Synthesis, structural characterization and in vitro inhibitory studies against human breast cancer of the bis-(2,6-di-tert-butylphenol)tin(IV) dichloride and its complexes.

Four new organotin(IV) complexes of bis-(2,6-di-tert-butylphenol)tin(IV) dichloride [(tert-Bu-)(2)(HO-Ph)](2)SnCl(2) (1) with the heterocyclic thioamides 2-mercapto-pyrimidine (PMTH), 2-mercapto-4-methyl-pyrimidine (MPMTH), 2-mercapto-pyridine (PYTH) and 2-mercapto-benzothiazole (MBZTH), of formulae {[(tert-Bu-)(2)(HO-Ph)](2)Sn(PMT)(2)} (2), {[(tert-Bu-)(2)(HO-Ph)](2)Sn(MPMT)(2)} (3), {[(tert-Bu-)(2)(HO-Ph)](2)SnCl(PYT)} (4) and {[(tert-Bu-)(2)(HO-Ph)](2)SnCl(MBZT)} (5), have been synthesized and characterized by elemental analysis, (1)H-, (13)C-, (119)Sn-NMR, EPR, FT-IR, Raman and Mössbauer spectroscopic techniques. The crystal and molecular structures of compounds 1­5 have been determined by X-ray diffraction. The geometries around the metal center adopted in complexes 1­5 varied between tetrahedral in 1, trigonal bipyramidal in 3, 4, 5 and distorted octahedral in 2. Two carbon atoms from aryl groups and two chlorine atoms form a distorted tetrahedron in the case of 1. Two carbon, two sulfur and two nitrogen atoms from thione ligands form a distorted octahedral geometry around tin(IV) with trans-C(2), cis-N(2), cis-S(2)-configurations in 2. However, in the case of 4 and 5 complexes two carbon, one sulfur, one nitrogen and one chloride atom form a distorted trigonal bipyramidal arrangement. Finally, in the case of 3 the trigonal bipyramidal geometry is achieved by two carbon, two sulfur and one nitrogen atom in a unique coordination mode of thioamides toward the tin(IV) cation. Compounds 1­5 were tested for their in vitro cytotoxicity against the human breast adenocarcinoma (MCF-7) cell line. Compound 3 exhibits strong cytotoxic activity against MCF-7 cells (IC(50) = 0.58 ± 0.1 µM).

Mixed ligand-silver(I) complexes with anti-inflammatory agents which can bind to lipoxygenase and calf-thymus DNA, modulating their function and inducing apoptosis.

A new mixed ligand-silver(I) complex of formula [Ag(tpp)(2)(p-Hbza)] (1) (p-HbzaH = 4-hydroxybenzoic acid and tpp = triphenylphosphine) has been synthesized and characterized by elemental analysis, mp, vibrational spectroscopy (mid- and far-FT-IR), (1)H-NMR, UV-vis, ESI-MS spectroscopic techniques and X-ray crystallography. Complex 1 and the already known mixed ligand-silver(I) complexes of formulae [Ag(tpp)(2)(salH)] (2) (salH(2) = salicylic acid or 2-hydroxy-benzoic acid) and {[Ag(tpp)(3)(asp)](dmf)} (3) (aspH = o-acetylsalicylic acid) were used for the clarification of the cytostatic activity mechanism. Thus, 1-3 were tested for their in vitro cytotoxic activity against leiomyosarcoma (LMS) and human breast adenocarcinoma (MCF-7) cells with trypan blue and Thiazolyl Blue Tetrazolium Bromide (MTT) assays. For both cell lines, complexes 1-3 were found to be more active than cisplatin. Due to the morphology of the LMS cells after incubation with 1-3, the type of cell death was evaluated by flow cytometry assay and DNA fragmentation. The results show that LMS cells undergo programmed cell death (apoptosis). DNA binding tests indicate the ability of complexes 1-3 to modify the activity of the cells. The binding constants of 1-3 towards calf-thymus DNA (CT-DNA) ((27.7 ± 7.9) × 10(4) (1), (13.3 ± 6.5) × 10(4) (2) and (11 ± 2.8) × 10(4) (3) M(-1)) indicate strong interaction. Moreover, the influence of complexes 1-3 on the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically studied. Finally, docking studies on DNA binding interactions were performed.

