Biomedical subjects

Adrian L Harris

Publications and source records attributed to Adrian L Harris.

At least 55 records · Page 3Linked to original sources

PubMed2005

Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function.

The Notch signaling pathway and the delta-like 4 ligand (DLL4) play key roles in embryonic vascular development. Many of the pathways involved in embryonic vascular development also play important roles in tumor angiogenesis. In this study, we assessed the expression of DLL4 in primary renal cancer and investigated the biological function of DLL4 in primary endothelial cells. Using real-time quantitative PCR and in situ hybridization, we showed that the expression of DLL4 was up-regulated within the vasculature of clear cell-renal cell carcinoma almost 9-fold more than normal kidney and was correlated with the expression of vascular endothelial growth factor (VEGF). The expression of DLL4 in endothelial cells was up-regulated by VEGF and basic fibroblast growth factor synergistically, and by hypoxia through hypoxia-inducible factor 1alpha. Down-regulation of DLL4 expression with RNA interference led to decreased expression of HEY1 and EphrinB2, and the inhibition of endothelial cell proliferation, migration, and network formation, all of which are important processes in tumor angiogenesis. The inhibition of proliferation occurred via the induction of cell cycle arrest in G0-G1 by increased expression of p21 and decreased phosphorylation of retinoblastoma. We conclude that an optimal window of the DLL4 expression is essential for tumor angiogenesis and that selective modulation of the DLL4 expression within human tumors may represent a potential novel antiangiogenic therapy.

Adaptor Proteins, Signal Transducing↗

PubMed2005

The role of hypoxia-inducible factor-1 in three-dimensional tumor growth, apoptosis, and regulation by the insulin-signaling pathway.

The purpose of this study was to establish the effect of hypoxia-inducible factor-1 (HIF-1) directly on tumor growth, independently of angiogenesis. This was done by growing wild-type mouse hepatoma cells (HEPA-1) and their HIF-1-deficient counterpart C4 as multicellular tumor spheroids and quantifying differences in growth rates and proliferative and apoptotic indices. Insulin and insulin-like growth factor-I are key growth factors, also able to regulate hypoxia-responsive genes via HIF-1; thus, the effects of insulin on this model were also investigated. Two-dimensional growth was serum dependent and no difference was seen between wild-type HEPA-1 and C4 cell growth profiles, but major differences were seen in three-dimensional growth. HIF-1 supported spheroid growth under hypoxia as the HEPA-1 spheroids grew faster than the C4. Surprisingly, the HIF-1-deficient cells had a higher proliferation rate in three-dimensional growth (C4 mean S-phase index, 13.6%; HEPA-1 mean S-phase index, 9%; P = 0.009) that was associated with an inhibition of apoptosis. However, the apoptosis rate was much greater in these spheroids (C4 mean apoptotic index, 6.4; HEPA-1 mean apoptotic index, 0.78%; P = 0.0006). Addition of insulin increased proliferation and apoptosis in both HEPA-1 and C4 spheroids, demonstrating an HIF-1-independent effect of insulin signaling in three-dimensional growth. These results indicate that the enhancing effect of HIF-1 in three-dimensional tumor growth is a balance of both reduced proliferation and enhanced survival, the latter being proportionally greater.

Animals↗

PubMed2005

Temozolomide pharmacodynamics in patients with metastatic melanoma: dna damage and activity of repair enzymes O6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1.

PURPOSE: Temozolomide, a DNA methylating agent used to treat melanoma, induces DNA damage, which is repaired by O6-alkylguanine alkyltransferase (ATase) and poly(ADP-ribose) polymerase-1 (PARP-1)-dependent base excision repair. The current study was done to define the effect of temozolomide on DNA integrity and relevant repair enzymes as a prelude to a phase I trial of the combination of temozolomide with a PARP inhibitor. EXPERIMENTAL DESIGN: Temozolomide (200 mg/m2 oral administration) was given to 12 patients with metastatic malignant melanoma. Peripheral blood lymphocytes (PBL) were analyzed for PARP activity, DNA single-strand breakage, ATase levels, and DNA methylation. PARP activity was also measured in tumor biopsies from 9 of 12 patients and in PBLs from healthy volunteers. RESULTS: Temozolomide pharmacokinetics were consistent with previous reports. Temozolomide therapy caused a substantial and sustained elevation of N7-methylguanine levels, a modest and sustained reduction in ATase activity, and a modest and transient increase in DNA strand breaks and PARP activity in PBLs. PARP-1 activity in tumor homogenates was variable (828 +/- 599 pmol PAR monomer/mg protein) and was not consistently affected by temozolomide treatment. CONCLUSIONS: The effect of temozolomide reported here are consistent with those documented in previous studies with temozolomide and similar drug, dacarbazine, demonstrating that a representative patient population was investigated. Furthermore, PARP activity was not inhibited by temozolomide treatment and this newly validated pharmacodynamic assay is therefore suitable for use in a proof-of-principle phase I trial a PARP-1 inhibitor in combination with temozolomide.

