Incidence of Rectal Injury After Radical Prostatectomy: A Systematic Review and Meta-analysis.

Context: Rectal injury (RI) is a dreaded complication after radical prostatectomy (RP), increasing the risk of early postoperative complications, such as bleeding and severe infection/sepsis, and late sequelae, such as a rectourethral fistula (RUF). Considering its traditionally low incidence, uncertainty remains as to predisposing risk factors and management. Objective: To examine the incidence of RI after RP in contemporary series and to propose a pragmatic algorithm for its management. Evidence acquisition: A systematic literature search was performed using the Medline and Scopus databases. Studies reporting data on RI incidence were selected. Subgroup analyses were conducted to assess the differential incidence by age, surgical approach, salvage RP after radiation therapy, and previous benign prostatic hyperplasia (BPH)-related surgery. Evidence synthesis: Eighty-eight, mostly retrospective noncomparative, studies were selected. The meta-analysis obtained a pooled RI incidence of 0.58% (95% confidence interval [CI] 0.46-0.73) in contemporary series with significant across-study heterogeneity (I2 = 100%, p < 0.00001). The highest RI incidence was found in patients undergoing open RP (1.25%; 95% CI 0.66-2.38) and laparoscopic RP (1.25%; 95% CI 0.75-2.08) followed by perineal RP (0.19%; 95% CI 0-276.95) and robotic RP (0.08%; 95% CI 0.02-0.31). Age ≥60 yr (0.56%; 95% CI 0.37-06) and salvage RP after radiation therapy (6.01%; 95% CI 3.99-9.05), but not previous BPH-related surgery (4.08%, 95% CI 0.92-18.20), were also associated with an increased RI incidence. Intraoperative versus postoperative RI detection was associated with a significantly decreased risk of severe postoperative complications (such as sepsis and bleeding) and subsequent formation of a RUF. Conclusions: RI is a rare, but potentially devastating, complication following RP. RI incidence was higher in patients ≥60 yr of age, and in those who underwent open/laparoscopic approach or salvage RP after radiation therapy. Intraoperative RI detection and repair apparently constitute the single most critical step to significantly decrease the risk of major postoperative complications and subsequent RUF formation. Conversely, intraoperatively undetected RI can lead more often to severe infective complications and RUF, the management of which remains poorly standardised and requires complex procedures. Patient summary: Accidental rectum tear is a rare, but potentially devastating, complication in men undergoing prostate removal for cancer. It occurs more often in patients aged 60 yr or older as well as in those who underwent prostate removal via an open/laparoscopic approach and/or prostate removal after radiation therapy for recurrent disease. Prompt identification and repair of this condition during the initial operation are the key to reduce further complications such as the formation of an abnormal opening between the rectum and the urinary tract.

Epigenetic remodelling in human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, being the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related death. As other heterogeneous solid tumours, HCC results from a unique synergistic combination of genetic alterations mixed with epigenetic modifications.In HCC the patterns and frequencies of somatic variations change depending on the nearby chromatin. On the other hand, epigenetic alterations often induce genomic instability prone to mutations. Epigenetics refers to heritable states of gene expression without alteration to the DNA sequence itself and, unlike genetic changes, the epigenetic modifications are reversible and affect gene expression more extensively than genetic changes. Thus, studies of epigenetic regulation and the involved molecular machinery are greatly contributing to the understanding of the mechanisms that underline HCC onset and heterogeneity. Moreover, this knowledge may help to identify biomarkers for HCC diagnosis and prognosis, as well as future new targets for more efficacious therapeutic approaches.In this comprehensive review we will discuss the state-of-the-art knowledge about the epigenetic landscape in hepatocarcinogenesis, including evidence on the diagnostic and prognostic role of non-coding RNAs, modifications occurring at the chromatin level, and their role in the era of precision medicine.Apart from other better-known risk factors that predispose to the development of HCC, characterization of the epigenetic remodelling that occurs during hepatocarcinogenesis could open the way to the identification of personalized biomarkers. It may also enable a more accurate diagnosis and stratification of patients, and the discovery of new targets for more efficient therapeutic approaches.

Infiltrating T lymphocytes and programmed cell death protein-1/programmed death-ligand 1 expression in endometriosis-associated ovarian cancer.

