Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury.

The currently accepted intestinal epithelial cell organization model proposes that Lgr5+ crypt-base columnar (CBC) cells represent the sole intestinal stem cell (ISC) compartment. However, previous studies have indicated that Lgr5+ cells are dispensable for intestinal regeneration, leading to two major hypotheses: one favoring the presence of a quiescent reserve ISC and the other calling for differentiated cell plasticity. To investigate these possibilities, we studied crypt epithelial cells in an unbiased fashion via high-resolution single-cell profiling. These studies, combined with in vivo lineage tracing, show that Lgr5 is not a specific ISC marker and that stemness potential exists beyond the crypt base and resides in the isthmus region, where undifferentiated cells participate in intestinal homeostasis and regeneration following irradiation (IR) injury. Our results provide an alternative model of intestinal epithelial cell organization, suggesting that stemness potential is not restricted to CBC cells, and neither de-differentiation nor reserve ISC are drivers of intestinal regeneration.

Inhibition of the Renin-Angiotensin System Improves Response to Neoadjuvant Therapy in Patients With Liver Metastasis of Colorectal Cancers.

INTRODUCTION: Renin-angiotensin-aldosterone system inhibitors (RAAS-I) have been shown to prolong overall survival in patients with liver metastasized colorectal cancer in combination with antiangiogenic treatment. The effects of RAAS-I combined with neoadjuvant chemotherapy on colorectal cancer liver metastasis remain unexplored. We aimed to study the response of patients undergoing liver resection to RAAS-I in combination with neoadjuvant therapy to elucidate their potential benefits. METHODS: Between February 2005 and May 2012, 62 patients fulfilled the inclusion criteria for distant metastasis (cM1) and comparable computed tomography or magnetic resonance tomography scans in the Picture Archiving Communication System of our center before and after neoadjuvant chemotherapy. Follow-up data and clinicopathological characteristics were collected from a prospective database and retrospectively investigated. The chemotherapeutic response to liver metastasis was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria 1.1. RESULTS: Comparing the average reduction of measured lesions, a significant response to chemotherapy was detected in the patients receiving RAAS-I (n = 24) compared to those who did not (n = 38) (P = 0.031). Interestingly, the effect was more distinctive when the size reduction was compared between high responses with more than 50% size reduction of all measured lesions (P = 0.011). In the subgroup analysis of patients receiving bevacizumab treatment, high responses to chemotherapy were observed only in the RAAS-I cohort (28.6% versus 0%, P = 0.022). CONCLUSIONS: For neoadjuvantly treated patients, concomitant antihypertensive treatment with RAAS-I showed a higher total size reduction of liver metastasis as a sign of treatment response, especially in combination with antiangiogenic treatment with bevacizumab.

[Evidence for Minimal Invasive Oesophageal Resection]. / Evidenz für die minimalinvasive Ösophagusresektion.

In the course of the last 20 years, minimally invasive therapy has become much more important in all areas. In particular, surgical procedures have been established in oncological surgery, even without generating the necessary evidence to assure that the quality is equal to that achieved with open procedures. For this purpose, it has only been in recent years that appropriate randomised controlled studies followed by meta-analyses have been carried out. In this article, we summarise the evidence for minimally invasive resection of the oesophagus and review current literature for each procedure.

Impact of the Surgical Approach for Neoadjuvantly Treated Gastroesophageal Junction Type II Tumors: A Multinational, High-volume Center Retrospective Cohort Analysis.

