5-Hydroxymethylcytosine （5hmC） is an important mammalian DNA epigenetic modification that has been linked to gene regulation and cancer pathogenesis. Here we explored the diagnostic potential of 5hmC ...in circulating cell-free DNA （cfDNA） using a sensitive chemical labeling-based low-input shotgun sequencing approach. We sequenced cell- free 5hmC from 49 patients of seven different cancer types and found distinct features that could be used to predict cancer types and stages with high accuracy. Specifically, we discovered that lung cancer leads to a progressive global loss of 5hmC in cfDNA, whereas hepatocellular carcinoma and pancreatic cancer lead to disease-specific changes in the cell-free hydroxymethylome. Our proof-of-principle results suggest that cell-free 5hmC signatures may potentially be used not only to identify cancer types but also to track tumor stage in some cancers.
Background and Aims
Tumor metastasis is a major factor of high recurrence and mortality in hepatocellular carcinoma (HCC), but its underlying mechanism remains elusive. We report that PDZ and LIM ...domain protein 1 (PDLIM1) is significantly down‐regulated in metastatic human HCC tissues, which predicts unfavorable prognosis, suggesting that PDLIM1 may play an important inhibitory role during HCC metastasis.
Approach and Results
Functional studies indicate that PDLIM1 knockdown induces epithelial‐to‐mesenchymal transition (EMT) of HCC cells, elevates their invasive capacity, and promotes metastasis in vitro and in vivo, whereas overexpression of PDLIM1 exhibits opposite phenotypes. Mechanistically, PDLIM1 competitively binds to the cytoskeleton cross‐linking protein alpha‐actinin 4 (ACTN4), leading to the disassociation of ACTN4 from F‐actin, thus preventing F‐actin overgrowth. In contrast, loss of PDLIM1 induces excessive F‐actin formation, resulting in dephosphorylation of large tumor suppressor kinase 1 and activation of Yes‐associated protein, thereby promoting HCC metastasis. Moreover, Asn145 (N145) of PDLIM1 is critical for its interaction with ACTN4, and N145A mutation abolishes its regulatory function in Hippo signaling and HCC metastasis.
Conclusions
Our findings indicate that PDLIM1 suppresses HCC metastasis by modulating Hippo signaling, suggesting that PDLIM1 may be a potential prognostic marker for metastatic HCC.
Signet-ring cell carcinoma (SRCC) has specific epidemiology and oncogenesis in gastric cancer, however, with no systematical investigation for prognostic genomic features. Here we report a systematic ...investigation conducted in 1868 Chinese gastric cancer patients indicating that signet-ring cells content was related to multiple clinical characteristics and treatment outcomes. We thus perform whole-genome sequencing on 32 pairs of SRC samples, and identify frequent CLDN18-ARHGAP26/6 fusion (25%). With 797 additional patients for validation, prevalence of CLDN18-ARHGAP26/6 fusion is noticed to be associated with signet-ring cell content, age at diagnosis, female/male ratio, and TNM stage. Importantly, patients with CLDN18-ARHGAP26/6 fusion have worse survival outcomes, and get no benefit from oxaliplatin/fluoropyrimidines-based chemotherapy, which is consistent with the fact of chemo-drug resistance acquired in CLDN18-ARHGAP26 introduced cell lines. Overall, this study provides insights into the clinical and genomic features of SRCC, and highlights the importance of frequent CLDN18-ARHGAP26/6 fusions in chemotherapy response for SRCC.
The relationship between the neutrophil-to-lymphocyte ratio (NLR) and tumours as a prognostic factor has been reported in many studies. In this meta-analysis, we evaluated the prognostic role of the ...NLR in pancreatic cancer (PC). A systematic search was performed in PubMed and Embase for relevant studies. Data from and characteristics of each study were extracted. A meta-analysis was performed to analyse the prognostic role of the NLR using the hazard ratio (HR) and 95% confidence intervals (95% CI). As a result, a total of 2035 patients in 9 cohorts were included in this meta-analysis. The pooled HR of 1.587 (95% CI: 1.411-1.785, p < 0.01) showed that patients with an elevated NLR were expected to have shorter overall survival (OS) after treatment. This meta-analysis suggests that an elevated NLR can be used as a predictor of survival in patients with pancreatic cancer.
Distant metastasis is a major cause of death in patients with colorectal cancer (CRC) but the management of advanced and metastatic CRC still remains problematic due to the distinct molecular ...alterations during tumor progression. Tumor angiogenesis is a key step in tumor growth, invasion and metastasis. However, the signaling pathways involved in angiogenesis are poorly understood. The results of the present study showed that secretogranin II (SCG2) was significantly downregulated in malignant CRC tissues, and higher expression of SCG2 was correlated with longer disease‐free survival and overall survival of CRC patients. The results of an animal study showed that ectopic expression of SCG2 significantly inhibited CRC tumor growth by disrupting angiogenesis. Furthermore, the inhibition of expression of vascular endothelial growth factor (VEGF) by SCG2 and rescue of VEGF effectively blocked SCG2‐induced inhibition of angiogenesis. Investigations into the underlying mechanism suggested that SCG2 promoted degradation of hypoxia‐inducible factor (HIF)‐1α by interacting with the von Hippel–Lindau tumor suppressor in CRC cells. Blocking of degradation of HIF‐1α effectively attenuated the SCG2‐mediated decrease in expression of VEGF in CRC cells. Collectively, these results demonstrated that treatment with SCG2 effectively inhibited CRC tumor growth by disrupting the activities of HIF‐1α/VEGF, thereby clarifying the anti‐tumor and anti‐angiogenesis roles of SCG2 in CRC, while providing a novel therapeutic target and a potential prognostic marker of disease progression.