OBJECTIVE: To characterize T lymphocyte infiltration and programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) expression in early-stage endometriosis-associated ovarian cancer (EAOC), ovarian endometriosis (OE), atypical endometriosis (AE), and deep endometriosis (DE). DESIGN: Case-control, retrospective study. SETTING: Research University Hospital. PATIENT(S): A total of 362 patients with a histologic diagnosis of EAOC, OE, AE, or DE were identified between 2000 and 2019 from Fondazione Policlinico Universitario Agostino Gemelli IRCCS and Gemelli Molise SpA tissue data banks. A 1:1 propensity score-matched method yielded matched pairs of 55 subjects with EAOC, 55 patients with OE, 12 patients with AE, and 42 patients with DE, resulting in no differences in family history of cancer, parity, and use of oral contraceptives. INTERVENTION(S): Immunohistochemistry assays using the following primary antibodies: CD3+; CD4+; CD8+; PD-1; and PD-L1. MAIN OUTCOME MEASURE(S): To characterize T lymphocyte infiltration and PD-1/PD-L1 expression in 4 different endometriosis-related diseases. RESULT(S): Endometriosis-associated ovarian cancer cases displayed significantly higher levels of PD-1/PD-L1 expression compared with all other endometriosis-related diseases (vs. OE vs. AE vs. DE). Moreover, a significantly lower count of infiltrating T lymphocytes was observed in EAOC cases compared with OE ones. Finally, one-third of OE cases showed a cancer-like PD-1/PD-L1 expression profile. CONCLUSION(S): Endometriosis-associated ovarian cancer is characterized by higher levels of PD-1/PD-L1 expression compared with benign endometriosis-related diseases. This profile was found in one-third of clinically benign cases, suggesting that it develops early in the carcinogenesis process.

Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumours worldwide. Sorafenib (SOR) is one of the most effective single-drug systemic therapy against advanced HCC, but the identification of novel combination regimens for a continued improvement in overall survival is a big challenge. Recent studies highlighted the crucial role of focal adhesion kinase (FAK) in HCC growth. The aim of this study was to investigate the antitumor effects of three different FAK inhibitors (FAKi), alone or in combination with SOR, using in vitro and in vivo models of HCC. METHODS: The effect of PND1186, PF431396, TAE226 on cell viability was compared to SOR. Among them TAE226, emerging as the most effective FAKi, was tested alone or in combination with SOR using 2D/3D human HCC cell line cultures and HCC xenograft murine models. The mechanisms of action were assessed by gene/protein expression and imaging approaches, combined with high-throughput methods. RESULTS: TAE226 was the more effective FAKi to be combined with SOR against HCC. Combined TAE226 and SOR treatment reduced HCC growth both in vitro and in vivo by affecting tumour-promoting gene expression and inducing epigenetic changes via dysregulation of FAK nuclear interactome. We characterized a novel nuclear functional interaction between FAK and the NuRD complex. TAE226-mediated FAK depletion and SOR-promoted MAPK down-modulation caused a decrease in the nuclear amount of HDAC1/2 and a consequent increase of the histone H3 lysine 27 acetylation, thus counteracting histone H3 lysine 27 trimethylation. CONCLUSIONS: Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduces HCC growth in vitro and in vivo. Also, our data highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising targets for HCC therapy.

Techniques for sentinel node biopsy in breast cancer.

Sentinel node biopsy (SNB) is the standard of care in women with breast cancer (BC) and clinically nonsuspicious axillary lymph nodes (LNs), due to its high negative predictive value (NPV) in the assessment of nodal status. SNB has significantly reduced complications related to the axillary lymph node dissection, such as lymphedema and upper limb dysfunction. The gold standard technique for SNB is the blue dye (BD) and technetium labelled nanocolloid (Tc-99m) double technique. However, nuclear medicine is not available in all Institutions and several new tracers and devices have been proposed, such as indocyanine green (ICG) and superparamagnetic iron oxides (SPIO). All these techniques show an accuracy and detection rate not inferior to that of the standard technique, with different specific pros and cons. The choice of how to perform a SNB primarily depends on the surgeon's confidence with the procedure, the availability of nuclear medicine and the economic resources of the Institutions. In this setting, new tracers, hybrid tracers and imaging techniques are being evaluated in order to improve the detection rate of sentinel lymph nodes (SNs) and minimize the number of unnecessary axillary surgeries through an accurate preoperative assessment of nodal status and to guide new minimally invasive diagnostic procedures of SNs. In particular, the contrast-enhanced ultrasound (CEUS) is an active field of research but cannot be recommended for clinical use at this time. The ICG fluorescence technique was superior in terms of DR, as well as having the lowest FNR. The DR descending order was SPIO, Tc, dual modality (Tc/BD), CEUS and BD. This paper is a narrative review of the most common SNB techniques in BC with a focus on recent innovations.

