Targeting FGFR Pathways in Gastrointestinal Cancers: New Frontiers of Treatment.

In carcinogenesis of the gastrointestinal (GI) tract, the deregulation of fibroblast growth factor receptor (FGFR) signaling plays a critical role. The aberrant activity of this pathway is described in approximately 10% of gastric cancers and its frequency increases in intrahepatic cholangiocarcinomas (iCCAs), with an estimated frequency of 10-16%. Several selective FGFR inhibitors have been developed in the last few years with promising results. For example, targeting the FGFR pathway is now a fundamental part of clinical practice when treating iCCA and many clinical trials are ongoing to test the safety and efficacy of anti-FGFR agents in gastric, colon and pancreatic cancer, with variable results. However, the response rates of anti-FGFR drugs are modest and resistances emerge rapidly, limiting their efficacy and causing disease progression. In this review, we aim to explore the landscape of anti-FGFR inhibitors in relation to GI cancer, with particular focus on selective FGFR inhibitors and drug combinations that may lead to overcoming resistance mechanisms and drug-induced toxicities.

Anti-Claudin Treatments in Gastroesophageal Adenocarcinoma: Mainstream and Upcoming Strategies.

Claudins (CLDNs) are a multigene family of proteins and the principal components of tight junctions (TJs), which normally mediate cell-cell adhesion and selectively allow the paracellular flux of ions and small molecules between cells. Downregulation of claudin proteins increases the paracellular permeability of nutrients and growth stimuli to malignant cells, which aids the epithelial transition. Claudin 18.2 (CLDN18.2) was identified as a promising target for the treatment of advanced gastroesophageal adenocarcinoma (GEAC), with high levels found in almost 30% of metastatic cases. CLDN18.2 aberrations, enriched in the genomically stable subgroup of GEAC and the diffuse histological subtype, are ideal candidates for monoclonal antibodies and CAR-T cells. Zolbetuximab, a highly specific anti-CLDN18.2 monoclonal antibody, demonstrated efficacy in phase II studies and, more recently, in the phase III SPOTLIGHT trial, with improvements in both PFS and OS with respect to standard chemotherapy. Anti-CLDN18.2 chimeric antigen receptor (CAR)-T cells showed a safety profile with a prevalence of hematologic toxicity in early phase clinical trials. The aim of this review is to present new findings in the treatment of CLDN18.2-positive GEAC, with a particular focus on the monoclonal antibody zolbetuximab and on the use of engineered anti-CLDN18.2 CAR-T cells.

Thrombotic Events during Lenvatinib Treatment: A Single Institution Experience.

Lenvatinib is the standard treatment for radioiodine-refractory differentiated thyroid cancer (RR-DTC). Thromboembolic (TE) side effects are quite rare (1-3% of treated patients) in clinical trials. Nevertheless, patients with predisposing factors are at a higher risk of developing cardiovascular adverse events. Reduction of lenvatinib starting dose and cardiologic counselling to provide appropriate supportive therapies are usually recommended for high-risk patients. From 2016 to 2022, we analyzed a series of 16 patients who were consecutively treated at our institution. All except one patient received a reduction in their dosage after two cycles of therapy because of toxicities, and four patients (25%) suffered from TE. The observed incidence in our patient sample seemed to be higher than expected. We hypothesized that our patient sample might be at higher risk probably because of the heavy prior loco-regional treatments performed.

Papillary Thyroid Carcinoma: Molecular Distinction by MicroRNA Profiling.

Papillary thyroid carcinoma (PTC) is a miscellaneous disease with a variety of histological variants, each with its own mutational profile, and clinical and prognostic characteristics. Identification of microRNA (miRNA) expression profiles represents an important benchmark for understanding the molecular mechanisms underlying the biological behavior of these unique PTC subtypes in order that they be better characterized. We considered a series of 35 PTC samples with a histological diagnosis of either hobnail (17 cases) or classical variant (nine cases) and with a specific BRAF p.K601E mutation (nine cases). We determined the overall miRNA expression profile with NanoString technology, and both quantitative reverse transcription-PCR and in situ hybridization were used to confirm selected miRNAs. The miRNA signature was found to consistently differentiate specific histotypes and mutational profiles. In contrast to the BRAF p.K601E mutation and classic PTCs, three miRNAs (miR-21-5p, miR-146b-5p, and miR-205-5p) were substantially overexpressed in the hobnail variant. The current study found that different miRNA signature profiles were linked to unique histological variants and BRAF mutations in PTC. Further studies focusing on the downstream pathogenetic functions of mRNAs in thyroid neoplasms are warranted.