Adult↗

PubMed2005

Enhanced response to radiotherapy in tumours deficient in the function of hypoxia-inducible factor-1.

BACKGROUND AND PURPOSE: To test the hypothesis that deficiency in expression of the transcription factor, HIF-1, renders tumours more radioresponsive than HIF-1 proficient tumours. PATIENTS AND METHODS: Tumours comprising mouse hepatoma cells lacking HIF-1beta (and thereby HIF-1 function) were grown in nude mice and radiation-induced growth delay compared with that seen for wild-type tumours and tumours derived from HIF-1beta negative cells where HIF-1 function had been restored. RESULTS: The xenografts that lack HIF-1 activity take longer to establish their growth and are more radioresponsive than both parental xenografts and those with restored HIF-1 function. Pre-treatment of the HIF-1 deficient xenografts with the hypoxic radiosensitizer misonidazole, had little effect on radioresponse. In contrast this treatment radiosensitized the parental xenografts. In spite of this, no difference in oxygenation status was found between the tumour types as measured by Eppendorf O(2)-electrodes and by binding of the hypoxic cell marker NITP. Admixing wild type and HIF-1 deficient cells in the same tumour at ratios of 1 in 10 and 1 in 100 restores the growth of the mixed tumours to that of a 100% HIF-1 proficient cell population. However, when comparing the effects of radiation on the mixed tumours, radioresponsiveness is maintained in those tumours containing the high proportion of HIF-1 deficient cells. CONCLUSIONS: The differences in radioresponse do not correlate with tumour oxygenation, suggesting that the hypoxic cells within the HIF-1 deficient tumours do not contribute to the outcome of radiotherapy. Thus, hypoxia impacts on tumour radioresponsiveness not simply because of the physio-chemical mechanism of oxygen with radiation-induced radicals causing damage 'fixation', but also because hypoxia/HIF-1 promotes expression of genes that allow tumour cells to survive under these adverse conditions. Further, the results from the cell mixing experiments uncouple the growth promoting effects of HIF-1 and the underlying mechanism by which HIF-1 may increase radiation resistance in solid tumours.

Animals↗

PubMed2005

HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression.

Hypoxia promotes genetic instability by undefined mechanisms. The transcription factor HIF-1alpha is crucial for the cellular response to hypoxia and is frequently overexpressed in human cancers, resulting in the activation of genes essential for cell survival. Here, we demonstrate that HIF-1alpha is responsible for genetic instability at the nucleotide level by inhibiting MSH2 and MSH6, thereby decreasing levels of the MSH2-MSH6 complex, MutSalpha, which recognizes base mismatches. HIF-1alpha displaces the transcriptional activator Myc from Sp1 binding to repress MutSalpha expression in a p53-dependent manner; Sp1 serves as a molecular switch by recruiting HIF-1alpha to the gene promoter under hypoxia. Furthermore, in human sporadic colon cancers, HIF-1alpha overexpression is statistically associated with the loss of MSH2 expression, especially when p53 is immunochemically undetectable. These findings indicate that the regulation of DNA repair is an integral part of the hypoxic response, providing molecular insights into the mechanisms underlying hypoxia-induced genetic instability.

Cell Hypoxia↗

PubMed2005

HIF-2alpha expression in human fetal paraganglia and neuroblastoma: relation to sympathetic differentiation, glucose deficiency, and hypoxia.