OBJECTIVE: The aim of this study was to explore oncologic outcomes of transhiatal gastrectomy (THG) or transthoracic esophagectomy (TTE) for neoadjuvantly treated gastroesophageal junction (GEJ) Siewert type II adenocarcinomas, a multinational, high-volume center cohort analysis was undertaken. BACKGROUND: Neoadjuvant radiochemotherapy or perioperative chemotherapy (CTx) followed by surgery is the standard therapy for locally advanced GEJ. However, the optimal surgical approach for type II GEJ tumors remains unclear, as the decision is mainly based on individual experience and assessment of operative risk. METHODS: A retrospective analysis of 5 prospectively maintained databases was conducted. Between 2012 and 2021, 800 patients fulfilled inclusion criteria for type II GEJ tumors and neoadjuvant radiochemotherapy or CTx. The primary endpoint was median overall survival (mOS). Propensity score matching was performed to minimize selection bias. RESULTS: Patients undergoing THG (n=163, 20.4%) had higher American Society of Anesthesiologists (ASA) classification and cT stage ( P <0.001) than patients undergoing TTE (n=637, 79.6%). Neoadjuvant therapy was different as the THG group were mainly undergoing CTx (87.1%, P <0.001). The TTE group showed higher tumor regression ( P =0.009), lower ypT/ypM categories (both P <0.001), higher nodal yield ( P =0.009) and higher R0 resection rate ( P =0.001). The mOS after TTE was longer (78.0 vs 40.0 months, P =0.013). After propensity score matching a higher R0 resection rate ( P =0.004) and mOS benefit after TTE remained ( P =0.04). Subgroup analyses of patients without distant metastasis ( P =0.037) and patients only after neoadjuvant chemotherapy ( P =0.021) confirmed the survival benefit of TTE. TTE was an independent predictor of longer survival. CONCLUSION: Awaiting results of the randomized CARDIA trial, TTE should in high-volume centers be considered the preferred approach due to favorable oncologic outcomes.

Adult enteric Dclk1-positive glial and neuronal cells reveal distinct responses to acute intestinal injury.

Intestinal ganglionic cells in the adult enteric nervous system (ENS) are continually exposed to stimuli from the surrounding microenvironment and need at times to respond to disturbed homeostasis following acute intestinal injury. The kinase DCLK1 and intestinal Dclk1-positive cells have been reported to contribute to intestinal regeneration. Although Dclk1-positive cells are present in adult enteric ganglia, their cellular identity and response to acute injury have not been investigated in detail. Here, we reveal the presence of distinct Dclk1-tdTom+/CD49b+ glial-like and Dclk1-tdTom+/CD49b- neuronal cell types in adult myenteric ganglia. These ganglionic cells demonstrate distinct patterns of tracing over time yet show a similar expansion in response to elevated serotonergic signaling. Interestingly, Dclk1-tdTom+ glial-like and neuronal cell types appear resistant to acute irradiation injury-mediated cell death. Moreover, Dclk1-tdTom+/CD49b+ glial-like cells show prominent changes in gene expression profiles induced by injury, in contrast to Dclk1-tdTom+/CD49b- neuronal cell types. Finally, subsets of Dclk1-tdTom+/CD49b+ glial-like cells demonstrate prominent overlap with Nestin and p75NTR and strong responses to elevated serotonergic signaling or acute injury. These findings, together with their role in early development and their neural crest-like gene expression signature, suggest the presence of reserve progenitor cells in the adult Dclk1 glial cell lineage.NEW & NOTEWORTHY The kinase DCLK1 identifies glial-like and neuronal cell types in adult murine enteric ganglia, which resist acute injury-mediated cell death yet differ in their cellular response to injury. Interestingly, Dclk1-labeled glial-like cells show prominent transcriptional changes in response to injury and harbor features reminiscent of previously described enteric neural precursor cells. Our data thus add to recently emerging evidence of reserve cellular plasticity in the adult enteric nervous system.

PD-1 Signaling Promotes Tumor-Infiltrating Myeloid-Derived Suppressor Cells and Gastric Tumorigenesis in Mice.