NTRK fusions in colorectal cancer: clinical meaning and future perspective.

INTRODUCTION: Despite the efforts of the scientific community, the prognosis of metastatic colorectal cancer (mCRC) remains poor. Actionable gene fusions such as Neurotrophic Tropomyosin Receptor Kinases (NTRK) rearrangements are rare but might represent a new target to improve outcomes in this setting. The first-generation TRK inhibitors, larotrectinib and entrectinib, have demonstrated efficacy and safety in mCRC cancer patients exhibiting NTRK pathogenic fusions. Moreover, second-generation molecules are emerging, able to overcome the acquired resistance to NTRK blocking. AREAS COVERED: This review aims to report the current knowledge and the available evidence on NTRK fusion in mCRC, with a focus on molecular bases, clinical characteristics, prognostic meaning, and new therapeutic approaches, from the perspective of the clinical oncologist. EXPERT OPINION: Considering the limited options associated with the treatment of mCRC patients, the possibility of identifying new molecular biomarkers is an urgent clinical need. The availability of new molecular targets and the combinations of different agents might represent the true breakthrough point, allowing for change in the clinical course of colorectal cancer patients.

Challenges and perspectives for immunotherapy in oesophageal cancer: A look to the future (Review).

Oesophageal cancer is one of the most aggressive malignancies with limited treatment options, thus resulting in a high morbidity and mortality. With 5­year survival rates of only 5­10%, oesophageal cancer holds a dismal prognosis for patients. In order to improve overall survival, the early diagnosis and tools for patient stratification for personalized treatment are urgent needs. A minority of oesophageal cancers belong to the spectrum of Lynch syndrome­associated cancers and are characterized by microsatellite instability (MSI). Microsatellite instability is a consequence of defective mismatch repair protein functions and it has been well characterized in other gastrointestinal tumours, such as colorectal and gastric cancer. In the latter, high levels of MSI are associated with a better prognosis and with an increased benefit to immune­based therapies. Therefore, similar therapeutic approaches could offer an opportunity of treatment for oesophageal cancer patients with MSI. Apart from immune checkpoint inhibitors, other immunotherapies such as adoptive T­cell transfer, peptide vaccine and oncolytic viruses are under investigation in oesophageal cancer patients. In the present review, the rationale and current knowledge about immunotherapies in oesophageal cancer are summarised.

Vault RNAs: hidden gems in RNA and protein regulation.

Non-coding RNAs are important regulators of differentiation during embryogenesis as well as key players in the fine-tuning of transcription and furthermore, they control the post-transcriptional regulation of mRNAs under physiological conditions. Deregulated expression of non-coding RNAs is often identified as one major contribution in a number of pathological conditions. Non-coding RNAs are a heterogenous group of RNAs and they represent the majority of nuclear transcripts in eukaryotes. An evolutionary highly conserved sub-group of non-coding RNAs is represented by vault RNAs, named since firstly discovered as component of the largest known ribonucleoprotein complexes called "vault". Although they have been initially described 30 years ago, vault RNAs are largely unknown and their molecular role is still under investigation. In this review we will summarize the known functions of vault RNAs and their involvement in cellular mechanisms.

Acute pancreatitis after the removal of a hyperplastic duodenal polyp: a case report.

A 59-year-old patient underwent the duodenal endoscopic mucosal resection of a hyperplastic polyp. Four hours after the procedure she developed severe epigastric pain. Laboratory and imaging results were consistent with mild acute edematous pancreatitis. After several days of dietary therapy and intravenous crystalloid fluids the patient recovered, and 1 month later was asymptomatic and had no signs of pancreatic inflammation. This case illustrates a rare but clinically important complication of therapeutic upper endoscopy, which may be attributable to thermal injury of the duodenal wall and the adjacent pancreas. It also underscores the importance of the close follow up of patients who undergo invasive endoscopic procedures and the need for additional preventive measures to be taken when resecting duodenal lesions.

Use of Antibiotics and Risk of Cancer: A Systematic Review and Meta-Analysis of Observational Studies.