Solid tumors are frequently necrotic and hypoxic due to poor vascularization. Tumor cells adapt to hypoxia by modulating their phenotype. Key players in this process are the hypoxia-inducible factors (HIF-1alpha to 3alpha). HIFs are also expressed during normal development; for example, HIF-2alpha is specifically expressed and appears to be involved in the development of the murine sympathetic nervous system (SNS). Here, we demonstrate that HIF-2alpha protein is selectively present in human fetal week 8.5 SNS paraganglia. Neuroblastoma is derived from SNS precursors. In a subset of neuroblastomas, a spontaneous neuronal to neuroendocrine differentiation occurs in areas adjacent to necrotic zones. As HIF-2alpha activity has been associated not only with hypoxic but also with hypoglycemic conditions, we have investigated putative effects of hypoxia, glucose depletion, and HIF-2alpha on the neuroblastoma phenotype. HIF-2alpha was detected in hypoxic and in well-oxygenized neuroblastoma cells and tissue, presumably reflecting their embryonic features. With regard to differentiation, hypoxic cells lost their neuronal/neuroendocrine features and gained marker gene expression associated with an immature, neural crest-like phenotype. Low glucose potentiated the effect of hypoxia. These findings suggest that poorly vascularized neuroblastomas become immature and maintain a more aggressive phenotype, which possibly could involve a sustained stabilization and activation of HIF-2alpha.

Base Sequence↗

PubMed2005

Phase I study of MetXia-P450 gene therapy and oral cyclophosphamide for patients with advanced breast cancer or melanoma.

PURPOSE: MetXia-P450 is a novel recombinant retroviral vector that encodes the human cytochrome P450 type 2B6 gene (CYP2B6), Escherichia coli lacZ, and neomycin resistance marker genes. Cytochrome P450 enzymes are primarily expressed in the liver and convert the prodrug cyclophosphamide to an active phosphoramide mustard and acrolein. Gene-based delivery of CYP2B6 to the tumor site leads to local prodrug activation and higher concentrations of the active metabolites at the target site. EXPERIMENTAL DESIGN: MetXia-P450 was directly injected into metastatic cutaneous tumor nodules on days 1 and 2 and nodules biopsied on day 7. Oral cyclophosphamide (100 mg/m(2)) was administered between days 8 and 22. Subsequent cycles of oral cyclophosphamide were repeated for 2 of 4 weeks. Gene transfer levels in biopsy samples were measured by histologic and quantitative PCR analyses. Safety assessments were made using PCR for vector dissemination to the blood after injection and using PCR and serologic analyses to detect replicating virus. Secondary end points included clinical response, toxicity, and evaluation of antitumor immune responses by measurement of carcinoembryonic antigen and 5T4 antibodies. RESULTS: Twelve patients with breast cancer (n = 9) and melanoma (n = 3) received three dose levels of MetXia-P450 ( approximately 8 x 10(5), approximately 8 x 10(6), and approximately 8 x 10(7) lacZ transferring units/mL). The product was safe and well tolerated. The lacZ transgene was detected in biopsy material by immunohistochemistry in 10 of 12 patients and integrated viral sequences by PCR in 3 of 6 patients. One (8%) patient with breast cancer had a partial response and received 7 months of oral cyclophosphamide. Four (33%) patients had stable disease for > or =3 months and the rest had progressive disease. Preliminary immunologic analyses were suggestive of an antitumor response in two patients (partial response in one patient and stable disease in one patient). CONCLUSION: MetXia was safe and well tolerated. Gene transfer was detected at all dose levels, and the initial suggestion of an antitumor response indicates that MetXia-P450 should undergo further clinical assessment.

Administration, Oral↗

PubMed2005

Prospective study of quantitation of plasma DNA levels in the diagnosis of malignant versus benign prostate disease.

PURPOSE: The aim of this study was to determine the potential of cell-free DNA levels as a diagnostic marker for prostate cancer, having first established the effect that blood sample processing has on this measurement. EXPERIMENTAL DESIGN: A total of 152 blood samples were collected prospectively from patients before their prostate biopsy and 25 from men in two distinct control groups. Blood was processed to yield three components: one-spin plasma (n = 68), two-spin plasma (n = 152), and serum (n = 56) samples. RESULTS: Having established the effect of sample preparation on the measured DNA level, the more reliable two-spin plasma sample was used to determine the relationship between DNA and the presence of prostate cancer. Those patients with cancer (n = 78) had a significantly higher level of DNA compared with the control groups (P < 0.0001 and P < 0.0001). However, DNA levels in patients with a benign biopsy (n = 74) were significantly higher than the 78 patients confirmed to have cancer (P = 0.02). CONCLUSIONS: We conclude that the sample type used in the quantitation of cell-free DNA has an effect on the level reported. Elevated levels are present in the two-spin plasma samples of patients with prostate cancer compared with healthy controls but are not of diagnostic value during the management of prostate cancer.

