Dual benefits of Xiao Chai Hu Tang and its active compounds in CPT-11 therapy: intestinal protection via barrier restoration and anti-inflammation combined with enhanced tumor apoptosis.

We reported earlier that adult FabplCre;Apc15lox/+ mice with either daily UV exposure or vitamin D supplementation developed not significantly fewer intestinal tumours but less tumour bulk (reduced outgrowth) than control mice that remained vitamin D deficient. Here, we report on a prior exploratory study in which parents (FabplCre and Apc15lox/15lox) and pups were fed either the vitamin D deficient (< 5 IU/kg) or supplemented (1500 IU/kg) diet before selecting the proper genotype and continuing on in adulthood with the respective diets. Then, a lifelong vitamin D rich diet did significantly reduce the number of intestinal tumours from 10.9 to 7.5 tumours/mouse (p = 0.02) at an age of 200 days. For this reduction, the vitamin D apparently needed to be already present in the earliest stages of tumour initiation shortly after intestinal truncation of floxed Apc alleles in utero. If our experimental results apply to other vitamin D susceptible cancer types, it may explain differences between observational studies on (long term) vitamin D statuses and randomized trials on (4-5 years) vitamin D supplementation in relation to cancer risk.

The intestinal epithelium is a highly regenerative tissue organized along the crypt-villus axis, where spatially compartmentalized gene expression governs stem cell renewal, proliferation, and differentiation. Super-enhancers (SEs) are large clusters of regulatory elements densely bound by transcription factors (TFs) and cofactors that drive high-level expression of genes controlling cell identity and fate, yet their roles in intestinal epithelial identity and differentiation remain unclear. Here, we generate a spatiotemporal map of SEs in the small intestine, identifying compartment-specific SEs that define crypt and villus programs. Using mouse genetic models, we identify CDX2, HNF4, and SMAD4 as core TFs orchestrating SE-driven transcriptional networks essential for epithelial differentiation. CDX2 is required for SE integrity, and its loss causes widespread SE collapse and silencing of intestinal identity genes. We further demonstrate SE remodeling during colorectal cancer, in which HNF4 and SMAD4 function as SE-associated tumor suppressors that restrain oncogenic enhancer programs. Together, our findings establish SEs as central regulators of intestinal architecture, epithelial fidelity, and tumor progression.

Promoting intestinal regeneration without tumor risk in immune-mediated inflammatory diseases.

Aspartame promotes intestinal tumor progression via Akkermansia muciniphila -mediated 5-hydroxytryptophan production.

Despite advances in the treatment of metastatic colorectal cancer (mCRC), it remains the second leading cause of cancer-related mortality, with limited effective therapeutic options. While EGFR inhibition is a standard first-line therapy for mCRC patients lacking KRAS mutations, resistance frequently develops, limiting its clinical benefit. Murine CRC models have shown that EGFR deletion in myeloid cells reduces tumor burden, and the presence of EGFR-positive myeloid cells is associated with poor prognosis in mCRC patients. However, the role of these cells in the therapeutic response to anti-EGFR therapies remains poorly understood. In this study, we integrated mouse models, single-cell RNA sequencing (scRNAseq), proteomics, and patient-derived mCRC datasets to investigate how EGFR signaling in myeloid cells shapes the tumor microenvironment (TME). In a preclinical therapeutic trial, we demonstrate that EGFR deletion in myeloid cells of tumor-bearing CRC mice reduced tumor growth, whereas EGFR loss in intestinal epithelial tumor cells alone had no therapeutic impact. EGFR deletion also decreased the abundance of F4/80hi macrophages, particularly the Spp1+ and C1qc+ subsets, and reduced inflammatory pathways like TGFβ, IFNγ, and JAK/STAT signaling in myeloid cells. These changes altered myeloid-T cell interactions, resulting in a less immunosuppressive TME characterized by reduced immune checkpoint expression. Furthermore, we identified thrombospondin-1 (THBS1) as a myeloid-derived ligand interacting with T cells, and confirmed its regulation by EGFR signaling through proteomic analysis. Analysis of human CRC datasets revealed that high EGFR and THBS1 expression correlates with poor patient outcomes. Collectively, these findings establish EGFR signaling in myeloid cells as a critical regulator of the immunosuppressive TME and suggest that targeting EGFR within specific myeloid subsets could represent a promising therapeutic strategy in mCRC.