Ovarian Reserve after Chemotherapy in Breast Cancer: A Systematic Review and Meta-Analysis.

Background: Worldwide, breast cancer (BC) is the most common malignancy in the female population. In recent years, its diagnosis in young women has increased, together with a growing desire to become pregnant later in life. Although there is evidence about the detrimental effect of chemotherapy (CT) on the menses cycle, a practical tool to measure ovarian reserve is still missing. Recently, anti-Mullerian hormone (AMH) has been considered a good surrogate for ovarian reserve. The main objective of this paper is to evaluate the effect of CT on AMH value. METHODS: A systematic review and meta-analysis were conducted on the PubMed and Scopus electronic databases on articles retrieved from inception until February 2021. Trials evaluating ovarian reserves before and after CT in BC were included. We excluded case reports, case-series with fewer than ten patients, reviews (narrative or systematic), communications and perspectives. Studies in languages other than English or with polycystic ovarian syndrome (PCOS) patients were also excluded. AMH reduction was the main endpoint. Egger's and Begg's tests were used to assess the risk of publication bias. RESULTS: Eighteen trials were included from the 833 examined. A statistically significant decline in serum AMH concentration was found after CT, persisting even after years, with an overall reduction of -1.97 (95% CI: -3.12, -0.82). No significant differences in ovarian reserve loss were found in the BRCA1/2 mutation carriers compared to wild-type patients. CONCLUSIONS: Although this study has some limitations, including publication bias, failure to stratify the results by some important factors and low to medium quality of the studies included, this metanalysis demonstrates that the level of AMH markedly falls after CT in BC patients, corresponding to a reduction in ovarian reserve. These findings should be routinely discussed during oncofertility counseling and used to guide fertility preservation choices in young women before starting treatment.

A Lipidomic Signature Complements Stemness Features Acquisition in Liver Cancer Cells.

Lipid catabolism and anabolism changes play a role in stemness acquisition by cancer cells, and cancer stem cells (CSCs) are particularly dependent on the activity of the enzymes involved in these processes. Lipidomic changes could play a role in CSCs' ability to cause disease relapse and chemoresistance. The exploration of lipid composition and metabolism changes in CSCs in the context of hepatocellular cancer (HCC) is still incomplete and their lipidomic scenario continues to be elusive. We aimed to evaluate through high-throughput mass spectrometry (MS)-based lipidomics the levels of the members of the six major classes of sphingolipids and phospholipids in two HCC cell lines (HepG2 and Huh-7) silenced for the expression of histone variant macroH2A1 (favoring stemness acquisition), or silenced for the expression of focal adhesion tyrosine kinase (FAK) (hindering aggressiveness and stemness). Transcriptomic changes were evaluated by RNA sequencing as well. We found definite lipidomic and transcriptomic changes in the HCC lines upon knockdown (KD) of macroH2A1 or FAK, in line with the acquisition or loss of stemness features. In particular, macroH2A1 KD increased total sphingomyelin (SM) levels and decreased total lysophosphatidylcholine (LPC) levels, while FAK KD decreased total phosphatidylcholine (PC) levels. In conclusion, in HCC cell lines knocked down for specific signaling/epigenetic processes driving opposite stemness potential, we defined a lipidomic signature that hallmarks hepatic CSCs to be exploited for therapeutic strategies.

Focal Adhesion Kinase (FAK) Over-Expression and Prognostic Implication in Pediatric Hepatocellular Carcinoma.