Public knowledge, beliefs and practices in Greece about cancer etiology and prevention.

This questionnaire survey of the parents of elementary schoolchildren in Greece assessed their self-reported knowledge, attitudes and practices towards smoking, diet and exposure to X-radiation. A random sample of 403 household units (379 fathers and 391 mothers) was selected from urban areas of Thessaloniki. Half of the parents who smoked (50.1%) did not ask for permission to smoke from other people and 66.0% regularly smoked in front of their children. On the other hand, 82.6% of smokers recognized the existence of a health risk to children from passive smoking. Parents overestimated the role of nuclear tests and accidents as factors in carcinogenesis. Two-thirds of parents did not know the beneficial role of the Mediterranean diet to health, and dietary intake analysis showed some departure from the traditional Mediterranean diet. A reconsideration of the policy regarding health education programmes concerning cancer prevention in Greece is needed.

Synthesis, structural characterization and biological studies of the triphenyltin(IV) complex with 2-thiobarbituric acid.

The reaction between 2-thiobarbituric acid (H(2)TBA), which was treated with an equimolar amount of potassium hydroxide, in a water with triphenytin chloride in methanol, results in the formation of the {[Ph(3)Sn(O-HTBA)]}(n) (1) complex. Crystals of the hydrated 1 with formula {[Ph(3)Sn(O-HTBA)]·0.7(H(2)O)}(n) were growth from methanol/acetonitrile solution, of the white precipitation, filtered off, from the reaction. The crystal structure of complex 1 has been determined by X-ray diffraction at 120 K. Complex 1 is polymeric. The geometry around the tin(IV) ions is trigonal bi-pyramidal with coordination to three C atoms from phenyl groups and one O atom from a de-protonated HTBA ligand. Complex 1 and the already known [(n-Bu)(3)Sn(O-HTBA)·H(2)O] (2) were evaluated for their in vitro cytotoxic activity (cell viability) against human cancer cell lines: HeLa (cervical), OAW-42 (ovarian), MCF-7 (breast, ER positive), MDA-MB-231 (breast, ER negative), A549 (lung), Caki-1 (renal) and additionally, the normal human lung cell line MRC-5 (normal human fetal lung fibroblast cells) and normal immortalized human mammary gland epithelial cell line MTSV17 with a Trypan Blue assay. Moreover complex 1 was evaluated for its in vitro cell growth proliferation activity against leiomyosarcoma cells (LMS), MCF-7 and MRC-5 cells with a Thiazolyl Blue Tetrazolium Bromide (MTT) assay. The type of cell death caused by complexes 1 and 2 was also evaluated by use of flow cytometry assay. The results showed that these compounds mediate a strong cytotoxic response to normal and cancer cell lines tested through apoptosis and induce cell cycle arrest in S phase of the cell cycle, suggesting DNA intercalation (direct or indirect) with the complexes. Finally, the influence of these complexes 1 and 2 upon the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically and theoretically studied.

Inhibition of lipoxygenase (LOX) and anticancer activity caused by gold(I) mixed ligands complexes of triphenylphosphine and thioamides.

Four mixed ligand gold(I) complexes with the thioamides 2-mercapto-thiazolidine (mtzdH), 2-mercapto-benzothiazole (mbztH) and 5-chloro-2-mercapto-benzothiazole (ClmbztH) and triphenylphosphine (tpp) of formulae [Au(tpp)Cl] (1) [Au(tpp)(mtzd)] (2), [Au(tpp)(mbzt)] (3) and [Au(tpp)(Clmbzt)] (4), already known, were used to study their mechanism of inhibition activity towards the catalytic oxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX), kinetically and theoretically. The results are compared to those of cisplatin. In addition, the anticancer cell screening results against leimyosarcoma (LMS) cells have shown that 2-4 complexes were more active than cisplatin. The uptake of complexes in LMS cells were also studied with electrospray ionisation mass spectrometry spectroscopy.

Intra-peritoneal application of catechins and EGCG as in vivo inhibitors of ozone-induced oxidative stress.

