Bile acids serve as endogenous antagonists of the Leukemia inhibitory factor (LIF) receptor in oncogenesis.

The leukemia inhibitory factor (LIF) is member of interleukin (IL)-6 family of cytokines involved immune regulation, morphogenesis and oncogenesis. In cancer tissues, LIF binds a heterodimeric receptor (LIFR), formed by a LIFRß subunit and glycoprotein(gp)130, promoting epithelial mesenchymal transition and cell growth. Bile acids are cholesterol metabolites generated at the interface of host metabolism and the intestinal microbiota. Here we demonstrated that bile acids serve as endogenous antagonist to LIFR in oncogenesis. The tissue characterization of bile acids content in non-cancer and cancer biopsy pairs from gastric adenocarcinomas (GC) demonstrated that bile acids accumulate within cancer tissues, with glyco-deoxycholic acid (GDCA) functioning as negative regulator of LIFR expression. In patient-derived organoids (hPDOs) from GC patients, GDCA reverses LIF-induced stemness and proliferation. In summary, we have identified the secondary bile acids as the first endogenous antagonist to LIFR supporting a development of bile acid-based therapies in LIF-mediated oncogenesis.

The leukemia inhibitory factor regulates fibroblast growth factor receptor 4 transcription in gastric cancer.

PURPOSE: The gastric adenocarcinoma (GC) represents the third cause of cancer-related mortality worldwide, and available therapeutic options remain sub-optimal. The Fibroblast growth factor receptors (FGFRs) are oncogenic transmembrane tyrosine kinase receptors. FGFR inhibitors have been approved for the treatment of various cancers and a STAT3-dependent regulation of FGFR4 has been documented in the H.pylori infected intestinal GC. Therefore, the modulation of FGFR4 might be useful for the treatment of GC. METHODS: To investigate wich factors could modulate FGFR4 signalling in GC, we employed RNA-seq analysis on GC patients biopsies, human patients derived organoids (PDOs) and cancer cell lines. RESULTS: We report that FGFR4 expression/function is regulated by the leukemia inhibitory factor (LIF) an IL-6 related oncogenic cytokine, in JAK1/STAT3 dependent manner. The transcriptomic analysis revealed a direct correlation between the expression of LIFR and FGFR4 in the tissue of an exploratory cohort of 31 GC and confirmed these findings by two external validation cohorts of GC. A LIFR inhibitor (LIR-201) abrogates STAT3 phosphorylation induced by LIF as well as recruitment of pSTAT3 to the promoter of FGFR4. Furthermore, inhibition of FGFR4 by roblitinib or siRNA abrogates STAT3 phosphorylation and oncogentic effects of LIF in GC cells, indicating that FGFR4 is a downstream target of LIF/LIFR complex. Treating cells with LIR-201 abrogates oncogenic potential of FGF19, the physiological ligand of FGFR4. CONCLUSIONS: Together these data unreveal a previously unregnized regulatory mechanism of FGFR4 by LIF/LIFR and demonstrate that LIF and FGF19 converge on the regulation of oncogenic STAT3 in GC cells.

Prognostic Survival Significance of Signet Ring Cell (SRC) Gastric Cancer: Retrospective Analysis from a Single Western Center.