BACKGROUND & AIMS: Immune checkpoint inhibitors have limited efficacy in many tumors. We investigated mechanisms of tumor resistance to inhibitors of programmed cell death-1 (PDCD1, also called PD-1) in mice with gastric cancer, and the role of its ligand, PD-L1. METHODS: Gastrin-deficient mice were given N-methyl-N-nitrosourea (MNU) in drinking water along with Helicobacter felis to induce gastric tumor formation; we also performed studies with H/K-ATPase-hIL1B mice, which develop spontaneous gastric tumors at the antral-corpus junction and have parietal cells that constitutively secrete interleukin 1B. Mice were given injections of an antibody against PD-1 or an isotype control before tumors developed, or anti-PD-1 and 5-fluorouracil and oxaliplatin, or an antibody against lymphocyte antigen 6 complex locus G (also called Gr-1), which depletes myeloid-derived suppressor cells [MDSCs]), after tumors developed. We generated knock-in mice that express PD-L1 specifically in the gastric epithelium or myeloid lineage. RESULTS: When given to gastrin-deficient mice before tumors grew, anti-PD-1 significantly reduced tumor size and increased tumor infiltration by T cells. However, anti-PD-1 alone did not have significant effects on established tumors in these mice. Neither early nor late anti-PD-1 administration reduced tumor growth in the presence of MDSCs in H/K-ATPase-hIL-1ß mice. The combination of 5-fluorouracil and oxaliplatin reduced MDSCs, increased numbers of intra-tumor CD8+ T cells, and increased the response of tumors to anti-PD-1; however, this resulted in increased tumor expression of PD-L1. Expression of PD-L1 by tumor or immune cells increased gastric tumorigenesis in mice given MNU. Mice with gastric epithelial cells that expressed PD-L1 did not develop spontaneous tumors, but they developed more and larger tumors after administration of MNU and H felis, with accumulation of MDSCs. CONCLUSIONS: In mouse models of gastric cancer, 5-fluorouracil and oxaliplatin reduce numbers of MDSCs to increase the effects of anti-PD-1, which promotes tumor infiltration by CD8+ T cells. However, these chemotherapeutic agents also induce expression of PD-L1 by tumor cells. Expression of PD-L1 by gastric epithelial cells increases tumorigenesis in response to MNU and H felis, and accumulation of MDSCs, which promote tumor progression. The timing and site of PD-L1 expression is therefore important in gastric tumorigenesis and should be considered in design of therapeutic regimens.

Clinical Relevance of Gastroesophageal Cancer Associated SNPs for Oncologic Outcome After Curative Surgery.

BACKGROUND: Gastric and esophageal cancers are malignant diseases with rising importance in Western countries. To improve oncologic outcome after surgery, it is essential to understand the relevance of germline mutations. The aim of the study was to identify and distinguish clinically relevant single-nucleotide polymorphisms (SNPs). PATIENTS AND METHODS: In total, 190 patients with curative oncological resections of gastric and distal esophageal adenocarcinomas at Heidelberg University Hospital were eligible for this study. Outcome differences were determined for each SNP by analysis of clinical variables, survival, and mRNA expression levels. RESULTS: Significant survival differences were found on univariate analysis for usual prognostic variables (such as pTNM) and for six SNPs. On multivariate survival analysis, the SNPs rs12268840 (intron variant of MGMT, p = 0.045) and rs9972882 (intron variant of STARD3 and eQTL of PGAP3, p = 0.030) were independent and significant survival predictors along with R status and pT/pN category. Group TT of rs12268840 had the highest rate of second primary carcinoma (30.4%, p = 0.0003), lowest expression of MGMT based on cis-eQTL analysis in normal gastroesophageal tissue (p = 1.99 × 10-17), and worst oncologic outcome. Group AA of rs9972882 had the highest rate of distant metastases pM1 (42.9%, p = 0.0117), highest expression of PGAP3 (p = 1.29 × 10-15), and worst oncologic outcome. CONCLUSIONS: Two intron variant SNPs of MGMT and STARD3 were identified that were significant survival predictors and may influence tumor biology. The data indicate that DNA methylation (MGMT) and malfunction of GPI anchoring (PGAP3) are distinct mechanisms that are relevant for tumor progression and relapse.

Mechanical stretching and chemical pyloroplasty to prevent delayed gastric emptying after esophageal cancer resection-a meta-analysis and review of the literature.