Focal adhesion kinase (FAK) is over-expressed and is correlated with aggressiveness in adult hepatocellular carcinoma (HCC). Inhibition of FAK decreases HCC invasiveness by down-regulating Enhancer of Zeste homolog 2 (EZH2), an epigenetic controller, that acts in transcriptional repression of a large number of genes via histone 3 methylation of lysine 27 (H3K27me3). Here, we investigated the hepatic expression of total FAK, EZH2, H3K27me3, and proliferating cell nuclear antigen (PCNA) in 17 pediatric HCCs and 8 healthy livers (CTRL). Quantitative imaging analysis showed that FAK gene/protein expression is up-regulated in HCCs compared to CTRL and, among tumor samples the levels of this gene/protein are significantly higher in cirrhotic HCCs than in a healthy milieu. Accordingly, the protein levels of EZH2 were also significantly increased in HCCs from a cirrhotic background. Intriguingly, the protein expression of FAK, EZH2, and PCNA significantly inversely correlated with tumor size. Finally, in HCC samples, mainly in cirrhotic background, the up-regulation of FAK gene positively correlated with that observed in ß-Catenin gene. Conclusion: FAK gene/protein is over-expressed in pediatric HCCs concomitantly to EZH2 protein and ß-Catenin gene, with a more significant up-regulation in a cirrhotic background. This triad of interactors deserves further investigations for translational application.

The Contribution of the Adipose Tissue-Liver Axis in Pediatric Patients with Nonalcoholic Fatty Liver Disease after Laparoscopic Sleeve Gastrectomy.

OBJECTIVE: To evaluate the histopathologic modifications in liver and visceral adipose tissue (VAT), and to correlate these changes with clinical measures, adipokine production, and proinflammatory cytokines in a population of adolescents with obesity with nonalcoholic fatty liver disease (NAFLD) who underwent laparoscopic sleeve gastrectomy (LSG). STUDY DESIGN: Twenty adolescents with obesity who underwent LSG and with biopsy-proven NAFLD were included. Patients underwent clinical evaluation and blood tests at baseline and 1 year after the surgical procedure. Liver and VAT specimens were processed for routine histology, immunohistochemistry, and immunofluorescence. RESULTS: In adolescents with obesity and NAFLD, hepatic histologic alterations were uncorrelated with VAT inflammation. LSG induced in both liver and VAT tissue histopathology amelioration and macrophage profile modification that were correlated with body mass index and improvement in insulin resistance. The adipokine profile in liver and VAT was associated with weight loss and histologic improvement after LSG. Serum proinflammatory cytokines were correlated with liver and VAT histopathology and IL-1ß and IL-6 levels were independently predicted by liver necroinflammatory grade. CONCLUSIONS: This study suggests a unique adipose tissue/fatty liver crosstalk in pediatric patients. LSG induces a similar pattern of histologic improvement in the liver and in VAT. Besides VAT, our results strengthen the role of the liver in adipocytokine production and its contribution to systemic inflammation in pediatric patients with NAFLD.

ß-Klotho gene variation is associated with liver damage in children with NAFLD.

BACKGROUND & AIM: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in adults and children. Along with obesity, diabetes and insulin resistance, genetic factors strongly impact on NAFLD development and progression. Dysregulated bile acid metabolism and the fibroblast growth factor 19 (FGF19) pathway play a pivotal role in NAFLD pathogenesis. However, the mechanism through which the FGF19 receptor system is associated with liver damage in NAFLD remains to be defined. METHODS: We evaluated the impact of the rs17618244 G>A ß-Klotho (KLB) variant on liver damage in 249 pediatric patients with biopsy-proven NAFLD and the association of this variant with the expression of hepatic and soluble KLB. In vitro models were established to investigate the role of the KLB mutant. RESULTS: The KLB rs17618244 variant was associated with an increased risk of ballooning and lobular inflammation. KLB plasma levels were lower in carriers of the rs17618244 minor A allele and were associated with lobular inflammation, ballooning and fibrosis. In HepG2 and Huh7 hepatoma cell lines, exposure to free fatty acids caused a severe reduction of intracellular and secreted KLB. Finally, KLB downregulation obtained by the expression of a KLB mutant in HepG2 and Huh7 cells induced intracellular lipid accumulation and upregulation of p62, ACOX1, ACSL1, IL-1ß and TNF-α gene expression. CONCLUSION: In conclusion, we showed an association between the rs17618244 KLB variant, which leads to reduced KLB expression, and the severity of NAFLD in pediatric patients. We can speculate that the KLB protein may exert a protective role against lipotoxicity and inflammation in hepatocytes. LAY SUMMARY: Genetic and environmental factors strongly impact on the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD). The FGF19/FGFR4/KLB pathway plays a pivotal role in the pathogenesis of NAFLD. The aim of the study was to investigate the impact of a genetic variant in the KLB gene on the severity of liver disease. Our data suggest that the KLB protein plays a protective role against lipotoxicity and inflammation in hepatocytes.