The association between antibiotic use and risk of cancer development is unclear, and clinical trials are lacking. We performed a systematic review and meta-analysis of observational studies to assess the association between antibiotic use and risk of cancer. PubMed, the Cochrane Library and EMBASE were searched from inception to 24 February 2019 for studies reporting antibiotic use and subsequent risk of cancer. We included observational studies of adult subjects with previous exposure to antibiotics and available information on incident cancer diagnoses. For each of the eligible studies, data were collected by three reviewers. Risk of cancer was pooled to provide an adjusted odds ratio (OR) with a 95% confidence interval (CI). The primary outcome was the risk of developing cancer in ever versus non-antibiotic users. Cancer risk's association with antibiotic intake was evaluated among 7,947,270 participants (n = 25 studies). Overall, antibiotic use was an independent risk factor for cancer occurrence (OR 1.18, 95%CI 1.12-1.24, p < 0.001). The risk was especially increased for lung cancer (OR 1.29, 95%CI 1.03-1.61, p = 0.02), lymphomas (OR 1.31, 95%CI 1.13-1.51, p < 0.001), pancreatic cancer (OR 1.28, 95%CI 1.04-1.57, p = 0.019), renal cell carcinoma (OR 1.28, 95%CI 1.1-1.5, p = 0.001), and multiple myeloma (OR 1.36, 95%CI 1.18-1.56, p < 0.001). There is moderate evidence that excessive or prolonged use of antibiotics during a person's life is associated with slight increased risk of various cancers. The message is potentially important for public health policies because minimizing improper antibiotic use within a program of antibiotic stewardship could also reduce cancer incidence.

Major innovations and clinical applications of disodium-levofolinate: a review of available preclinical and clinical data.

The association of folinate salts with 5-fluorouracil (5-FU) represents a gold standard in the treatment of many cancers. In several clinical trials, the simultaneous administration of calcium-folinic acid (Ca-FA) and the prolonged infusion of 5-FU resulted in a better clinical response compared with fluoropyrimidine alone and 5-FU bolus. However, the simultaneous infusion of 5-FU and Ca-FA mixed in the same infusion pump is hindered by the crystallization of calcium salts, which eventually leads to catheter obstruction and damage. The sodium salt of leucovorin-disodium levofolinate (Na-Lv) is a novel molecule with a pharmacological profile similar to Ca-FA. Owing to its higher solubility, it can be safely mixed with 5-FU in a single pump without the risk of precipitation and catheter occlusion. The efficacy and safety of Na-Lv have been widely examined in preclinical and clinical phase II studies in combination with various schedules of 5-FU and in several cancer types. PubMed, EMBASE, SCOPUS and Web of Science databases were searched from inception to November 2018 to retrieve available published phase I and II series, including Western patients. Compared with Ca-FA, Na-Lv shows a more favourable efficacy and toxicity profile in terms of overall response rate, progression-free survival, time to progression and occurrence of severe adverse events. Moreover, it allows treatment time to be shortened, decreasing the number of required human resources for drug administration and limiting the occurrence of catheter damage.

Biliary tract cancer: current challenges and future prospects.

PURPOSE: Incidence and mortality of biliary tract carcinoma (BTC) are increasing, especially in South America and Asia. Such a disease often bears a dismal prognosis because of diagnosis occurring at late stages and for the frequent relapses after surgery. The aims of this review were to summarize the state of the art of the treatment of BTC and give a view at possible future prospects linked with molecular profiling, immunotherapy, and targeted therapies. DESIGN: We conducted a systematic literature search using MEDLINE and the 2018 ASCO Meeting abstract databases to identify published clinical trials, translational series, and meeting abstracts. All significant papers and abstracts available to date were included. RESULTS: For resected BTC, thanks to the BILCAP study, adjuvant chemotherapy (CT) with capecitabine should be regarded as the new standard of care. For locally advanced inoperable and metastatic diseases, the use of chemoradiotherapy and radioembolization has not been supported by any randomized Phase III study. The standard of care remains the combination of CT with gemcitabine and cisplatin, as reported by the ABC-02 trial. All targeted therapies have failed to improve the survival outcomes, either in combination with CT or as single agents and are not recommended in the treatment of BTC. Whole-exome sequencing and molecular profiling have helped in identifying genetic signatures typical of different BTC subtypes. With this support, new trials with targeted agents and immunotherapy have been designed, and results are awaited. CONCLUSION: BTC still remains a disease with very few treatment options. Different BTC subtypes own peculiar gene mutations and pathways alterations. Therefore, molecular profiling may be the only key to enable new tailored strategies with targeted agents and immunotherapy.

Clinical development of mTor inhibitors for renal cancer.