Oxidative stress is considered as a prominent feature of many acute and chronic diseases as well as of the normal aging process. We examined the effects of intra-peritoneal administration of catechins and EGCG as in vivo inhibitors of oxidative stress induced by ozone administration in two groups of Wistar rats. The first group was treated by intra-peritoneal administration of catechins and EGCG after the administration of ozone and the second group was pretreated by intra-peritoneal administration of catechins and EGCG prior to ozone administration. We determined in blood the activity of the enzymes superoxide dismutase and glutathione peroxidase, total antioxidant capacity, levels of copper and zinc and in urine malonaldehyde contents. Ozone administration resulted in significant reduction of glutathione peroxidase activity, plasma zinc levels and plasma and Red Blood Cells antioxidant capacity. Catechins and EGCG upregulate superoxide dismutase activity and maintain plasma and Red Blood Cells antioxidant capacity. Malonaldehyde levels at the end of the study were significantly increased only in the first group. Our data demonstrate that treatment with catechins and EGCG cannot reverse or prevent the effects of oxidative stress although some modulation occurs.

Public knowledge, beliefs and practices in Greece about cancer etiology and prevention

This questionnaire survey of the parents of elementary schoolchildren in Greece assessed their self-reported knowledge, attitudes and practices towards smoking, diet and exposure to X-radiation. A random sample of 403 household units [379 fathers and 391 mothers] was selected from urban areas of Thessaloniki. Half of the parents who smoked [50.1%] did not ask for permission to smoke from other people and 66.0% regularly smoked in front of their children. On the other hand, 82.6% of smokers recognized the existence of a health risk to children from passive smoking. Parents overestimated the role of nuclear tests and accidents as factors in carcinogenesis. Two-thirds of parents did not know the beneficial role of the Mediterranean diet to health, and dietary intake analysis showed some departure from the traditional Mediterranean diet. A reconsideration of the policy regarding health education programmes concerning cancer prevention in Greece is needed

Alcohol consumption and prostate cancer: a mini review.

Prostate cancer has become a major public health problem worldwide although the etiology of prostate cancer remains largely unknown. Dietary factors, dietary supplements, and physical activity might be important in the prevention of the disease. In the majority of studies published, it was observed that high consumption of meat, alcohol and dairy products has been linked to a greater risk. Specifically, alcohol use, and particularly heavy use, may cause cancers of liver, esophagus, larynx, pharynx and oral cavity, with risks for the aero-digestive cancers. Moderate use among women has been related with increases in breast cancer. Alcohol consumption is a modifiable lifestyle factor that may affect prostate cancer risk. Alcohol alters the hormonal environment and in parallel, containing chemical substances such as flavonoids (red wine), may alter tumor cell growth. In this mini review, the relation between alcohol consumption and prostate cancer risk is analyzed.

Structural properties, cytotoxicity, and anti-inflammatory activity of silver(I) complexes with tris(p-tolyl)phosphine and 5-chloro-2-mercaptobenzothiazole.

The synthesis and characterization of the silver(I) chloride complex of formula {[AgCI(CMBZT)(TPTP)(2)] . (MeOH)} (1) (CMBZT = 5-chloro-2-mercaptobenzothiazole, TPTP = tris(p-tolyl)phosphine) is described. Also the structure of the hydrate derivative {[AgCI(TPTP)(3)] . (0.5 . H(2)O)} (2) of the corresponding known anhydrous silver complex (Zartilas et al., 2009), and the polymorph 3 of the known [AgI(TPTP)(3)] complex (Zartilas et al., 2009) were determined and compared with the known ones. In addition, the structure of the known one silver(I) cluster {[AgI(TPTP)](4)} (4) (Meijboom et al., 2009) was re-determined at 120(2) K and possible Ag-Ag interactions were analyzed. The compounds 1-4 were characterized by X-ray crystallography at r.t (1) and 120 K (2-4). All these complexes and {[(Et(3)NH)(+)](2) . [Ag(6)(mu(3)-Hmna)(4)(mu(3)-mna)(2)](2-) . (DMSO)(2) . (H(2)O)} (5) (Hmna = 2-mercaptonicotinic acid) were evaluated for cytotoxic and anti-inflammatory activity. The in vitro testing of cytotoxic activity of 1-5 against leiomyosarcoma cancer cells (LMS), were evaluated with Trypan Blue and Thiazolyl Blue Tetrazolium Bromide or 3-(4.5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide (MTT) assays. The flow cytometry assay for complex 1 and showed that at 15 muM of 1, 62.38% of LMS cells undergo apoptosis, while 7% of LMS cells undergo cell necrosis. The antitumor activity of 3 is comparable with that of its reported polymorph (Zartilas et al., 2009). The anti-inflammatory, activity of complexes 1-3 and 5 was also studied. The activity towards cell viability was 2 > 3 > 5 > 1 > 4, while the order of the inhibitory activity in cell growth proliferation follows the order, 2 > 3 > 1 > 4 > 5. The anti-inflammatory activity on the other hand is 1 > 2 > 5 > cdots, three dots, centered >3.