Aged↗

PubMed2005

Antiangiogenic activity of a domain deletion mutant of tissue plasminogen activator containing kringle 2.

OBJECTIVE: The thrombolytic therapy drug, Reteplase, is a domain deletion mutant of tissue plasminogen activator (tPA), comprising the kringle 2 and protease (K2P) domains. Some kringle domains of hemostatic proteins are antiangiogenic and promote apoptosis. The objective of this study was to investigate whether K2P is an angiogenesis inhibitor because of the presence of kringle 2. METHODS AND RESULTS: K2P inhibited basic fibroblast growth factor-induced human endothelial cell proliferation and migration. Inhibition was not dependent on the protease activity of K2P because similar results were obtained with catalytically inactivated K2P. Purification of the kringle 2 domain derived from elastase cleavage of K2P at the Arg275-Ile276 bond revealed that inhibition was mediated by this domain. In addition, K2P inhibited angiogenesis in vivo and increased endothelial cell apoptosis. CONCLUSIONS: Wound healing and angiogenesis are severely compromised by K2P. These data provide new mechanistic insights into the bleeding complications observed in some patients while undergoing thrombolytic therapy with this drug. In addition, we identify the kringle 2 domain of tPA as a novel target for antiangiogenic therapy.

Animals↗

PubMed2005

Recombinant modified vaccinia Ankara primes functionally activated CTL specific for a melanoma tumor antigen epitope in melanoma patients with a high risk of disease recurrence.

Recombinant plasmid DNA and attenuated poxviruses are under development as cancer and infectious disease vaccines. We present the results of a phase I clinical trial of recombinant plasmid DNA and modified vaccinia Ankara (MVA), both encoding 7 melanoma tumor antigen cytotoxic T lymphocyte (CTL) epitopes. HLA-A*0201-positive patients with surgically treated melanoma received either a "prime-boost" DNA/MVA or a homologous MVA-only regimen. Ex vivo tetramer analysis, performed at multiple time points, provided detailed kinetics of vaccine-driven CTL responses specific for the high-affinity melan-A(26-35) analogue epitope. Melan-A26-35-specific CTL were generated in 2/6 patients who received DNA/MVA (detectable only after the first MVA injection) and 4/7 patients who received MVA only. Ex vivo ELISPOT analysis and in vitro proliferation assays confirmed the effector function of these CTL. Responses were seen in smallpox-vaccinated as well as vaccinia-naive patients, as defined by anti-vaccinia antibody responses demonstrated by ELISA assay. The observations that 1) CTL responses were generated to only 1 of the recombinant epitopes and 2) that the magnitude of these responses (0.029-0.19% CD8(+) T cells) was below the levels usually seen in acute viral infections suggest that to ensure high numbers of CTL specific for multiple recombinant epitopes, a deeper understanding of the interplay between CTL responses specific for the viral vector and recombinant epitopes is required.

Adult↗

PubMed2005

Angiogenin is up-regulated in the nucleus and cytoplasm in human primary breast carcinoma and is associated with markers of hypoxia but not survival.

Angiogenin, a 14.2 kD polypeptide that was originally noted for its angiogenic activity, is now increasingly recognized to have a multiplicity of biological roles in both physiological and pathological conditions. In breast cancer, there are conflicting studies questioning the role of angiogenin. Here, the pattern of expression of angiogenin during the transition from normal breast tissue to ductal carcinoma in situ and invasive carcinoma is reported together with the correlates between the level of angiogenin in 239 invasive carcinomas and standard clinicopathological parameters, hypoxia-inducible factor (HIF)-1 alpha and the HIF-1 alpha target gene DEC-1. This study shows that angiogenin expression is up-regulated in the cytoplasmic and nuclear compartments in in situ carcinoma and invasive carcinoma compared with normal breast tissue and that angiogenin expression in invasive carcinomas is significantly positively associated with high tumour grade (p = 0.03), positive oestrogen receptor (ER) status (p = 0.01), HIF-1 alpha (p = 0.001) and DEC 1 (p = 0.001), but not with patient age (p = 0.8), tumour size (p = 0.25), lymph node status (p = 0.69), epidermal growth factor receptor (p = 0.56) or microvessel density (p = 0.32). No difference in relapse-free (p = 0.26) or overall (p = 0.63) survival was observed in patients stratified by angiogenin expression. This study suggests that angiogenin may be important in breast cancer progression and that, through its relationship with ER, it may be a target for tamoxifen.