Organ-on-a-chip technology holds great value for modeling intestinal tumors. However, how to more accurately replicate the tumor microenvironment and implement high-throughput drug screening on-chip remains to be further explored. In this study, we developed a biomimetic intestinal tumor-on-a-chip platform that simulates the 3D structure of intestinal crypts and villi, and incorporates a herringbone fluidic mixer. Compared to conventional chips, this design significantly improves the dynamic interplay between tumor cells and their surrounding microenvironment. Inside the chip, patient-derived primary epithelial and tumor cells successfully form a 3D tumor model. Furthermore, the platform enables monitoring of dynamic drug response in tumor cells derived from individual patients. Preliminary findings indicate that mitophagy could be a key contributor to the development of chemoresistance. This biomimetic intestinal tumor-on-a-chip platform effectively reproduces the complex characteristics of intestinal tumors through its high-fidelity 3D structure and dynamic microenvironment.

Evaluating the utility of ICG-based NIR imaging for small intestine neuroendocrine tumors: Challenges and the need for tumor-specific tracers.

Cancer trends among young adults in Russian Federation: An analysis of population-based cancer registry data.

The Farnesoid X receptor-bile acid axis contributes to immune evasion in gastric cancer and its inhibition enhances efficacy of anti-PD-L1 therapy

IntroductionEvidence indicates that being married may influence prognosis in various malignancies; however, whether this association extends to small intestinal stromal tumors (SISTs) remains unclear. To address this gap, we analyzed population-based data to determine the prognostic significance of marital status for SIST patients.MethodsThis population-based, retrospective cohort study leveraged data from the Surveillance, Epidemiology, and End Results (SEER) database for the period 2000 to 2019. We classified patients as either married or unmarried according to their recorded marital status. To minimize bias from confounders, we performed 1:1 propensity score matching (PSM). Survival outcomes, including overall survival (OS) and cancer-specific survival (CSS), were estimated via the Kaplan-Meier method and Cox proportional hazards models.ResultsOur analysis included 3315 SIST patients, of whom 2132 were married and 1183 were unmarried. Compared with unmarried individuals, married patients experienced significantly better OS and CSS (both P<0.05). Multivariable analysis identified marital status as an independent predictor for both endpoints, with adjusted HRs of 1.35 (95% CI: 1.20-1.52) for OS and 1.27 (95% CI: 1.10-1.48) for CSS. Following PSM, the survival advantage for married patients persisted (P<0.05 for both OS and CSS). Notably, the 5-year OS and CSS rates favored the married cohort over the unmarried cohort (75.2% vs. 64.0%, P <0.001; 83.7% vs. 76.1%, P = 0.001, respectively). Subgroup analyses further revealed that the survival benefit associated with marriage was particularly evident among elderly, female, Caucasian, and surgically treated patients.ConclusionsMarital status independently predicts prognosis in small intestinal stromal tumors (SISTs), with married patients exhibiting superior outcomes.

Abdominal ultrasound attenuates early-stage aberrant proliferation and depressive behavior in AOM/DSS-induced colorectal cancer: regulatory mechanisms of the Wnt/β-catenin pathway and HPA axis.

Here we determined whether myeloid Mir34a has a tumor suppressive function in ApcMin/+ mice, a model for intestinal and colon cancer. Myeloid cell-specific deletion of Mir34a in ApcMin/+ mice increased tumor initiation and allowed progression towards invasive carcinomas, which are generally not observed in ApcMin/+ mice. Loss of Mir34a facilitated the polarization of tumor-associated macrophages (TAMs) towards a pro-tumorigenic M2-like state, implying that Mir34a is required to maintain TAMs in a tumor-suppressive state. Also, Mir34a-deficient, bone-marrow-derived macrophages (BMDMs) from ApcMin/+ mice were polarized towards a pro-tumorigenic, M2-like state and displayed enhanced migration when compared to Mir34a-proficient BMDMs. Intestinal tumors in myeloid Mir34a-deficient mice showed elevated expression of several known Mir34a target mRNAs, including Csf1r, Pd-l1, Mmp9, Ccl22, and c-Myc. In addition, the number of immuno-suppressive, pro-tumorigenic CD4+Foxp3+ Treg cells increased in myeloid Mir34a-deficient intestinal tumors. Moreover, ApcMin/+ mice with myeloid-specific deletion of Mir34a had a significantly diminished survival rate. Following the induction of inflammatory colitis, these mice showed enhanced colon cancer initiation and progression towards invasive carcinomas with an increase in M2-like TAMs, N2-like neutrophils and Treg cells. These findings imply that myeloid Mir34a suppresses tumor formation and progression by maintaining myeloid and T-cells in an anti-tumorigenic state. Therefore, the p53-miR-34a axis has a central role in non-tumor cell mediated suppression of intestinal and colon cancers.