The introduction of medical humanities in the undergraduate curriculum of Greek medical schools: challenge and necessity.

BACKGROUND AND AIM: Medical humanities is a multidisciplinary field, consisting of humanities (theory of literature and arts, philosophy, ethics, history and theology), social sciences (anthropology, psychology and sociology) and arts (literature, theater, cinema, music and visual arts), integrated in the undergraduate curriculum of Medical schools. The aim of the present study is to discuss medical humanities and support the necessity of introduction of a medical humanities course in the curriculum of Greek medical schools. MATERIALS, METHODS AND RESULTS: Through the relevant Pub-Med search as well as taking into account various curricula of medical schools, it is evident that medical education today is characterized by acquisition of knowledge and skills and development of medical values and attitudes. Clinical observation with the recognition of key data and patterns in the collected information, is crucial in the final medical decision, i.e. in the complex process, through which doctors accumulate data, reach conclusions and decide on therapy. All sciences included in medical humanities are important for the high quality education of future doctors. The practice of Medicine is in large an image-related science. The history of anatomy and art are closely related, already from the Renaissance time. Studies have shown that attendance of courses on art critics improves the observational skills of medical students. Literature is the source of information about the nature and source of human emotions and behavior and of narratives of illness, and increases imagination. Philosophy aids in the development of analytical and synthetical thinking. Teaching of history of medicine develops humility and aids in avoiding the repetition of mistakes of the past, and quite often raises research and therapeutic skepticism. The comprehension of medical ethics and professional deontology guides the patient-doctor relationship, as well as the relations between physicians and their colleagues. The Medical Humanities course, which is already integrated in the undergraduate curriculum of many medical schools of Europe, USA and Australia, includes lectures by experts and students presentations on the above-mentioned areas and could be offered, for a semester, during the first years. CONCLUSION: The aim of Medical Humanities course is the development of imagination and interpretation of data through analytical complex procedures, the development of skills of close observation and careful interpretation of the patient "language" and the enhancement of empathy for the patients, as well as the development of the physician-patient relationship and finally the conceptualization/construction of personal and professional values.

Long-term results of plastipore prostheses in reconstruction of the middle ear ossicular chain.

PURPOSE: To examine the acoustic results over a long period of time, in patients who underwent ossiculoplasty with Plastipore, and to report the percentage of prosthesis extrusion and factors related to the prognosis. PROCEDURES: Forty-two patients, who underwent ossiculoplasty with Plastipore, were studied. Patients were followed up for the next 14 years. The surgical procedures were classified as: tympanoplasty, tympanoplasty with mastoidectomy with canal wall up, and tympanoplasty with mastoidectomy with canal wall down. A successful hearing result was defined as a postoperative air-bone gap (ABG) of 20 dB or less. RESULTS: Successful results were seen in 65% of our patients, 68.8% with a partial ossicular replacement prosthesis (PORP) and a 62.5% success rate with a total ossicular replacement prosthesis (TORP). The mean value for ABG improvement was 25.5 dB. Prosthesis extrusion occurred in 4.7%. CONCLUSIONS: The ossiculoplasty-Plastipore technique leads to good hearing results and a low percentage of prosthesis extrusion in long-term follow-ups.

Amplification and co-regulators of androgen receptor gene in prostate cancer.

Prostate cancer is the second most common malignancy among males after lung cancer. The growth of prostate cancer cells depends on the presence of androgens, a group of steroid hormones that include testosterone and its more active metabolite dihydrotestoste-rone. Most prostate cancers are androgen-dependent and respond to the antiandrogens or androgen-deprivation therapy. However, the progression to an androgen-independent stage occurs frequently. Possible mechanisms that could be involved in the development of hormone resistant prostate cancer causes including androgen receptor (AR) mutations, AR amplification/over expression, interaction between AR and other growth factors, and enhanced signaling in a ligand-independent manner are discussed.