Biomarkers, Tumor↗

PubMed2005

Distinct molecular signature of inflammatory breast cancer by cDNA microarray analysis.

Inflammatory breast cancer (IBC) is a clinically distinct and aggressive form of locally advanced breast cancer with largely unknown genetic determinants. Overexpression of the RhoC GTPase and of HER2, and decreased ER-expression are involved in IBC. Multimodality treatment has increased survival but prognosis is still poor. Novel molecular targets for improved neoadjuvant treatment are necessary. Using cDNA microarrays, we performed genome-wide expression profiling of pre-treatment tumour samples of 16 patients with IBC and 18 patients with non-stage-matched non-IBC. Rigid clinical diagnostic criteria according to the TNM classification of the American Joint Committee on Cancer were adopted. Unsupervised hierarchical clustering accurately distinguished IBC and non-IBC samples. A set of 50 discriminator genes was identified in a learning group of tumour samples and was successful in diagnosing IBC in a validation group of samples (accuracy of 88%). Exclusion of ER-related or HER2-related genes did not alter this discriminatory accuracy, indicating that the expression of other genes in addition to ER and HER2 characterize the IBC phenotype. The molecular signature of IBC revealed the overexpression of a large number of NF-kappaB target genes, explaining at least part of the aggressive nature of IBC. Successful validation of some of the overexpressed genes by immunohistochemistry or real-time quantitative PCR demonstrated the robustness of the cDNA microarray experiments. The results of our study provide potential targets for the treatment of patients with IBC.

Belgium↗

PubMed2005

The role of copper in tumour angiogenesis.

Copper stimulates the proliferation and migration of endothelial cells and is required for the secretion of several angiogenic factors by tumour cells. Copper chelation decreases the secretion of many of these factors. Serum copper levels are upregulated in many human tumours and correlate with tumour burden and prognosis. Copper chelators reduce tumour growth and microvascular density in animal models. New orally active copper chelators have enabled clinical trials to be undertaken, and there are several studies ongoing. A unifying mechanism of action by which copper chelation inhibits endothelial cell proliferation and tumour secretion of angiogenic factors remains to be elucidated, but possible targets include copper-dependent enzymes, chaperones, and transporters.

Animals↗

PubMed2005

Notch signaling from tumor cells: a new mechanism of angiogenesis.

Notch signaling is an evolutionarily conserved pathway and plays key roles in embryonic vascular development and angiogenesis. Multiple components of the Notch pathway are expressed in vasculature, and mice deficient for a variety of these components display embryonic lethality with vascular remodeling defects. Alteration of Notch signaling in various endothelial cells generates profound effects on angiogenesis in vitro. New evidence shows that Notch signaling from tumor cells is able to activate endothelial cells and trigger tumor angiogenesis in vitro and in a xenograft mouse tumor model. Selective interruption of Notch signaling within tumors may provide an antiangiogenic strategy.

Angiogenesis Inhibitors↗

PubMed2005

Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma.

Defective function of the von Hippel-Lindau (VHL) tumor suppressor ablates proteolytic regulation of hypoxia-inducible factor alpha subunits (HIF-1alpha and HIF-2alpha), leading to constitutive activation of hypoxia pathways in renal cell carcinoma (RCC). Here we report a comparative analysis of the functions of HIF-1alpha and HIF-2alpha in RCC and non-RCC cells. We demonstrate common patterns of HIF-alpha isoform transcriptional selectivity in VHL-defective RCC that show consistent and striking differences from patterns in other cell types. We also show that HIF-alpha isoforms display unexpected suppressive interactions in RCC cells, with enhanced expression of HIF-2alpha suppressing HIF-1alpha and vice-versa. In VHL-defective RCC cells, we demonstrate that the protumorigenic genes encoding cyclin D1, transforming growth factor alpha, and vascular endothelial growth factor respond specifically to HIF-2alpha and that the proapoptotic gene encoding BNip3 responds positively to HIF-1alpha and negatively to HIF-2alpha, indicating that HIF-1alpha and HIF-2alpha have contrasting properties in the biology of RCC. In keeping with this, HIF-alpha isoform-specific transcriptional selectivity was matched by differential effects on the growth of RCC as tumor xenografts, with HIF-1alpha retarding and HIF-2alpha enhancing tumor growth. These findings indicate that therapeutic approaches to targeting of the HIF system, at least in this setting, will need to take account of HIF isoform-specific functions.