INTRODUCTION: Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. In the last 10 years, clinical trials have established multitargeted tyrosine kinase inhibitors (TKIs) as the standard first-line treatment in patients with metastatic disease. Multiple agents are now available for treatment in subsequent lines.The mammalian target of rapamycin (mTOR) inhibitors (e.g., everolimus alone or with lenvatinib) are among the most effective options. Areas covered: This paper provides a complete and updated overview on mTOR inhibitors for the treatment of advanced RCC. The authors revised the results of the most recent completed clinical trials and provided information about ongoing trials. Expert opinion: mTOR pathway still represents an important driver for RCC management. Combination of everolimus and lenvatinib is considered a category 1 choice with cabozantinib and nivolumab for subsequent therapy in metastatic RCC according to NCCN guidelines v2.2017. These three treatments (levantinib/everolimus, cabozantinib, and nivolumab) all resulted in a superior efficacy compared to everolimus alone. Moreover, mTOR inhibitors, and in particular temsirolimus for poor risk patients, are available choices for treatment in non-clear cell carcinomas together with TKIs.

Clinical outcome and molecular characterization of brain metastases from esophageal and gastric cancer: a systematic review.

The aim of the study was to collect the available data on central nervous system (CNS) metastases from esophageal and gastric cancer. A PubMed, EMBASE, SCOPUS, Web of Science, LILACS, Ovid and Cochrane Library search was performed. Thirty-seven studies including 779 patients were considered. Among the data extracted, treatment of tumor and brain metastases (BMs), time to BMs development, number and subsite, extracerebral metastases rate, median overall survival (OS) and prognostic factors were included. For esophageal cancer, the median OS from diagnosis of BMs was 4.2 months. Prognostic factors for OS included: performance status, multimodal therapy, adjuvant chemotherapy, single BM, brain only disease and surgery. For gastric cancer, median OS was 2.4 months. Prognostic factors for OS included: recursive partitioning analysis class 2, stereotactic radiosurgery (SRT) and use of intrathecal therapy. HER2-positive gastric cancer was shown to be associated with a higher risk and shorter time to CNS relapse. Patients harboring BMs from gastric and esophageal tumors, except cases with single lesions that are treated aggressively, have a poor prognosis. SRT (plus or minus surgery and whole brain radiotherapy) seems to give better results in terms of longer OS after brain relapse.

Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers.

OBJECTIVE: Transcribed-ultraconserved regions (T-UCR) are long non-coding RNAs which are conserved across species and are involved in carcinogenesis. We studied T-UCRs downstream of the Wnt/ß-catenin pathway in liver cancer. DESIGN: Hypomorphic Apc mice (Apcfl/fl) and thiocetamide (TAA)-treated rats developed Wnt/ß-catenin dependent hepatocarcinoma (HCC) and cholangiocarcinoma (CCA), respectively. T-UCR expression was assessed by microarray, real-time PCR and in situ hybridisation. RESULTS: Overexpression of the T-UCR uc.158- could differentiate Wnt/ß-catenin dependent HCC from normal liver and from ß-catenin negative diethylnitrosamine (DEN)-induced HCC. uc.158- was overexpressed in human HepG2 versus Huh7 cells in line with activation of the Wnt pathway. In vitro modulation of ß-catenin altered uc.158- expression in human malignant hepatocytes. uc.158- expression was increased in CTNNB1-mutated human HCCs compared with non-mutated human HCCs, and in human HCC with nuclear localisation of ß-catenin. uc.158- was increased in TAA rat CCA and reduced after treatment with Wnt/ß-catenin inhibitors. uc.158- expression was negative in human normal liver and biliary epithelia, while it was increased in human CCA in two different cohorts. Locked nucleic acid-mediated inhibition of uc.158- reduced anchorage cell growth, 3D-spheroid formation and spheroid-based cell migration, and increased apoptosis in HepG2 and SW1 cells. miR-193b was predicted to have binding sites within the uc.158- sequence. Modulation of uc.158- changed miR-193b expression in human malignant hepatocytes. Co-transfection of uc.158- inhibitor and anti-miR-193b rescued the effect of uc.158- inhibition on cell viability. CONCLUSIONS: We showed that uc.158- is activated by the Wnt pathway in liver cancers and drives their growth. Thus, it may represent a promising target for the development of novel therapeutics.

MicroRNA 193b-3p as a predictive biomarker of chronic kidney disease in patients undergoing radical nephrectomy for renal cell carcinoma.