Acute septic cholelithiasic cholecystitis and adenocarcinoma of the gallbladder; an interesting association.

BACKGROUND AND STUDY AIMS: Primary carcinoma of the gallbladder may present as acute lithiasic cholecystitis that leads to severe septic complications. The correlation between severe sepsis of the gallbladder and primary carcinoma is unclear. The goal of the present study is to examine the relation between severe septic complications of lithiasic cholecystitis and primary carcinoma of the gallbladder. PATIENTS AND METHODS: A group of 72 patients (22 males, 50 females, age range: 45-99, mean age: 68.6 years), with severe septic cholelithiasic cholecystitis was treated with emergency surgery after failure of conservative treatment, and patients found with primary carcinoma of the gallbladder were registered. The resectability and operability of the tumor were studied, as well as tumor staging and overall patient survival. RESULTS: During urgent surgery for severe septic lithiasic cholecystitis, 12 patients (12/72, 16.6%) were found with gallbladder carcinoma. Patients with septic acute lithiasic cholecystitis and carcinoma had a higher mean age compared to those without carcinoma (74.8 vs. 67.4 yrs). Eleven of 12 (91.6%) carcinomas were inoperable, despite resectability of 8 out of 12 (66.6%), and overall patient survival was limited to a few months after surgery. CONCLUSIONS: Severe septic complications in elderly patients with a long-standing history of gallbladder stones may co-exist with primary carcinoma of the gallbladder. The percentage of a gallbladder carcinoma detected in septic patients reaches up to 16.6%. Even if these patients have a poor general health, surgical intervention is a solution when they appear with severe septic clinical symptoms caused by gallstones or carcinoma, in order to avoid lethal sepsis. The possibility of a carcinoma hidden in the gallbladder must be in mind during surgery. Imaging studies before surgery may detect the carcinoma; in most cases carcinomas are inoperable, although colecystectomy may be performed during surgery.

Review. Leukocyte and endothelial cell adhesion molecules in inflammation focusing on inflammatory heart disease.

In multicellular organisms the development of adhesion bonds, either among cells or among cells and components of the extracellular matrix, is a crucial process. These interactions are mediated by molecules which are named adhesion molecules and play a main role both at the early stages of the development of tissue integrity and later. Cell adhesion molecules (CAMs) have a key role in several pathologies such as cancer and inflammatory diseases. Selectins, integrins and immunoglobulin gene superfamily of adhesion receptors mediate different steps of leukocyte migration from the bloodstream towards the inflammatory foci. Leukocyte interactions with the vascular endothelium are highly orchestrated processes that include the capture of free-flowing leukocytes from the blood with subsequent leukocyte rolling, arrest, firm adhesion and ensuing diapedesis. These interactions occur under high shear stresses within venules and depend on multiple families of adhesion molecules. As a response to infection mediators, leukocyte gathering is considered to be crucial for the adequate defence of the organism to any kind of injury or infection. Endothelial activation contributes significantly to the systemic inflammatory response to bacteraemia and increased expression. Release of soluble endothelial markers into the circulation has been demonstrated together with elevated plasma levels of CAMs and has been reported in bacteraemic patients. It has been proposed that infection of endothelial cells with Staphylococcus aureus, Streptococcus sanguis, or Staphylococcus epidermidis induces surface expression of ICAM-1 and VCAM-1 and monocyte adhesion. In general, leukocyte/endothelial cell interactions such as capture, rolling, and firm adhesion can no longer be viewed as occurring in discrete steps mediated by individual families of adhesion molecules but rather as a series of overlapping synergistic interactions among adhesion molecules resulting in an adhesion cascade. These cascades thereby direct leukocyte migration, which is essential for the generation of effective inflammatory responses and the development of rapid immune responses.

Thoracoabdominal wall tumour seeding after percutaneous radiofrequency ablation for recurrent colorectal liver metastatic lesion: a case report with a brief literature review.

