessed through 11 tests that tapped crystallized, fluid, memory, and spatial abilities and perceptual speed. Results indicated stability for measures of crystallized ability, linear age changes for many cognitive abilities, and a significant acceleration in linear decline after age 65 for measures with a large speed component. Gender differences were found only in mean level, not in rate of decline. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Inhibition of tumor growth and microvascular angiogenesis by the potent angiogenesis inhibitor, TNP-470, in rats

OBJECTIVE: To analyse the longitudinal relationships between body mass index (BMI)/sum of skinfolds (SSF) and biological and lifestyle risk factors for coronary heart disease (CHD). DESIGN: An observational longitudinal study; that is, the Amsterdam Growth and Health Study. SUBJECTS: 181 males and females, initially aged 13 y. Over a period of 15 y, six repeated measurements were carried out. MEASUREMENTS: BMI and SSF, biological CHD risk factors; that is, total cholesterol (TC), high density lipoprotein (HDL), TC:HDL ratio, systolic/diastolic blood pressure (SBP/DBP) and cardiopulmonary fitness (VO2-max) and lifestyle CHD risk factors (that is, daily physical activity, dietary parameters, smoking, and alcohol consumption). The longitudinal relationships were analysed by an autoregressive model, in which the value of the outcome variable at time-point t is not only related to the value of the predictor variable at t, but also to the value of the outcome variable at t-1. RESULTS: Both BMI and SSF were positively related to TC and the TC:HDL ratio. Only BMI was positively related to SBP and only SSF was negatively related to VO2-max. Physical activity was negatively related to SSF. None of the other lifestyle parameters were related to SSF and/or BMI. CONCLUSIONS: Both BMI and SSF were related to a high risk profile regarding CHD. Different relationships for SSF and BMI are found, because BMI not only reflects body fatness, but also lean body mass. Analyses with BMI as an indicator for body fatness should therefore be interpreted cautiously.     

Crack initiation and growth toughness of an aluminum metal-matrix composite

The effects of systematic changes in matrix microstructure on crack initiation and growth toughnesses were determined on an AlZnMgCu alloy containing 0, 15, 20% by volume of SiC particulates. Materials were heat treated to underaged (UA) and overaged (OA) conditions of equivalent matrix microhardness and flow stress. Although both the fracture initiation and growth toughnesses, as measured by J_Ic and tearing modulus, were similar for the unreinforced materials in the UA and OA conditions, significant effects of microstructure on both J_Ic and tearing modulus were observed in the composites. SEM and TEM observations of fracture paths in the two conditions are utilized to rationalize these observations in light of existing theories of ductile fracture propagation.     

Phenylbutazone increases right atrial pressure and heart rate of running horses

The effect of inhibition of cyclooxygenase activity on the hemodynamic response to exertion was examined in 6 horses. Rates of O2 consumption and CO2 production and carotid, pulmonary arterial, and right atrial pressures were measured while the horses performed a standardized exercise test on a treadmill after treatment with phenylbutazone or a placebo. Phenylbutazone (8.8 mg/kg p.o. for 2 days and 4.4 mg/kg i.v. 60 min before exertion) abolished the exertion-induced increases in plasma 6-ketoprostaglandin F1 alpha and thromboxane B2 concentrations, confirming inhibition of cyclooxygenase activity. Phenylbutazone treatment resulted in significantly (P < 0.05) higher heart rates and right atrial pressures during exertion than did treatment with placebo, which may have been due to increased myocardial sensitivity to sympathetic stimulation and/or decreased venous compliance. There was not a detectable effect of phenylbutazone on carotid or pulmonary arterial pressures, O2 consumption, CO2 production, or blood lactate concentration. Changes in plasma volume during exertion were not influenced by phenylbutazone. These results demonstrate that cyclooxygenase products likely mediate or modulate some of the systemic hemodynamic responses to exertion in horses.     

Cardiac troponin I phosphorylation increases the rate of cardiac muscle relaxation

Cardiac troponin (Tn) I (CTnI), compared with skeletal TnI, contains extra amino acids (32 to 33) at its amino terminus, including two adjacent serine residues. These two serine residues are believed to be phosphorylated by protein kinase A (PKA) upon stimulation of the heart by beta-agonists. In this study, we found that phosphorylation of a cardiac skinned muscle preparation by PKA, mainly at CTnI, results in a decrease in the Ca2+ sensitivity of muscle contraction. The pCa50 decreased by approximately 0.27 +/- 0.06 pCa units upon phosphorylation. To study cardiac muscle relaxation, we used diazo-2, a photolabile Ca2+ chelator with a low Ca2+ affinity in its intact form that is converted to a high-affinity form after photolysis. We found that the rate of cardiac muscle relaxation increased from a time of half-relaxation (t1/2) = 110 +/- 10 milliseconds to t1/2 = 70 +/- 8 milliseconds after CTnI phosphorylation. This result demonstrates that CTnI phosphorylation can be linked with the increased rate of muscle relaxation in a relatively intact muscle preparation. Since CTnI phosphorylation has been shown previously to affect the Ca2+ affinity and Ca2+ off-rate of CTnC in vitro, it is likely that the faster relaxation seen here reflects faster dissociation of Ca2+ from cardiac TnC (CTnC). Model calculations show that increased dissociation of Ca2+ from CTnC, coupled with the faster uptake of Ca2+ by the sarcoplasmic reticulum stimulated by PKA phosphorylation of phospholamban, can account for the faster relaxation seen in the inotropic response of the heart to catecholamines.     

Expression of two angiogenic factors, vascular endothelial growth factor and platelet-derived endothelial cell growth factor in human pancreatic cancer, and its relationship to angiogenesis

Twenty-three cases of ductal carcinoma in situ (DCIS), ten of which had an associated invasive component, were studied for loss of heterozygosity (LOH) of microsatellite markers on chromosome 9p and the results compared with a panel of 20 invasive breast carcinomas. In addition to the gene encoding p16, chromosome 9p is also thought to contain other putative tumour-suppressor genes. If the three panels of breast tumours showed LOH of markers in this region this would suggest that such putative genes were important in breast carcinogenesis. By studying both preinvasive and invasive breast tumours, it should also be possible to gain further information about the relationship between lesions of a different stage and to determine whether DCIS is indeed a precursor of invasive ductal carcinoma. Levels of LOH were low in the invasive-only set of tumours. Surprisingly, considerably higher levels of loss were observed in the tumours with an in situ component. Also, much heterogeneity was observed between different DCIS ducts or invasive tumour and DCIS from the same case.     

Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo

Perlecan, a ubiquitous heparan sulfate proteoglycan, possesses angiogenic and growth-promoting attributes primarily by acting as a coreceptor for basic fibroblast growth factor (FGF-2). In this report we blocked perlecan expression by using either constitutive CMV-driven or doxycycline- inducible antisense constructs. Growth of colon carcinoma cells was markedly attenuated upon obliteration of perlecan gene expression and these effects correlated with reduced responsiveness to and affinity for mitogenic keratinocyte growth factor (FGF-7). Exogenous perlecan effectively reconstituted the activity of FGF-7 in the perlecan-deficient cells. Moreover, soluble FGF-7 specifically bound immobilized perlecan in a heparan sulfate-independent manner. In both tumor xenografts induced by human colon carcinoma cells and tumor allografts induced by highly invasive mouse melanoma cells, perlecan suppression caused substantial inhibition of tumor growth and neovascularization. Thus, perlecan is a potent inducer of tumor growth and angiogenesis in vivo and therapeutic interventions targeting this key modulator of tumor progression may improve cancer treatment.