BACKGROUND: A significant proportion of patients undergoing radical nephrectomy (RN) for clear-cell renal cell carcinoma (RCC) develop chronic kidney disease (CKD) within a few years following surgery. Chronic kidney disease has important health, social and economic impact and no predictive biomarkers are currently available. MicroRNAs (miRs) are small non-coding RNAs implicated in several pathological processes. METHODS: Primary objective of our study was to define miRs whose deregulation is predictive of CKD in patients treated with RN. Ribonucleic acid from formalin-fixed paraffin embedded renal parenchyma (cortex and medulla isolated separately) situated >3 cm from the matching RCC was tested for miR expression using nCounter NanoString technology in 71 consecutive patients treated with RN for RCC. Validation was performed by RT-PCR and in situ hybridisation. End point was post-RN CKD measured 12 months post-operatively. Multivariable logistic regression and decision curve analysis were used to test the statistical and clinical impact of predictors of CKD. RESULTS: The overexpression of miR-193b-3p was associated with high risk of developing CKD in patients undergoing RN for RCC and emerged as an independent predictor of CKD. The addition of miR-193b-3p to a predictive model based on clinical variables (including sex and estimated glomerular filtration rate) increased the sensitivity of the predictive model from 81 to 88%. In situ hybridisation showed that miR-193b-3p overexpression was associated with tubule-interstitial inflammation and fibrosis in patients with no clinical or biochemical evidence of pre-RN nephropathy. CONCLUSIONS: miR-193b-3p might represent a useful biomarker to tailor and implement surveillance strategies for patients at high risk of developing CKD following RN.

New developments in the treatment of chemotherapy-induced neutropenia: focus on balugrastim.

Neutropenia and febrile neutropenia are two major complications of chemotherapy. Dose reductions, delays in treatment administration, and the use of granulocyte colony-stimulating factors are equally recommended options to preserve absolute neutrophil count in case of chemotherapy regimens bringing a risk of febrile neutropenia of 20% or higher. Recombinant granulocyte colony-stimulating factors, such as filgrastim and lenograstim, have a short elimination half-life (t1/2) and need to be used daily, while others, like pegfilgrastim and lipegfilgrastim, are characterized by a long t1/2 requiring only a single administration per cycle. Balugrastim is a novel long-acting recombinant granulocyte colony-stimulating factor obtained by means of a genetic fusion between recombinant human serum albumin and granulocyte colony-stimulating factor. Albumin binding increases the molecular weight and determines a high plasmatic stability leading to a t1/2 of ~19 days. Balugrastim's efficacy, safety, and tolerability have been assessed in four different clinical trials involving breast cancer patients treated with doxorubicin and docetaxel. Pegfilgrastim was chosen as a comparator. Balugrastim was noninferior to pegfilgrastim with regard to the reduction of mean duration of severe neutropenia during cycle 1. Moreover, both treatments were comparable in terms of efficacy and safety profile. Balugrastim was well tolerated, with the only related adverse event being mild to moderate bone pain. The aim of this review is to summarize the currently available literature data on balugrastim.

Sequence variation in mature microRNA-608 and benefit from neo-adjuvant treatment in locally advanced rectal cancer patients.

Single nucleotide polymorphisms (SNPs) in microRNA genes have been associated with colorectal cancer (CRC) risk, survival and response to treatment. Conflicting results are available on the association between rs4919510, a SNP in mature miR-608 and clinical outcome in CRC. Here, we analyzed the association between rs4919510 and benefit from perioperative treatment in a randomised phase II trial of neoadjuvant Capecitabine and Oxaliplatin (CAPOX) followed by chemo-radiotherapy, surgery and adjuvant CAPOX ± Cetuximab in high-risk locally advanced rectal cancer (LARC). A total of 155/164 (94.5%) patients were assessable. 95 (61.3%) were homozygous for CC, 55 (35.5%) heterozygous (CG) and 5 (3.2%) homozygous for GG. Median follow-up was 64.9 months. In the CAPOX arm the 5-year progression-free survival (PFS) and overall survival (OS) rates were 54.6% and 60.7% for CC and 82.0% and 82.1% for CG/GG, respectively (HR PFS 0.13, 95% CI: 0.12-0.83, P = 0.02; HR OS 0.38, 95% CI: 0.14-1.01, P = 0.05). In the CAPOX-C arm PFS and OS were 73.2 and 82.2%, respectively for CC carriers and 64.6 and 73.1% for CG/GG carriers (HR PFS 1.38, 95% CI: 0.61-3.13, P = 0.44; HR OS 1.34, 95% CI: 0.52-3.48, P = 0.55). An interaction was found between study treatment and rs4919510 genotype for both PFS (P = 0.02) and OS (P = 0.07). This is the first study investigating rs4919510 in LARC. The CC genotype appeared to be associated with worse prognosis compared to the CG/GG genotype in patients treated with chemotherapy and chemo-radiotherapy alone. Addition of Cetuximab to chemotherapy and chemo-radiotherapy in CC carriers appeared to improve clinical outcome.