BACKGROUND: Delayed gastric emptying (DGE) occurs in up to 40% of patients after esophageal resection and prolongs recovery and hospital stay. Surgically pyloroplasty does not effectively prevent DGE. Recently published methods include injection of botulinum toxin (botox) in the pylorus and mechanical interventions as preoperative endoscopic dilatation of the pylorus. The aim of this study was to investigate the efficacy of those methods with respect to the newly published Consensus definition of DGE. METHODS: A systematic literature search using CENTRAL, Medline, and Web of Science was performed to identify studies that described pre- or intraoperative botox injection or mechanical stretching methods of the pylorus in patients undergoing esophageal resection. Frequency of DGE, anastomotic leakage rates, and length of hospital stay were analyzed. Outcome data were pooled as odd's ratio (OR) or mean difference using a random-effects model. Risk of bias was assessed using the Robins-I tool for non-randomized trials. RESULTS: Out of 391 articles seven retrospective studies described patients that underwent preventive botulinum toxin injection and four studies described preventive mechanical stretching of the pylorus. DGE was not affected by injection of botox (OR 0.87, 95% confidence interval [CI] 0.37-2.03, P = 0.75), whereas mechanical stretching resulted in significant reduction of DGE (OR 0.26, 95% CI 0.14-0.5, P < 0.0001). CONCLUSION: Mechanical stretching of the pylorus, but not injection of botox reduces DGE after esophageal cancer resection. A newly developed consensus definition should be used before the conduction of a large-scale randomized-controlled trial.

Mist1+ gastric isthmus stem cells are regulated by Wnt5a and expand in response to injury and inflammation in mice.

BACKGROUND AND AIMS: The gastric epithelium undergoes continuous turnover. Corpus epithelial stem cells located in the gastric isthmus serve as a source of tissue self-renewal. We recently identified the transcription factor Mist1 as a marker for this corpus stem cell population that can give rise to cancer. The aim here was to investigate the regulation of the Mist1+ stem cells in the response to gastric injury and inflammation. METHODS: We used Mist1CreERT;R26-Tdtomato mice in two models of injury and inflammation: the acetic acid-induced ulcer and infection with Helicobacter felis. We analysed lineage tracing at both early (7 to 30 days) and late (30 to 90 days) time points. Mist1CreERT;R26-Tdtomato;Lgr5DTR-eGFP mice were used to ablate the corpus basal Lgr5+ cell population. Constitutional and conditional Wnt5a knockout mice were used to investigate the role of Wnt5a in wound repair and lineage tracing from the Mist1+ stem cells. RESULTS: In both models of gastric injury, Mist1+ isthmus stem cells more rapidly proliferate and trace entire gastric glands compared with the normal state. In regenerating tissue, the number of traced gastric chief cells was significantly reduced, and ablation of Lgr5+ chief cells did not affect Mist1-derived lineage tracing and tissue regeneration. Genetic deletion of Wnt5a impaired proliferation in the gastric isthmus and lineage tracing from Mist1+ stem cells. Similarly, depletion of innate lymphoid cells, the main source of Wnt5a, also resulted in reduced proliferation and Mist1+ isthmus cell tracing. CONCLUSION: Gastric Mist1+ isthmus cells are the main supplier of regenerated glands and are activated in part through Wnt5a pathway.

Characteristics and Prognostic Factors of Metachronous Second Primary Upper Gastrointestinal Cancer.