INTRODUCTION: Signet ring cell carcinoma accounts for 35% to 45% of all gastric cancer. Despite the acknowledgment of its more aggressive pathological features, various controversies surrounding this topic still exist. Thus, we investigate the clinical pathological characteristics and survival prognostic significance of signet ring cell components in patients affected by gastric cancer. METHODS: From January 2004 to December 2020, in a retrospective study, we enrolled 404 patients with gastric cancer who were curatively treated in our department. The male-to-female ratio was 249/142, and the median age was 75 (range 37-94). We dichotomized patients into two groups (75 patients vs. 316 patients) based on the signet ring cell presence; according to preoperative, operative, and postoperative characteristics, we performed a univariate and multivariate analysis for overall survival. RESULTS: Signet ring cell carcinoma indicated an increasing incidence trend over the time analyzed. Overall median survival of signet ring cell and non-signet ring cell carcinoma were, respectively, 16 vs. 35 months, p < 0.05. In early gastric cancer, the prognosis of the signet ring cell is better than that of the non-signet ring cell, as opposed to advanced cancer. Among the entire population in the multivariate analysis, the only independent factors were preoperative serum albumin level, complete surgical resection, level of lymphadenectomy, and pathological stage. Recurrence occurred more frequently in patients affected by signet ring cell, but in our data, we could not identify a peculiar site of recurrence. CONCLUSIONS: Signet ring cell carcinoma has a specific oncogenetic phenotype and treatment resistance heterogeneity; however, it is not always associated with poor prognosis. According to our results, a radical surgical procedure associated with an adequate lymphadenectomy should be advocated to improve patients survival. Gastric cancer patients with signet ring cell components should draw clinicians' attention.

Evaluation of peritoneal Carcinoembryonic Antigen as a survival prognostic factor in gastric cancer patients: a single western center experience.

The aim of this study is to define the importance of peritoneal CEA (pCEA) as a prognostic factor of overall survival (OS) and disease-free survival (DFS) in gastric cancer (GC) patients surgically treated with a curative intent In our department. A total of 64 patients affected by gastric cancer with intraoperatively measurement of CEA on peritoneal lavage were enrolled in the study. Patients were divided into two groups: (A) the peritoneal lavage CEA ( -) with CEA < 0.5 ng/ml and (B) the peritoneal lavage CEA ( +) with CEA ≥ 0.5 ng/ml. Then we analyzed OS and DFS of the two groups correlating them to others clinico-pathological features. Furthermore, we investigated the correlation between pCEA and peritoneal cytology. We demonstrated a strong significant difference in OS and in DFS in CEA ( +) patients. We emphasized that pCEA had a strong survival impact, in both OS and DFS, in selected patients affected by diffuse histotype GC (p = 0.0048 and p = 0.0030 respectively), stage III (p = 0.015 and p = 0.021, respectively) and distal gastric cancer (p = 0.0036 and p = 0.0017, respectively). There is a strong need to recognize prognostic factors that can help clinicians to stratify patients at high risk to develop post-surgical recurrences and moreover to recognize who could benefit from an aggressive surgical treatment of cytoreductive surgery and intra-peritoneal chemotherapy.pCEA is a good predictor of survival in advanced gastric cancer and could discriminate which patients need a more accurate follow-up program and an intensive therapeutic strategy.

Rationale in the Use of Adjuvant Chemotherapy in pT3N0M0 Gastric Cancer Resected Patients. Comment on Chen et al. Prognostic Factors and the Role of Adjuvant Chemotherapy in Pathological Node-Negative T3 Gastric Cancer. J. Pers. Med. 2023, 13, 553.

I read with great interest the well-written and well-made study by Yi-Fu Chen et al. recently published in the "Journal of Personalized Medicine" [...].

A rare case of polypoid primary anorectal melanoma with subsequent giant stomach metastasis: A gastrointestinal involvement of both primary and metastatic mucosal melanoma.

Melanoma can involve the gastrointestinal apparatus as both primary and metastatic lesions. Primary anorectal mucosal melanoma (ARMM) and metastatic gastric melanoma are rare entities and usually resulted in a poor prognosis. We presented a case of a 61-year-old man who after the complete excision of an ARMM developed a gastric metastasis after almost three years form the complete tumour excision. Upon esophagogastroduodenoscopy, a giant ulcered mass resulted in melanoma metastasis. The patient underwent a near-total gastrectomy. After five months of follow-up, the patient is disease-free. The incidence of ARMMs is increasing, highlighting the necessity of new prevention and treatment strategies in order to achieve a better prognosis for these patients. There are no known risk factor for ARMMs but surgery, together with the combination of anti-CTLA-4 and anti-PD-1 antibodies, are promising therapeutic options. Early and aggressive treatments are required, together with a strict multidisciplinary approach.