Autotaxin (ATX) is a member of the ectonucleotide pyrophosphate/phosphodiesterase (ENPP) family; it is encoded by the ENPP2 gene. ATX is a secreted glycoprotein and catalyzes the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is responsible for the transduction of various signal pathways through the interaction with at least six G protein-coupled receptors, LPA Receptors 1 to 6 (LPAR1–6). The ATX–LPA axis is involved in various physiological and pathological processes, such as angiogenesis, embryonic development, inflammation, fibrosis, and obesity. However, significant research also reported its connection to carcinogenesis, immune escape, metastasis, tumor microenvironment, cancer stem cells, and therapeutic resistance. Moreover, several studies suggested ATX and LPA as relevant biomarkers and/or therapeutic targets. In this review of the literature, we aimed to deepen knowledge about the role of the ATX–LPA axis as a promoter of cancer development, progression and invasion, and therapeutic resistance. Finally, we explored its potential application as a prognostic/predictive biomarker and therapeutic target for tumor treatment.

INTRODUCTION: Helicobacter pylori (Hp)-related atrophic gastritis (AG) affects corpus and antral mucosa, resulting in multifocal AG (MF-AG); autoimmunity-driven AG is corpus-restricted (CR-AG). AG carries increased gastric dysplasia (GD) and gastric cancer (GC) risk, well established in MF-AG, but debated in CR-AG. This study aimed to assess clinical, endoscopic-histological characteristics of GD-GC in patients with MF-AG and CR-AG. METHODS: This was the multicenter cross-sectional study across 11 Italian gastroenterology centers on data of non-cardia GD-GC in adult patients with MF-AG or CR-AG based on clinical, endoscopic, and histological charts. RESULTS: Eighty-four patients were included with MF-AG and CR-AG in 45 (53.6%) and 39 (46.4%), respectively. Low-grade GD, high-grade GD, and GC were diagnosed in 31 (36.9%), 6 (7.1%), and 47 (56.0%), respectively. GD-GC similarly occurred in patients with MF-AG and CR-AG: high-grade GD in 4 (8.9%) vs 2 (5.1%), low-grade GD in 17 (37.8%) vs 14 (35.9%), and GC in 24 (53.5%) vs 23 (59.0%) (P > 0.05). Compared with MF-AG, in patients with CR-AG, GD-GC were more commonly polypoid (51.6% vs 27.3%, P = 0.048) and more frequent in the corpus (55.3% vs 28.6%, P = 0.02), but occurred also in the antrum (34.2%) and incisura (10.5%). Surgery was more frequent in CR-AG than in MF-AG (48.6% vs 23.1%, P = 0.02). Corpus atrophy severity and intestinal metaplasia were not different (P > 0.05), histological Hp positivity was low in both (2.3% vs 2.9%, P = 0.87), but in Hp negatives, active inflammation was present in the antrum in 26.7% and 7.7% (P = 