BACKGROUND: Patients with metachronous malignancies before carcinomas of the upper gastrointestinal tract were analyzed regarding clinical parameters, oncological outcome, and prognosis. METHODS: We analyzed the data of 1583 patients with gastroesophageal cancer who underwent oncological resections between 2002 and 2018. Of 1583 patients, 172 had a malignant tumor before the upper gastrointestinal cancer (second primary carcinomas) and 1411 without preceding malignancies served as the control group. The analyses were performed between both groups and within the subgroup of second primary carcinomas. RESULTS: Patients with second primary carcinomas were older (P < 0.0001), had more comorbidities (P < 0.0001), and underwent longer surgical resections (P = 0.0024). They had lower (y)pT-categories (P = 0.0427) and had longer stays in intensive care unit (P = 0.0002) and hospital (P = 0.0018). R0-resection was more frequent (P = 0.0275) while having more surgical complications (P = 0.0378). The median survival was 39.5 mo (primary carcinoma) versus 32.9 mo for (second primary carcinoma) and was not significantly different (P = 0.5359).In the subgroup analysis of second primaries, there were no significant survival differences depending on primary tumor entity (P = 0.4989). pT status (P = 0.0062), pN status (P < 0.0001), pM status (P < 0.0001), and R-status (P < 0.0001) were significant prognostic factors. A time period >9 y after the primary cancer could be identified as a novel and beneficial survival factor (P = 0.0496). Most patients with primary colorectal, prostate, hematogenous, or breast cancer had adenocarcinoma, whereas patients with initial otolaryngologic cancers mainly had squamous cell carcinoma. CONCLUSIONS: Second primary carcinomas of the upper gastrointestinal tract show distinct clinical and oncological characteristics. Common prognostic factors are applicable, and oncologic resection is recommended.

Expression of Angiogenic Proteins in Tumor and Stroma Affects Survival in Patients With Gastric Cancer.

BACKGROUND: Gastric cancer is one of the most frequent malignancies worldwide. Angiogenic growth factors play a crucial role in mediating the crosstalk between cancer cells and the surrounding microenvironment. In this exploratory study, we investigate the impact of angiogenic proteins within the tumor cell or stroma compartment on survival of patients with gastric cancer. MATERIALS AND METHODS: In 29 patients, tumor and stromal compartments were separated using laser capture microdissection. Angiogenic protein expression was measured using a bead-based immunoassay and correlated with tumor stage and overall survival. RESULTS: Overall survival was significantly shorter in patients with a high stroma concentration of vascular endothelial growth factor (VEGF)-A (23.5 (±17.6) versus 33.6 (±21.0) mo; P = 0.009) and stem cell factor (22.2 (±18.5) versus 33.6 (±21.8) mo; P = 0.01) compared with patients with a low stroma concentration. High stromal VEGF-D showed a trend toward worse survival (26.8 (±22.0) versus 37.2 (±19.0) mo; P = 0.09). We did not observe any significant correlation between tumor-specific expression of angiogenic cytokines and survival. CONCLUSIONS: This translational study highlights the difference in clinical impact between tumor and stromal expression of angiogenic proteins. Compartment-specific concentrations of VEGF-A and stem cell factor affect the clinical prognosis and help to identify the best therapy for patients with gastric cancer.

Esophageal Tumor Microenvironment.

Treatment options for patients with esophageal cancer are limited and the overall survival is disappointing. While surgical resection remains the only curative treatment option, there is a need for innovative medical therapies to extend patient survival. The tumor microenvironment represents an interesting target for the development of new treatment strategies. The tumor microenvironment consists of different cell types including immune, inflammatory, and stromal cells. In the past two decades many potential targets for the treatment of esophageal cancers were evaluated in preclinical experiments and transferred into clinical trials.In this chapter of the book, we will provide an overview of in vitro data, preclinical animal studies, and translational research on the role of the tumor microenvironment in the development and treatment of esophageal cancer. In particular, we will discuss the impact of inflammatory cytokines like interleukins. Preclinical mouse models with interleukin overexpression develop Barrett lesions in the esophagus and clinical studies have shown an association between an interleukin overexpression in human tumors and shortened overall survival.Beside the inflammatory cells in the tumor microenvironment, recent preclinical studies have shown an important role for stem cells in the development of esophageal carcinoma. In this chapter we summarize the current research on stem cells in the development of esophageal cancer and highlight potential therapeutic options. In addition, we will discuss the role of angiogenesis and anti-angiogenic therapy in the development and treatment of esophageal cancer. In the last section of this chapter, we provide an overview of current clinical trials that investigate the therapeutic potential of the tumor microenvironment.