ObjectivesRefractory celiac disease type II (RCDII) is an intestinal tumor of aberrant intra‐epithelial T‐lymphocytes (IEL). The severe enteropathy found in RCDII is caused by aberrant IEL that exert cytotoxicity against enterocytes. In this study, we investigated the cell death mechanism responsible for villous atrophy in RCDII.MethodsAberrant IEL were isolated from duodenal biopsies of RCDII patients. Enterocyte and RCDII patient‐derived cell lines and human small intestinal organoids were used. mRNA expression was determined with reverse transcriptase‐multiplex ligation‐dependent probe amplification. Protein expression, degranulation and enterocyte killing were measured using flow cytometry, immunofluorescence or bright field microscopy. Secretion of granzyme‐B was detected by enzyme immunoassay.ResultsLevels of granzyme‐B expression were significantly upregulated in aberrant IEL of RCDII patients compared to patients with celiac disease (CD) on gluten‐free diet (P = 0.0001) and correlated with severity of villous atrophy and clinical response to therapy. Killing of intestinal epithelial cells was caused by granzyme‐B. For granzyme‐B degranulation and subsequent cytotoxicity, cell–cell binding via the CD103‐receptor, which was upregulated on aberrant IEL, was essential. In a preclinical model, aberrant IEL migrated to the intestinal organoids and induced organoid disintegration and CD103‐dependent cell death. Targeting CD103‐heterodimeric partner β7 with therapeutic monoclonal antibody etrolizumab prevented enterocyte cell killing and resulted in survival of organoids.ConclusionKilling of enterocytes in RCDII patients depends on degranulation of granzyme‐B by aberrant IEL through CD103‐β7 binding. By blocking this interaction, etrolizumab restores the intestinal epithelium and therefore should be considered as potential therapy for RCDII patients.

ABSTRACTGastrointestinal leiomyosarcomas are rare malignancies. Herein, we present a case report of a previously healthy 60‐year‐old female presenting with periumbilical abdominal pain, vomiting, and difficulty in passing stool, with clinical workup, imaging, and surgery defining a small intestine tumor. Histology defined the tumor as a mesenteric pleomorphic leiomyosarcoma.

Effects of low and moderate doses of ionizing radiation on colon carcinogenesis: Experimental models and current evidence.

Several HSP90 inhibitors are in use or late-stage trials: pimitespib is approved in Japan for intestinal tumors, hypericin sodium under US regulatory review, and WP-1303 in Phase III development. However, their efficacy depends on tumor HSP90 expression levels, necessitating probes for subtype-specific detection in vivo. Translation is limited by inadequate validation in specific subtypes and off-target accumulation in kidneys and liver. We developed and optimized an HSP90-targeted radiotracer addressing these limitations. Chemical modifications enhanced tumor uptake in colorectal and gastric cancer models (10.02 ± 2.05% and 5.02 ± 0.08% ID/g), while reducing liver and kidney retention (∼2% and ∼5% ID/g), yielding tumor/muscle ratios of 23.28 ± 9.70 and 16.73 ± 2.80. Clinical evaluation confirmed translational potential, enabling tumor delineation and high-contrast imaging (SUVmax ∼ 5). This probe supports comprehensive cancer management and may guide clinical application of emerging HSP90 inhibitors.

Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting, well-differentiated neuroendocrine tumors of enterochromaffin (EC) cell origin. However, EC cell-derived tumorigenesis remains poorly understood. Prior studies using TPH1 Cre-ERT2-driven RPM mice [EC cell-targeted RB1 (R) and Trp53 (P) loss and Myc (M) gain] showed nonendocrine adenocarcinomas in the small intestine through dedifferentiation of EC cells to intestinal stem cells, which are prone to transformation. However, these studies were limited by early death from tumors at other sites, leaving the potential for SI-NET development unclear over longer periods. To circumvent this time-limited off-target effect, the present study used intestinal enteroids from RPM mice to examine the effect of RB1 and Trp53 loss with or without gain of Myc function on EC cell-derived tumors. Initial results confirmed the previous in vivo induction of nonendocrine adenoma/adenocarcinoma. However, the addition of TNF-α to the enteroid media induced EC cell clusters in multiple crypts and well-differentiated neuroendocrine tumor versus carcinoma in the absence and presence of gain of Myc function, respectively. These findings suggest that TNF-α blocked EC cell dedifferentiation to intestinal stem cells, promoting their survival and expansion and shifting their fate from intestinal adenoma/carcinoma to a differentiated neuroendocrine tumor type. The present study thus highlights the crucial role of the microenvironment in influencing EC cell-derived tumorigenesis and provides insights into SI-NET development.NEW & NOTEWORTHY Small intestinal neuroendocrine tumors are of putative enterochromaffin (EC) cell origin and are the most common malignancy in the small intestine. However, the tumorigenesis of these specified tumor types remains poorly understood. The present organoid studies show that the addition of TNF-α to the microenvironment maintains the specificity of EC cells during their transformation to neuroendocrine tumors while blocking their dedifferentiation to ISC-derived adenomas.

Ki-67 index and mitotic count form the basis of grading of small intestinal neuroendocrine tumours (siNET). We hypothesized that the mitosis-specific marker phosphohistone H3 (PHH3) might better correlate with cancer-specific survival (CSS) and with response to treatment. We evaluated the association between Ki-67 index, PHH3-estimated mitotic count, and survival outcomes in a retrospective cohort of 73 consecutive patients with metastatic siNET. Additionally, we estimated the optimal cut-off for PHH3 and cross-validated the outcome. Both markers adequately distinguished CCS when comparing lower and higher proliferation groups (Ki-67: 128 vs. 95 m; PHH3: 149 vs. 88 m). They were strongly associated with CSS as continuous (HR 1.18 [1.08-1.28] and 1.16 [1.09-1.25]), and dichotomous variables (HR 2.96 [1.31-6.67] and 3.11 [1.50-6.46]). The Cox model based on PHH3 displayed slightly better optimism-corrected Harrell's c-index (0.71 vs. 0.68) and Akaike information criterion (219 vs. 223). Additionally, PHH3 showed significant association with PFS after treatment with somatostatin analogues (HR 1.12 [1.03-1.21]), and borderline significant association with PFS after treatment with peptide receptor radionuclide therapy (HR 1.11 [1.00-1.24]). A cut-off of >2 mitoses per 10 high-power fields estimated by PHH3 seemed to have better discrimination power compared to the standard WHO cut-off (<2). Mitotic count based on PHH3 is associated with CSS and with PFS after treatment with first-line SSA and possibly with PRRT for metastatic siNET. It may be an alternative to Ki-67 for estimation of proliferation and grading. A cut-off of >2 mitoses per 10 HPF might better distinguish G1 and G2 tumours.

BACKGROUND Small intestinal hemangioma is a rare benign tumor (accounting for 0.05% of intestinal tumors), and there are currently no clinical guidelines. Small intestinal serosal layer hemangioma is even rarer (no epidemiological studies have been conducted), and its pathogenesis remains unclear. This article focuses on a rare case of ileal serosal hemangioma and reviews the relevant literature to enhance clinicians’ understanding of this condition, highlighting the necessity of timely diagnosis and treatment. CASE SUMMARY An ileal mass was discovered during the patient’s cesarean section. As its nature remained unclear, it was not addressed at the time. The patient subsequently presented to our hospital for treatment. Upon admission, the patient was asymptomatic with no significant abnormalities on routine laboratory tests. Ultrasound revealed a heterogeneous echo adjacent to the right ovary. Contrast-enhanced computed tomography showed focal thickening of the small intestinal wall. The preoperative diagnosis was small intestinal lymphoma. Laparoscopic exploration revealed a well-defined, red-purple, root-like growth mass measuring approximately 15 cm in length on the serosal layer of the terminal ileum. The procedure was subsequently converted to an open laparotomy, during which segmental resection and intestinal anastomosis were performed. Postoperative pathological diagnosis confirmed a cavernous hemangioma of the ileal serosal layer. Multiple follow-ups over three years after surgery showed no abnormalities. CONCLUSION We present a case of ileal serosal hemangioma. Due to its rarity, clinical understanding of this condition remains limited. This article reviews the relevant literature, elaborates on its pathological and physiological characteristics, and highlights the necessity of timely diagnosis and treatment.