Tumor angiogenesis is a key step in tumor growth, invasion and metastasis. However, the signaling pathways involved in colorectal cancer (CRC) angiogenesis are poorly understood. Here we show that secretogranin II (SCG2) was significantly downregulated in malignant CRC tissues and higher expression of SCG2 correlated with longer disease‐free survival and overall survival of patients with CRC. SCG2 impaired tumor growth and angiogenesis by inhibiting vascular endothelial growth factor expression and promoting hypoxia‐inducible factor‐1α degradation. Therefore, SCG2 may serve as a novel therapeutic target and a potential prognostic marker of disease progression in patients with CRC.
The adenoma-carcinoma sequence is a well-accepted roadmap for the development of sporadic colorectal cancer. However, cellular heterogeneity in aberrant epithelial cells limits our understanding of ...carcinogenesis in colorectal tissues. Here, we performed a single-cell RNA sequencing survey of 54,788 cells from patient-matched tissue samples, including blood, normal tissue, para-cancer, polyp, and colorectal cancer. At each stage of carcinogenesis, we characterized cell types, transcriptional signatures, and differentially expressed genes of distinct cell populations. The molecular signatures of epithelial cells at normal, benign, and malignant stages were defined at the single-cell scale. Adenoma and carcinoma precursor cell populations were identified and characterized followed by validation with large cohort biopsies. Protein tyrosine kinases (PTKs) BMX and HCK were identified as potential drivers of adenoma initiation. Specific BMX and HCK upregulations were observed in adenoma precursor cell populations from normal and adenoma biopsies. Overexpression of BMX and HCK significantly promoted colorectal epithelial cell proliferation. Importantly, in the organoid culture system, BMX and HCK upregulations resulted in the formation of multilayered polyp-like buds protruding towards the organoid lumen, mimicking the pathological polyp morphology often observed in colorectal cancer. Molecular mechanism analysis revealed that upregulation of BMX or HCK activated the JAK-STAT pathway. In conclusion, our work improved the current knowledge regarding colorectal epithelial evolution during carcinogenesis at the single-cell resolution. These findings may lead to improvements in colorectal cancer diagnosis and treatment.
During laparoscopic left hemicolectomy procedures, a previously overlooked consistently thick blood vessel within the gastrocolic ligament near the splenic hilum may contribute to post-operative ...bleeding complications. The purpose of this study was to investigate the identification and management of the previously overlooked blood vessel.
This is a retrospective descriptive study of patients undergoing laparoscopic left colectomy for splenic fexure cancer conducted at a national gastrointestinal surgery centre in China. Consecutive patients with splenic fexure cancer who underwent laparoscopic left colectomy using our"five-step process"(n = 34) between January 2021 and July 2023 were included.
The vessels can be effectively exposed using the aforementioned "five-step process." It was observed that the overlooked vessels consistently present in all patients were identified as the omental branch of the left gastroepiploic artery and vein.
We have identified the origin of previously overlooked blood vessels and recommended a safe method for their management. This may offer advantages to colorectal surgeons performing laparoscopic left colectomy for splenic flexure cancer.
Background
The aim of this study was to identify the indications and oncological outcomes of selective lateral lymph node dissection (sLLND) in rectal cancer patients.
Methods
A retrospective study ...was conducted on consecutive patients with rectal cancer who had standard total mesorectal excision and sLLND at our institution. Clinicopathological characteristics and oncological outcomes were analyzed. We performed subgroup analysis and multivariate analysis based on patients with or without preoperative chemoradiotherapy to identify the related risk factors.
Results
A total of 77 consecutive patients with TME and sLLND were included. Twenty-two (28.6%) patients with pathological positive lateral lymph nodes metastasis (LLNM) were identified. Forty-seven (61%) patients accepted neoadjuvant chemoradiotherapy (nCRT). The pretreatment maximum short-axis diameters of LLN (≥ 8 mm) were the independent risk factors for LLNM among patients with LLN ≥ 5 mm. Lymph node metastasis were significantly higher in patients with pretreatment LLN ≥ 8 mm than in patients with LLN 5–8 mm (63% vs. 10%,
p
< 0.001). The receiver operating curve analysis suggested that the optimal cutoff value of LLN short-axis diameter for predicting LLNM was 8 mm. At a median follow-up of 42 months (range 6–140 months) 3 (3.9%) patients with lateral pelvic recurrence were observed. The 3-year cumulative overall survival in patients with LLNM and patients without LLNM was 76.7% and 89.8%, respectively (
p
= 0.01). The 3-year cumulative disease-free survival was 53.6% in patients with LLNM and 88.3% in patients without LLNM (
p
= 0.008).
Conclusion
Patients with LLNM had a worse prognosis. The pretreatment maximum short-axis diameter of LLN (≥ 8 mm) should be considered as an indication for sLLND.
Cancer associated fibroblasts (CAFs) support tumors via multiple mechanisms, including maintaining the immunosuppressive tumor microenvironment and limiting infiltration of immune cells. The prolyl ...isomerase Pin1, whose overexpression in CAFs has not been fully profiled yet, plays critical roles in tumor initiation and progression. To decipher effects of selective Pin1 inhibition in CAFs on pancreatic cancer, here we formulate a DNA-barcoded micellular system (DMS) encapsulating the Pin1 inhibitor AG17724. DMS functionalized with CAF-targeting anti-FAP-α antibodies (antiCAFs-DMS) can selectively inhibit Pin1 in CAFs, leading to efficacious but transient tumor growth inhibition. We further integrate DNA aptamers (AptT), which can engage CD8+ T lymphocytes, to obtain a bispecific antiCAFs-DMS-AptT system. AntiCAFs-DMS-AptT inhibits tumor growth in subcutaneous and orthotopic pancreatic cancer models.
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