Oligometastatic Gastroesophageal Adenocarcinoma: Molecular Pathophysiology and Current Therapeutic Approach.

Gastric and esophageal cancers are dreaded malignancies, with a majority of patients presenting in either a locally advanced or metastatic state. Global incidences are rising and the overall prognosis remains poor. The concept of oligometastasis has been established for other tumor entities and is also proposed for upper gastrointestinal tract cancers. This review article explores metastasis mechanisms on the molecular level, specific to esophageal and gastric adenocarcinoma. Existing data and recent studies that deal with upper gastrointestinal tumors in the oligometastatic state are reviewed. Furthermore, current therapeutic targets in gastroesophageal cancers are presented and discussed. Finally, a perspective about future diagnostic and therapeutic strategies is given.

Thoracoabdominal versus transhiatal surgical approaches for adenocarcinoma of the esophagogastric junction-a systematic review and meta-analysis.

PURPOSE: The aim of this systematic review and meta-analysis was to compare the oncological and perioperative outcomes of transhiatally extended gastrectomy (TEG) and thoracoabdominal esophagectomy (TAE) for therapy of adenocarcinomas of the esophagogastric junction (AEG) with focus on AEG type II, as the optimal approach for these tumors is still unclear. METHODS: MEDLINE, EMBASE, and the Cochrane Library (CENTRAL) were searched until July 24, 2018. Studies comparing TAE and TEG for surgical treatment of AEG type tumors have been included. Patient's baseline and perioperative data have been extracted and meta-analyses have been conducted for the outcomes: number of dissected lymph nodes, R0-resection rate, anastomotic leak rate, postoperative morbidity, and 30-day mortality. RESULTS: Of 6709 articles identified, 8 studies have been included for further analysis. One thousand thirty-four patients underwent TAE, and 1177 patients TEG. No differences were found between the approaches in regard to number of dissected lymph nodes (MD - 0.96; 95% CI - 3.07 to 1.15; p = 0.37), R0-resection rates (OR 0.97; 95% CI 0.57 to 1.63; p = 0.90), anastomotic leak rates (OR 1.13; 95% CI 0.69 to 1.86; p = 0.63), and 30-day mortality (OR 1.53; 95% CI 0.90 to 2.61; p = 0.11). However, a higher rate of postoperative morbidity was found after TAE (OR 1.55; 95% CI 1.12 to 2.14; p = 0.008). CONCLUSIONS: The optimal approach to surgical therapy of AEG II still remains unclear. This study identified a significantly higher rate of postoperative morbidity after TAE at comparable surgical outcomes. Due to major limitations concerning the quality of included studies, current data strongly mandates a properly designed randomized controlled trial to identify the optimal surgical approach for AEG type II tumors.

Neoadjuvant Therapy Improves Outcomes in Locally Advanced Signet-Ring-Cell Containing Esophagogastric Adenocarcinomas.