Evaluation of effects caused by differentially spliced Ets-1 transcripts in fibroblasts.

The transcription factor Ets-1 is known to be involved in a broad variety of cellular functions such as cell proliferation, migration, invasion, apoptosis and angiogenesis. In nearly all these reports, the full-length Ets-1 (p51) is commonly considered to be the active form and the role of the Ets-1ΔVII splice variant (p42) has not been addressed. Therefore, we studied the functional effects of p42 Ets-1 in comparison to p51 Ets-1 expression in a well-characterized mouse fibroblast cell line. Furthermore, the specific role of Ets-1 was evaluated using mouse fibroblasts with a reduced Ets-1 expression caused by RNAi and compared to fibroblasts with a binding inhibition of the whole ETS transcription factor family by stably overexpressing the ETS DNA binding domain as transdominant-negative mutant. Our results demonstrate that p42 Ets-1 has quite different functions and target genes compared to p51 Ets-1 (e.g. TIMP-4, MMP-3, MMP-9, MMP-13). In some cases (e.g. in cytokine expression) p42 Ets-1 is a functional transcription factor which acts in the same manner as a transdominant-negative approach.

Identification of ETS-1 target genes in human fibroblasts.

The transcription factor Ets-1 plays several distinct critical roles in tumour development and progression by acting both in neoplastic cells and in the tumour stroma. Increased expression of Ets-1 in tumours is often associated with a worse prognosis. Stromal fibroblasts attribute an important part to the behaviour of malignant tumours. In this study we investigated the role of Ets-1 in the tumour stroma. It is well known that ets-1 expression in fibroblasts--one of the main components of the tumour stroma--can be induced by basic fibroblast growth factor (bFGF). We applied suppression subtractive hybridization (SSH) to identify genes that are differentially expressed between bFGF stimulated wild-type fibroblasts and fibroblasts with reduced Ets-1 expression. We selected clones up- or down-regulated in bFGF stimulated wild-type fibroblasts using SSH and functionally characterized them by reference to public databases using NCBI BLAST tools. Expression levels of genes corresponding to subtracted clones were analyzed using RT-PCR. Known genes were associated with diverse functions; novel Ets-1 regulated genes identified by SSH not only encoded components involved in matrix degradation (as cathepsin and PAI-2) but also constituents of the extracellular matrix (ECM) including α-2-Type I collagen, TGF-ß induced protein, lumican and decorin. Our findings identify several potential novel target genes of Ets-1, and they provide potentially important insights into the role of Ets-1 in stromal fibroblasts for both remodelling and different functionalities of the ECM.

Regulation of protein tyrosine kinases in tumour cells by the transcription factor Ets-1.

Tyrosine phosphorylation is one of the key covalent modifications that occurs in multicellular organisms as a result of intercellular communication. The family of tyrosine kinases (PTKs) are responsible for part of the cellular phosphorylation and are involved in a broad variety of cellular functions including differentiation, proliferation, migration, invasion, angiogenesis and survival under physiological as well as pathological conditions. Aberration in PTK signalling occurs in inflammatory diseases and diabetes, and aberrant expression can lead to benign proliferative conditions as well as to various forms of cancer. Indeed, more than 70% of the known oncogenes and proto-oncogenes involved in cancer code for PTKs. Therefore, these enzymes are now used as targets in the treatment of different tumours. Ets-1 is a transcription factor expressed in a number of human malignancies with demonstrated roles within both neoplastic cells and tumour stroma. These roles include stimulation of tumour cell proliferation and invasion as well as tumour angiogenesis. Database searches have revealed that ETS binding sites are present in several promoters of PTK-encoding genes. We investigated the role of Ets-1 in transcriptional regulation of a panel of 89 PTKs in epithelial HeLa tumour cells. In this study, HeLa cells stably overexpressing and underexpressing Ets-1 were used for real-time PCR analysis of all known human PTKs. The results suggest that Ets-1 is an essential transcription factor that cannot be substituted by other members of the ETS family. Transcription of most PTKs was found to be increased by Ets-1. In contrast Ets-1 seems to act as a transcriptional repressor of other PTKs. The data presented here underscore the importance of Ets-1 in tumour development and progression.