Plasma N-terminal propeptide of type III procollagen accurately predicts liver fibrosis severity in children with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: We examined the diagnostic performance of plasma N-terminal propeptide of type III procollagen (PIIINP) levels, aspartate aminotransferase to platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score for predicting non-alcoholic steatohepatitis (NASH) and liver fibrosis stage in children/adolescents with non-alcoholic fatty liver disease (NAFLD). METHODS: We enrolled 204 children/adolescents with biopsy-proven NAFLD at the "Bambino Gesù" Children's Hospital. We measured plasma PIIINP levels using a commercially available enzyme-linked immunosorbent assay kit and calculated APRI and FIB-4 scores using standard methods. RESULTS: Children with NASH had higher plasma PIIINP levels, APRI and FIB-4 scores compared with those without NASH (all P < .001). However, PIIINP levels had much better diagnostic performance and accuracy than APRI and FIB-4 scores for predicting liver fibrosis stage. PIIINP levels correlated with the total NAFLD activity score (NAS) and its constituent components (P < .0001). The risk of either NASH or F ≥ 2 fibrosis progressively increased with increasing PIIINP levels (P < .0001), independent of age, gender, adiposity measures, insulin resistance, NAS score and the patatin-like phospholipase domain-containing protein-3 rs738409 polymorphism. For every 3.6 ng/mL increase in PIIINP levels, the likelihood of having F ≥ 2 fibrosis increased by ~14-fold (adjusted-odds ratio 14.1, 95% CI 5.50-35.8, P < .0001) after adjustment for the aforementioned risk factors. The area under the receiver operating characteristics curve was 0.921 (95% CI 0.87-0.97) for F ≥ 2 fibrosis, and 0.993 (95% CI 0.98-1.0) for F3 fibrosis respectively. CONCLUSIONS: Unlike APRI and FIB-4 scores, plasma PIIINP levels are a promising, non-invasive biomarker for diagnosing liver fibrosis stage in children/adolescents with biopsy-proven NAFLD.

Laparoscopic Sleeve Gastrectomy Improves Nonalcoholic Fatty Liver Disease-Related Liver Damage in Adolescents by Reshaping Cellular Interactions and Hepatic Adipocytokine Production.

OBJECTIVES: To investigate whether the modulation of local cellular cross-talks and the modification of hepatic adipocytokine expression could mechanistically explain the improvement of liver histopathology after laparoscopic sleeve gastrectomy (LSG) in adolescents with nonalcoholic fatty liver disease (NAFLD). STUDY DESIGN: Twenty obese (body mass index of ≥35 kg/m2) adolescents who underwent LSG and with biopsy-proven NAFLD were included. At baseline (T0) and 1 year after treatment, patients underwent clinical evaluation, blood tests, and liver biopsy. Hepatic progenitor cells, hepatic stellate cells (HSCs), macrophages, and adipocytokines were evaluated by immunohistochemistry and immunofluorescence. RESULTS: Liver biopsy samples after LSG demonstrated a significant improvement of NAFLD Activity Score and fibrosis. Immunohistochemistry indicated a significant reduction of hepatocyte cell cycle arrest, ductular reaction, activated HSC, and macrophage number after LSG compared with T0. The activation state of HSC was accompanied by modification in the expression of the autophagy marker LC3. Hepatocyte expression of adiponectin was significant higher after LSG than into T0. Moreover, LSG caused decreased resistin expression in Sox9+ hepatic progenitor cells compared with T0. The number of S100A9+ macrophages was also reduced by LSG correlating with resistin expression. Finally, serum levels of proinflammatory cytokines significantly correlated with macrophages and activated HSC numbers. CONCLUSIONS: The histologic improvement induced by LSG is associated with the reduced activation of local cellular compartments (hepatic progenitor cells, HSCs, and macrophages), thus, strengthening the role of cellular interactions and hepatic adipocytokine production in the pathogenesis of NAFLD.

Renal and Hepatic Functions after A Week of Controlled Ovarian Hyperstimulation during In Vitro Fertilization Cycles.