0.02), and in the corpus in 31.1% and 21.5% (P = 0.27). DISCUSSION: Non-cardia GC and GD may occur in both MF-AG and CR-AG, displaying differences in topography and endoscopic presentation but similarities in nonlesional mucosa, differentiation, and staging. Surveillance should be considered in corpus AG, regardless of extension and supposed etiology. BACKGROUND: La gastrite atrofica (AG) Helicobacter pylori (Hp)-relata interessa la mucosa dell'antro e del corpo-fondo dando luogo alla gastrite atrofica multifocale (MF-AG); la gastrite atrofica autoimmune invece è limitata al corpo-fondo risparmiando l'antro (CR-AG). L'AG è ad aumentato rischio per displasia (GD) e cancro gastrico (GC). Questo rischio è ben stabilito nella MF-AG, ma ancor adibattuto nella CR-AG. Questo studio ha come scopo di valutare le caratteristiche cliniche e endoscopico-istologiche di pazienti affetti da GD o GC in MF-AG e CR-AG. METODI: E' stato condotto uno studio trasversale multicentrico in 11 centri gastroenterologici italiani su dati di pazienti adulti con GD o GC non cardiali in MF-AG o CR-AG basati su schede cliniche e referti endoscopici e istologici. RISULTATI: Sono stati inclusi 84 pazienti, di cui 45 (53.6%) con MF-AG e 39 (46.4%) con CR-AG. GD di basso (LG-GD) e di alto grado (HG-GD) e GC sono stati diagnosticati in 31 (36.9%), 6 (7.1%), and 47 (56.0%) pazienti, rispettivamente. GD e GC sono stati riscontrati con frequenza simile in pazienti con MF-AG e CR-AG: HG-GD in 4 (8.9%) vs 2 (5.1%), LG-GD in 17 (37.8%) vs 14 (35.9%), e GC in 24 (53.5%) vs 23 (59.0%) (p>0.05). Rispetto ai pazienti con MF-AG, nei pazienti con CR-AG GD e GC erano più frequentemente di aspetto polipoide (51.6% vs 27.3%, p=0.048) e più frequentemente localizzati nel corpo-fondo (55.3% vs 28.6%, p=0.02), ma venivano riscontrati anche nell'antro (34.2%) e a livello dell'incisura (10.5%). Il trattamento chirurgico era più frequente nei pazienti con CR-AG rispetto a coloro con MF-AG (48.6% vs 23.1%, p=0.02). La severità dell'atrofia del corpo-fondo e la presenza di metaplasia intestinale non erano differenti (p>0.05), mentre la positività istologica per l'Hp era bassa in ambedue i gruppi ((2.3% vs 2.9%, p=0.87), ma nei Hp negativi l'attività infiammatoria era presente nell'antro nel 26.7% e 7.7% (p=0.02), e nel corpo-fondo nel 31.1% e 21.5% (p=0.027). CONCLUSIONI: GD e i GC non cardiali possono sviluppare sia in pazienti con MF-AG che con CR-AG, con differenze nella topografia e nella presentazione endoscopica ma con similitudini nella mucosa non lesionale circostante, nella differenziazione e nella stadiazione. Pertanto, la sorveglianza dovrebbe essere considerata in tutti i pazienti con AG del corpo, a prescindere dall'estensione e dalla presunta eziologia.