Amino Acid Sequence↗

PubMed2005

Pyruvate dehydrogenase and pyruvate dehydrogenase kinase expression in non small cell lung cancer and tumor-associated stroma.

Pyruvate dehydrogenase (PDH) catalyzes the conversion of pyruvate to acetyl-coenzyme A, which enters into the Krebs cycle, providing adenosine triphosphate (ATP) to the cell. PDH activity is under the control of pyruvate dehydrogenase kinases (PDKs). Under hypoxic conditions, conversion of pyruvate to lactate occurs, a reaction catalyzed by lactate dehydrogenase 5 (LDH5). In cancer cells, however pyruvate is transformed to lactate occurs, regardless of the presence of oxygen (aerobic glycolysis/Warburg effect). Although, hypoxic intratumoral conditions account for HIF1alpha stabilization and induction of anaerobic metabolism, recent data suggest that high pyruvate concentrations also result in HIF1alpha stabilization independently of hypoxia. In the present immunohistochemical study, we provide evidence that the PDH/PDK pathway is repressed in 73% of non small cell lung carcinomas, which may be a key reason for HIF1alpha stabilization and "aerobic glycolysis." However, about half of PDH-HIF pathway, and patients harboring these tumors have an excellent postoperative outcome. A small subgroup of clinically aggressive tumors maintains a coherent PDH and HIF/LDH5 expression. In contrast to cancer cells, fibroblasts in the tumor supporting stroma exhibit an intense PDH but reduced PDK1 expression favoring maximum PDH activity. This means that stroma may use lactic acid produced by tumor cells, preventing the creation of an intolerable intratumoral acidic environment at the same time.

Autopsy↗

PubMed2005

Expression of bone morphogenetic protein 2 in breast cancer cells inhibits hypoxic cell death.

BMP-2 is involved in the fetal and postnatal development of the mammary gland but has also been detected in breast cancer cells. To clarify the biological role of BMP-2 in breast cancer, we used the human breast cancer cell line MCF-7. Incubation with BMP-2 under serum-free conditions induced activation of the mitogen activated protein kinases (MAPKs) ERK1/2 and the basic helix-loop-helix transcription factors Id-1, proteins that can protect from apoptosis. Stably transfected MCF-7 cells overexpressing BMP-2 revealed significantly increased resistance to hypoxia-induced apoptosis compared to empty vector controls. Cytoplasmic BMP-2/4 protein expression was detected in carcinoma cells of 81 samples of invasive breast cancer in contrast to adjacent normal mammary epithelial cells. BMP-2/4 expression did not correlate with common prognostic parameters and was not associated with relapse-free or overall survival. We conclude that BMP-2/4 expression is reactivated in invasive breast cancer and part of an autocrine/paracrine mechanism rescuing malignant cells from hypoxic cell death via activation of the MAPK and Id-1 pathway.

Bone Morphogenetic Protein 2↗

PubMed2005

Bone morphogenetic protein 2 (BMP-2) induces in vitro invasion and in vivo hormone independent growth of breast carcinoma cells.

Breast cancer cell lines migrated towards a BMP-2 source depending on BMP-2 concentration. After a short exposure to BMP-2, the cells were able to migrate through matrigel. MCF-7 cells transfected with the BMP-2 gene also showed enhanced migratory properties and high expression of the metastasis-related gene BCSG1. In a xenograft model without estrogen supplementation MCF-7/BMP-2 cells formed tumors. These tumors were characterised by an enhanced vasculature and the formation of chondroid and osseous structures. In conclusion elevated levels of BMP-2 enhance the tumorigenic properties of breast carcinoma cells and drive the cells towards a more aggressive phenotype with estrogen independent growth.

Animals↗