BACKGROUND: Only a few studies have analyzed multimodal treatment concepts in the subgroup of signet-ring-cell containing upper gastrointestinal (GI) cancer. Recent retrospective, multicentric data favor primary resection without neoadjuvant chemotherapy for gastric signet-ring-cell containing carcinomas (SRCs). We compared the outcomes of primarily resected carcinomas with neoadjuvantly treated, locally advanced esophagogastric SRCs. METHODS: A total of 310 patients with esophagogastric SRC-staged cT3/4/Nany/Many from a prospective unicentric database were included in this study; 192 (61.9%) received neoadjuvant therapy (NEO group) and 118 (38.1%) were primarily resected (RES group). RESULTS: Overall, 128 (41.3%) patients presented with adenocarcinoma of the esophagogastric junction (AEG) and 182 (58.7%) presented with gastric cancer. Neoadjuvant therapy was significantly associated with resection in curative intent (NEO: 91.1%; RES: 75.4%; P = 0.001), improved (y)pT category (P = 0.035), improved (y)pN category (P < 0.001), and R0 resections (curative intent cohort: 76.0% in NEO vs. 60.7% in RES; P = 0.010), among others, but not with postoperative complications. Overall survival was significantly improved by neoadjuvant treatment {median survival 28.5 months (95% confidence interval [CI] 14.4-39.6) vs. RES: 14.9 months (10.6-17.5); P < 0.001}, as well as in subgroups (AEG and gastric tumors, R0-resected patients, and patients with and without relevant comorbidities). Independent prognostic factors were neoadjuvant therapy (hazard ratio [HR] 0.66; P = 0.023), pT4 category (HR 1.71; P = 0.041), pN2 category (HR 1.86; P = 0.013), pN3 category (HR 2.40; P < 0.001), pM1 category (HR 1.95; P = 0.003), age > 70 years (HR 1.79; P = 0.006), gastric localization (HR 0.69; P = 0.032), American Society of Anesthesiologists classification 3/4 (HR 1.71; P = 0.004), and incomplete resection R1/2 (HR 1.6; P = 0.014). CONCLUSIONS: Our results demonstrate a survival advantage for advanced-stage esophagogastric SRC patients by neoadjuvant treatment.

Angiogenesis and Anti-Angiogenic Therapy in Gastric Cancer.

Gastric cancer is one of the most frequent malignancies worldwide. Despite improvements in diagnosis and therapy, the overall prognosis remains poor. In the last decade, several anti-angiogenic drugs for cancer treatment have been approved and lately also introduced to gastric cancer treatment. While the initial trials focused only on unresectable or metastatic cancer, anti-angiogenic treatment is now also investigated in the perioperative and neoadjuvant setting. In this review, an overview of the role of angiogenesis and angiogenic factors in gastric cancer as well as anti-angiogenic treatment of gastric cancer is provided. Findings from in vitro and animal studies are summarized and put in a context with translational data on angiogenesis in gastric cancer. The most important angiogenic factors and their effect in gastric cancer are highlighted and clinical trials including anti-angiogenic drugs are discussed. Finally, an outlook of biomarkers for predicting response to anti-angiogenic treatment is presented, the ongoing trials on this topic are discussed and current challenges of anti-angiogenic therapy are outlined.

Targeting the receptor tyrosine kinase MerTK shows therapeutic value in gastric adenocarcinoma.

BACKGROUND: Despite multiple therapeutic modalities, the overall survival of patients with gastric adenocarcinoma remains poor, especially for advanced tumor stages. Although the tyrosine kinase MerTK has shown therapeutic relevance in several tumor entities, its potential effects in gastric adenocarcinoma have not yet been sufficiently characterized. METHODS: MerTK expression and its influence on patient survival were evaluated by immunohistochemistry in a cohort of 140 patients with gastric adenocarcinoma. CRISPR/Cas9 knockout and siRNA knockdown of MerTK in the gastric cancer cell lines SNU1, SNU5, and MKN45 was used to analyze protein expression, growth, migration, and invasion properties in vitro and in a murine xenograft model. MerTK was pharmacologically targeted with the small molecule inhibitor UNC2025 in vitro and in vivo. RESULTS: In patients, high MerTK expression was associated with decreased overall survival (OS) and lymph node metastasis especially in patients without neoadjuvant therapy (p < 0.05). Knockout and knockdown of MerTK reduced cell proliferation and migration both in vitro and in vivo. UNC2025, a small-molecule inhibitor of MerTK, exhibited a significant therapeutic response in vitro and in vivo. Additionally, MerTK expression attenuated the response to neoadjuvant treatment, and its inhibition sensitized tumor cells to 5-Fluorouracil (5-FU)-based chemotherapy in vitro. CONCLUSIONS: Our findings demonstrate the potential value of MerTK as a prognostic biomarker for gastric adenocarcinoma. Targeting MerTK may become a new treatment option, especially for patients with advanced tumors, and may overcome resistance to established chemotherapies.