Although biliary tract cancers are traditionally considered rare in Western countries, their incidence and mortality rates are rising worldwide. A better knowledge of the genomic landscape of these tumor types has broadened the number of molecular targeted therapies, including angiogenesis inhibitors. The role of immune checkpoint inhibitors (ICIs) could potentially change the first-line therapeutic approach, but monotherapy with ICIs has shown disappointing results in CCA. Several clinical trials are evaluating combination strategies that include immunotherapy together with other anticancer agents with a synergistic activity. The tumor microenvironment (TME) composition plays a pivotal role in the prognosis of BTC patients. The accumulation of immunosuppressive cell types, such as tumor-associated macrophages (TAMs) and regulatory T-cells, together with the poor infiltration of cytotoxic CD8+ T-cells, is known to predispose to a poor prognosis owing to the establishment of resistance mechanisms. Likewise, angiogenesis is recognized as a major player in modulating the TME in an immunosuppressive manner. This is the mechanistic rationale for combination treatment schemes blocking both immunity and angiogenesis. In this scenario, this review aims to provide an overview of the most recent completed or ongoing clinical trials combining immunotherapy and angiogenesis inhibitors with/without a chemotherapy backbone.

Angiogenesis inhibition treatments are limited and are often too late for advanced gastric cancer (GC) patients, in whom its efficacy is reduced. New molecular biomarkers are needed to optimize therapy regimens. In regard to this framework, circulating miRNAs, with high sensitivity and specificity, could be useful biomarkers of GC. The present longitudinal study was focused on analyzing the expression levels of a blood miRNA signature in a cohort of 40 patients receiving second-line therapy combining Ramucirumab and Paclitaxel, stratified based on their Progression-Free Survival (PFS). Using differential and bioinformatic analysis, miR-205-5p, miR-30e-3p, and miR-23b-3p were selected as possible predictive biomarkers, with the results showing that they were more highly expressed in patients exhibiting longer PFS and that they were involved in modulating angiogenesis. Furthermore, patients with longer PFS showed a progressive and significant decrease in the selected miRNA to minimal levels. The loss of the protective effect and the increased expression of the hypothetical targets, including angiopoietin-2, were then observed. The hypothesis was supported by the inverse correlation found for miR-205-5p and angiopoietin-2. Circulating levels of miR-205-5p were protective (HR = 0.37, p = 0.02) and patients with higher baseline miRNA levels had longer OS (12.47 vs. 9.00 months). Our findings suggest that these three miRNAs may be novel candidates as non-invasive predictive markers of therapy outcomes.

Metastatic gastric cancer (mGC) often has a poor prognosis and may benefit from a few targeted therapies. Ramucirumab-based anti-angiogenic therapy targeting the VEGFR2 represents a milestone in the second-line treatment of mGC. Several studies on different cancers are focusing on the major VEGFR2 ligand status, meaning VEGFA gene copy number and protein overexpression, as a prognostic marker and predictor of response to anti-angiogenic therapy. Following this insight, our study aims to examine the role of VEGFA status as a predictive biomarker for the outcome of second-line therapy with Ramucirumab and paclitaxel in mGC patients. To this purpose, the copy number of the VEGFA gene, by fluorescence in situ hybridization experiments, and its expression in tumor tissue as well as the density of micro-vessels, by immunohistochemistry experiments, were assessed in samples derived from mGC patients. This analysis found that amplification of VEGFA concomitantly with VEGFA overexpression and overexpression of VEGFA with micro-vessels density are more represented in patients showing disease control during treatment with Ramucirumab. In addition, in the analyzed series, it was found that amplification was not always associated with overexpression of VEGFA, but overexpression of VEGFA correlates with high micro-vessel density. In conclusion, overexpression of VEGFA could emerge as a potential biomarker to predict the response to anti-angiogenic therapy.

Background: Gastric cancer (GC) is a highly aggressive disease often complicated by resistance to chemotherapy agents like paclitaxel (PTX), which targets microtubules to induce apoptosis. Resistance arises through complex molecular mechanisms, including the overexpression of pro-angiogenic factors (VEGFA, ANG-2), activation of survival pathways (PDGFRβ, PPARγ), and epithelial-mesenchymal transition (EMT) driven by proteins such as VIM, E-CAD, N-CAD, and FLOT-1. The extracellular matrix (ECM), regulated by COL1A1 and influenced by PPARγ, acts as a physical barrier to drug penetration. Small extracellular vesicles (sEVs) have emerged as critical mediators of intercellular communication and may influence these resistance pathways. Methods: This study investigated the role of sEVs isolated from metastatic GC patients treated with Ramucirumab and PTX. Patients were stratified by progression-free survival (PFS) into rapidly progressing (RP) and controlled disease (CD) groups. sEVs from these patients were applied to HCEC-1CT and HEPA-RG cell lines. Cell viability assays, gene and protein expression analyses, and bioinformatic studies were conducted to assess the impact of sEVs on resistance-related markers. Results: Results showed that sEVs from CD patients reduced the expression of markers associated with drug resistance, while sEVs from RP patients increased these markers, promoting angiogenesis, EMT, and ECM remodeling. These changes correlated with enhanced cell survival and resistance phenotypes. Bioinformatic analyses confirmed that sEVs modulate inflammation, ECM dynamics, and EMT pathways. Conclusions: In conclusion, sEVs from metastatic GC patients significantly influence chemoresistance and tumor progression. Targeting sEV-mediated signaling may offer novel therapeutic strategies to overcome resistance and improve treatment outcomes in gastric cancer.