Radiofrequency is a safe and effective minimally invasive procedure in the treatment of liver and other organs neoplastic lesions. Percutaneous access of neoplastic liver tissue is the most common access and electrodes are placed with imaging guidance into the tumour to be ablated. Complications during and after radiofrequency ablation (RFA) are of major or minor severity. Tumour dissemination related to the percutaneous access seems to be very unusual. Herein, we present a rare case of thoracoabdominal tumour wall dissemination after RFA of a recurrent hepatic colorectal metastasis previously removed by surgery. A 64-year-old man with a recurrent hepatic metastatic lesion was treated with internally cooled radiofrequency (RF) for ablation of a 3x3 cm in size tumour mass. Two sessions of RFA in one-month period were performed. Computed tomography (CT) of the upper abdomen and carcinoembryonic (CEA) antigen were used for estimation of the disease progression in the patient's follow-up. Ten months after RFA the patient presented abdominal pain and a mass appeared on the right thoracoabdominal area with simultaneous lung metastases. In conclusion, a large size, bulky and superficial mass on the liver parenchyma adjacent to the thoracoabdominal wall as well as multiple RFA sessions, seem to represent risk factors for tumour dissemination through the needle electrode used during the RFA procedure in hepatic metastases of colorectal cancer.

Molecular profiling and genomic microarrays in prostate cancer.

In the present review article a global approach regarding the usefulness of genomic microarrays in prostate cancer management, is attempted. Cancer is a multistep process of mutations in key regulatory genes and epigenetic alterations that result in loss of balanced gene expression. A complete knowledge of the interaction between the genetic variability of the neoformation (tumor profiling) and the genetic variability of the host (inherited genome profiling), will be able to determine the better strategy against the cancer and the less toxicity for the patient. Alterations in the sequence of the hormone binding domain of the androgen receptor as well as mutations in some genes, determine radioresistance and resistance or sensitivity to some chemotherapeutic drugs. New therapies using monoclonal antibodies directed against specific extracellular binding domains of some receptors are based on molecular alterations observed in tumors.

In breast carcinoma dysadherin expression is correlated with invasiveness but not with E-cadherin.

Reduction/loss of E-cadherin is associated with the development and progression of many epithelial tumours. Dysadherin, recently characterised by members of our research team, has an anti-cell-cell adhesion function and downregulates E-cadherin in a post-transcriptional manner. The aim of the present study was to study the role of dysadherin in breast cancer progression, in association with the E-cadherin expression and the histological type. We have selected ductal carcinoma, which is by far the most common type and lobular carcinoma, which has a distinctive microscopic appearance. Dysadherin and E-cadherin expression was examined immunohistochemically in 70 invasive ductal carcinomas, no special type (NST), and 30 invasive lobular carcinomas, with their adjacent in situ components. In ductal as well as in lobular carcinoma dysadherin was expressed only in the invasive and not in the in situ component, and this expression was independent of the E-cadherin expression. Specifically, all 10 (100%) Grade 1, 37 out of 45(82.2%) Grade 2 and six out of 15 (40%) Grade 3 invasive ductal carcinomas showed preserved E-cadherin expression, while 'positive dysadherin expression' was found in six out of 10 (60%) Grade 1, 34 out of 45(75.5%) Grade 2 and all 15 (100%) Grade 3 neoplasms. None of the 30 infiltrating lobular carcinomas showed preserved E-cadherin expression, while all the 30 infiltrating lobular carcinomas exhibited 'positive dysadherin expression'. Dysadherin may play an important role in breast cancer progression by promoting invasion and, particularly in lobular carcinomas, it might also be used as a marker of invasion.

Expression of adhesion molecules during normal pregnancy.

We review the available information regarding the role of adhesive molecules as potential participants in the complex events of fertilization, embryogenesis, implantation and placentation. Studies that specifically relate to the expression and modulation of adhesive molecules in fertilization, embryogenesis, and implantation have been identified in the literature and by Medline searches. Cell-cell and cell-extracellular matrix interactions play a critical role in various developmental processes and in the cascade of events that lead to implantation and to the normal development of the fetus during pregnancy. Adhesion molecules influence, directly or indirectly, numerous aspects of cell behaviour, cell migration, cell growth, cell survival, cell proliferation, angiogenesis, invasion and metastasis.