BACKGROUND: One the main aspects of in vitro fertilization (IVF) cycle is to avoid any possible systemic damage on women undergoing a controlled ovarian hyperstimulation (COH). The aim of this work is to evaluate renal and hepatic function blood tests in patients undergoing controlled ovarian hyperstimulation during IVF cycles. MATERIALS AND METHODS: We performed a prospective cohort analysis. All patients re- ceived a long stimulation protocol with gonadotropin-releasing hormone (GnRH) analogues by daily administration, since the twenty-first day of the previous ovarian cycle followed by COH with recombinant follicle-stimulating hormone (FSH). The daily dose of exogenous gonadotropins for every single patient was modified according to her follicular growth. The oocytes were retrieved during the oocyte pick up and fertilized by standard procedures of intracytoplasmic sperm injection (ICSI). The blood samples to evaluate renal and hepatic functions were taken at the 7th day of ovarian stimulation. RESULTS: We enrolled 426 women aged between 19 and 44 years, with a mean body mass index (BMI) of 24.68 Kg/m2. The mean value of blood urea nitrogen was 14 ± 3.16 mg/ dl, creatinine: 1 ± 0.45 mg/dl, uric acid: 4 ± 1.95 mg/dl, total proteins: 7 ± 3.93 mg/dl, aspartate aminotransferase: 18 ± 6.29 mU/ml, alanine aminotransferase: 19 ± 10.41 mU/ ml, alkaline phosphatase: 81 ± 45.25 mU/ml, total bilirubin 1 ± 0.35 mg/dL. All of the results were considered as a normal range following the Medical Council of Canada. CONCLUSION: Our data suggest that, unlike ovarian hyperstimulation syndrome (OHSS), COH patients did not show any alteration to renal and hepatic functions.

Focal adhesion kinase depletion reduces human hepatocellular carcinoma growth by repressing enhancer of zeste homolog 2.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer in humans. The focal adhesion tyrosine kinase (FAK) is often over-expressed in human HCC and FAK inhibition may reduce HCC cell invasiveness. However, the anti-oncogenic effect of FAK knockdown in HCC cells remains to be clarified. We found that FAK depletion in HCC cells reduced in vitro and in vivo tumorigenicity, by inducing G2/M arrest and apoptosis, decreasing anchorage-independent growth, and modulating the expression of several cancer-related genes. Among these genes, we showed that FAK silencing decreased transcription and nuclear localization of enhancer of zeste homolog 2 (EZH2) and its tri-methylation activity on lysine 27 of histone H3 (H3K27me3). Accordingly, FAK, EZH2 and H3K27me3 were concomitantly upregulated in human HCCs compared to non-tumor livers. In vitro experiments demonstrated that FAK affected EZH2 expression and function by modulating, at least in part, p53 and E2F2/3 transcriptional activity. Moreover, FAK silencing downregulated both EZH2 binding and histone H3K27me3 levels at the promoter of its target gene NOTCH2. Finally, we found that pharmacological inhibition of FAK activity resembled these effects although milder. In summary, we demonstrate that FAK depletion reduces HCC cell growth by affecting cancer-promoting genes including the pro-oncogene EZH2. Furthermore, we unveil a novel unprecedented FAK/EZH2 crosstalk in HCC cells, thus identifying a targetable network paving the way for new anticancer therapies.

Focal Adhesion Kinase: Insight into Molecular Roles and Functions in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Due to the high incidence of post-operative recurrence after current treatments, the identification of new and more effective drugs is required. In previous years, new targetable genes/pathways involved in HCC pathogenesis have been discovered through the help of high-throughput sequencing technologies. Mutations in TP53 and ß-catenin genes are the most frequent aberrations in HCC. However, approaches able to reverse the effect of these mutations might be unpredictable. In fact, if the reactivation of proteins, such as p53 in tumours, holds great promise as anticancer therapy, there are studies arguing that chronic activation of these types of molecules may be deleterious. Thus, recently the efforts on potential targets have focused on actionable mutations, such as those occurring in the gene encoding for focal adhesion kinase (FAK). This tyrosine kinase, localized to cellular focal contacts, is over-expressed in a variety of human tumours, including HCC. Moreover, several lines of evidence demonstrated that FAK depletion or inhibition impair in vitro and in vivo HCC growth and metastasis. Here, we provide an overview of FAK expression and activity in the context of tumour biology, discussing the current evidence of its connection with HCC development and progression.